SECTION 2.7 CLINICAL SUMMARY
Section 2.7.5 — Literature References
EMTRICITABINE/RILPIVIRINE/ TENOFOVIR DISOPROXIL FUMARATE FIXED-DOSE COMBINATION
Gilead Sciences International Limited
18 August 2010
CONFIDENTIAL AND PROPRIETARY INFORMATION Emtricitabine/Rilpivirine/Tenofovir Disoproxil Fumarate Section 2.7.5 Literature References Final
2.7. CLINICAL SUMMARY
2.7.5. Literature References
1469 Mulato AS, Cherrington JM. Anti-HIV activity of adefovir (PMEA) and PMPA in combination with antiretroviral compounds: in vitro analyses. Antiviral Res 1997 Nov;36 (2):91-7.
1574 Robbins BL, Srinivas RV, Kim C, Bischofberger N, Fridland A. Anti-human immunodeficiency virus activity and cellular metabolism of a potential prodrug of the acyclic nucleoside phosphonate 9-R-(2-phosphonomethoxypropyl)adenine (PMPA), Bis(isopropyloxymethylcarbonyl) PMPA. Antimicrob Agents Chemother 1998 Mar;42 (3):612-7.
2190 DeGruttola V, Dix L, D'Aquila R, Holder D, Phillips A, Mounir A-K, et al. The relation between baseline HIV drug resistance and response to antiretroviral therapy: re-analysis of retrospective and prospective studies using astandardized data analysis plan. Antivir Ther 2000;5 (1):41-8.
2226 Fischl MA, Richman DD, Hansen N, Collier AC, Carey JT, Pra MF, et al. The safety and efficacy of zidovudine (AZT) in the treatment of subjects with mildy symptomatic human immunodeficiency virus type 1 (HIV) infection. A double- blind, placebo-controlled trial. Ann Intern Med 1990;112 (10):727-37.
2520 Cihlar T, Ho ES, Lin DC, Mulato AS. Human renal organic anion transporter 1 (hOAT1) and its role in the nephrotoxicity of antiviral nucleotide analogs. Nucleosides Nucleotides Nucleic Acids 2001;20 (4-7):641-8.
3019 Clarke SM, Mulcahy FM, Tjia J, Reynolds HE, Gibbons SE, Barry MG, et al. The pharmacokinetics of methadone in HIV-positive patients receiving the non- nucleoside reverse transcriptase inhibitor efavirenz. Br J Clin Pharmacol 2001 Mar;51 (3):213-7.
3854 Boelaert JR, Dom GM, Huitema ADR, Beijnen JH, Lange JMA. The boosting of didanosine by allopurinol permits a halving of the didanosine dosage. AIDS 2002 Nov 8;16 (16):2221-3.
4249 Wilson JE, Martin JL, Borroto-Esoda K, Hopkins S, Painter G, Liotta DC, et al. The 5'-triphosphates of the (-) and (+) enantiomers of cis-5-fluoro-1-[2- (hydroxymethyl)-1,3-oxathiolane-5-yl]cytosine equally inhibit human immunodeficiency virus type 1 reverse transcriptase. Antimicrob Agents Chemother 1993 Aug;37 (8):1720-2.
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4527 Paff MT, Averett DR, Prus KL, Miller WH, Nelson DJ. Intracellular metabolism of (-)- and (+)-cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine in HepG2 derivative 2.2.15 (subclone P5A) cells. Antimicrob Agents Chemother 1994 Jun;38 (6):1230-8.
4535 Furman PA, Davis M, Liotta DC, Paff M, Frick LW, Nelson DJ, et al. The anti- hepatitis B virus activities, cytotoxicities, and anabolic profiles of the (-) and (+) enantiomers of cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine. Antimicrob Agents Chemother 1992 Dec;36 (12):2686-92.
4620 Kaul S, Damle B, Bassi K, Xie J, Gale J, Ryan K, et al. Pharmacokinetic evaluation of reduced doses of didanosine enteric coated capsules (ddI-EC) in combination with tenofovir disoproxil fumarate (TDF) and food for a once-daily antiretroviral regimen [poster]. 4th International Workshop on Clinical Pharmacology of HIV Therapy; 2003 March 27-29; Cannes, France. Poster 8.1.
5024 Thio CL, Seaberg EC, Skolasky R, Jr, Phair J, Visscher B, Munoz A, et al. HIV-1, hepatitis B virus, and risk of liver-related mortality in the Multicenter Cohort Study (MACS). Lancet 2002 Dec 14;360 (9349):1921-6.
5040 Nasca MR, Micali G, Cheigh NH, West LE, West DP. Dermatologic and nondermatologic uses of thalidomide. Ann Pharmacother 2003 Sep;37 (9):1307- 20.
5059 Food and Drug Administration/CDER Web site. Guidance for Industry: Antiretroviral Drugs Using Plasma HIV RNA Measurements - Clinical Considerations for Accelerated and Traditional Approval. October 2002. Available at: http://www.fda.gov/cder/guidance/3647fnl.doc. Accessed September 29, 2003.
5467 Kaul S, Bassi K, Damle, Xie J, Gale J, Kearney B, et al. Pharmacokinetic (PK) evaluation of the combination of Atazanavir (ATV), enteric coated Didanosine (ddI-EC), and Tenofovir Disoproxil Fumarate (TDF) for a once-daily antiretroviral regimen [abstract A-1616]. 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy; 2003 September 14-17; Chicago, Ill.
5468 Robbins BL, Wilcox CK, Fridland A, Rodman JH. Metabolism of tenofovir and didanosine in quiescent or stimulated human peripheral blood mononuclear cells. Pharmacotherapy 2003 Jun;23 (6):695-701.
5966 Roden MM, Nelson LD, Knudsen TA, Jarosinski PF, Starling JM, Shifflett SE, et al. Triad of acute infusion-related reactions associated with liposomal amphotericin B: analysis of clinical and epidemiological characteristics. Clin Infect Dis 2003 May 15;36 (10):1213-20.
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5968 Moylett EH, Chinen J, Shearer WT. Trichosporon pullulans infection in 2 patients with chronic granulomatous disease: an emerging pathogen and review of the literature. J Allergy Clin Immunol 2003 Jun;111 (6):1370-4.
6042 Kaul S, Bassi K, Damle B, Smith R, Gale J, O'Mara E, et al. Lack of interaction between stavudine extended release formulation (d4T XR) and tenofovir disoproxil fumarate (TDF) [abstract]. 10th Conference on Retroviruses and Opportunistic Infections; 2003 February 10-14; Boston, Mass, USA. Abstract 534-W.
6043 Taburet AM, Piketty C, Gerard L, Vincent I, Chazallon C, Clavel F, et al. Pharmacokinetic parameters of atazanavir/ritonavir when combined to tenofovir in HIV infected patients with multiple treatment failures: a sub-study of Puzzle2- ANRS 107 Trial [poster]. 10th Conference on Retroviruses and Opportunistic Infections; 2003 February 10-14; Boston, Mass, USA. Poster 537.
6054 Ray A, Olson L, Fridland A. Role of purine nucleoside phosphorylase in drug interactions between 2',3'-dideoxyinosine and allopurinol, ganciclovir or tenofovir. Antimicrob Agents Chemother 2004 Apr;48 (4):1089-95.
6086 Gathe J, Podzamczer D, Johnson M, Schwartz R, Yeh V, Travers N, et al. Once- daily vs. twice-daily lopinavir/ritonavir in antiretroviral-naïve patients: 48-week results [poster]. 11th Conference on Retroviruses and Opportunistic Infections; 2004 February 8-11; San Francisco, Calif, USA. Poster 570.
6113 The European Agency for the Evaluation of Medicinal Products. Committee for Proprietary Medicinal Products (CPMP). Note for Guidance on the Clinical Development of Medicinal Products for the Treatment of HIV Infection. Report No. CPMP/EWP/633/02 draft. July 25, 2002.
6116 Kaul S, Bassi K, Damle B, Xie J, Gale J, O'Mara E, et al. Stavudine extended release formulation (D4T XR) and tenofovir disoproxil fumarate (TDF): Lack of a pharmacokinetic (PK) drug interaction [abstract]. 11th Conference on Retroviruses and Opportunistic Infections; 2004 February 8-11; San Francisco, Calif, USA.
6180 Bica I, McGovern B, Dhar R, Stone D, McGowan K, Scheib R, et al. Increasing mortality due to end-stage liver disease in patients with human immunodeficiency virus infection. Clin Infect Dis 2001 Feb 1;32 (3):492-7.
6181 Dore GJ, Cooper DA. The impact of HIV therapy on co-infection with hepatitis B and hepatitis C viruses. Curr Opin Infect Dis 2001 Dec;14 (6):749-55.
6266 Videx EC (SmPC). Bristol-Myers Squibb Pharmaceuticals. Hounslow. 06 January 2003.
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6766 Gatell J, Lange J, Gartland J, The AVANTI study group. AVANTI 1: randomized, double-blind trial to evaluate the efficacy and safety of zidovudine plus lamivudine versus zidovudine plus lamivudine plus loviride in HIV-infected antiretroviral- naive patients. Antivir Ther 1999;4 (2):79-96.
6772 Jones R, Stebbing J, Nelson M, Moyle G, Bower M, Mandalia S, et al. Renal dysfunction with tenofovir DF containing HAART regimens is not observed more frequently: a cohort and case control study [poster]. 10th Anniversary Conference of the British HIV Association (BHIVA); 2004 April 15-17; Cardiff, United Kingdom.
7034 Maggiolo F, Migliorino M, Maserati R, Rizzi L, Pan A, Rizzi A, et al. Once-a-day treatment for HIV infection: Final 48-week results. 8th Conference on Retroviruses and Opportunistic Infections; 2001 February 4-8; Chicago, IL. Abstract 320.
7035 Felizarta F, Becker S, Bellos N, Jayaweera D, Sands M, Slater L, et al. Adherence and efficacy with a once-daily efavirenz-based regimen: 48-week results from the Daily Antiretroviral Therapy II (DART II) Study [poster 5842]. XV International AIDS Conference; 2004 July 11-16; Bangkok, Thailand.
7036 Arribas JR, Iribarren JA, Knobel H, Ribera E, Rubio R, Viciana P, et al. Adherence, treatment satisfaction and effectiveness of once-daily (QD) vs twice- daily (BID) antiretroviral therapy (AT), in a large prospective observational cohort (CUVA Study) [poster WePeB5780]. XV International AIDS Conference; 2004 July 11-16; Bangkok, Thailand.
7374 Johnson M, De Jesus E, Grinsztein B. Comparison of Atazanavir (ATV) with Ritonavir or Saquinavir vs Lopinavir/ritonavir in Patients with Multiple Virologic Failures: BMS AI424-045 96 Week Results. Long-term Efficacy and Durability of Atazanavir With Ritonavir or Saquinavir vs Lopinavir/Ritonavir in HIV-Infected Patients With Multiple Virologic Failures (Oral presentation PL14.4). 7th International Congress on Drug Therapy in HIV Infection; 2004 November 14-18; Glasgow, UK.
7380 Yeh V, Barros C, Easterbrook P, Lutz F, Naylor C, Luff K, et al. Virologic Response to a Once-Daily Lopinavir/ritonavir (LPV/r) Based Regimen in ARV- Naïve Patients Is Not Associated with Trough Lopinavir Concentrations or Baseline HIV RNA and CD4 Count [Poster H-570]. 44th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2004 October; Washington.
7625 Becker SL, Balu RB, Fusco JS, Fusco GP. Beyond serum creatinine: Identification of renal insufficiency using GFR: Implications for clinical research and care [poster 819]. 12th Conference on Retroviruses and Opportunistic Infections; 2005 February 22-25; Boston, Mass, USA.
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7672 Gallant JE, Parish MA, Keruly JC, Moore RD. Changes in renal function associated with tenofovir disoproxil fumarate treatment, compared with nucleoside reverse-transcriptase inhibitor treatment. Clin Infect Dis 2005;40 (8):1194-8.
7725 Harris M, Zalunardo N, Yip B, Werb R, Valyi M, Hogg R, et al. Nephrotoxicity of tenofovir DF in an expanded access program [oral presentation]. Presented at the 12th Annual Canadian Conference on HIV/AIDS Research; 2003 April 10-13; Nova Scotia, Canada.
7871 Barrios A, Rendon A, Negredo E, Barreiro P, Garcia-Benayas T, Labarga P, et al. Paradoxical CD4+ T-cell decline in HIV-infected patients with complete virus suppression taking tenofovir and didanosine. AIDS 2005;19 (6):569-75.
7987 Gallant JE, Parish MA, Keruly JC, Moore RD. Changes in renal function in patients treated with Tenofovir DF (TDF) compared to nucleoside reverse transcriptase inhibitors (NRTIs) [abstract]. 3rd International AIDS Society Conference on HIV Pathogenesis and Treatment; 2005 July 24-27; Rio de Janeiro, Brazil.
8056 Jones R, Stebbing J, Nelson M, Moyle G, Bower M, Mandalia S, et al. Renal dysfunction with tenofovir disoproxil fumarate-containing highly active antiretroviral therapy regimens is not observed more frequently: a cohort and case- control study. J Acquir Immune Defic Syndr Hum Retrovirol 2004;37 (4):1489-95.
8057 Levey AS,BoschJP,LewisJB,GreeneT,Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999;130 (6):461-70.
8160 Negredo E, Bonjoch A, Paredes R, Puig J, Clotet B. Compromised immunologic recovery in treatment-experienced patients with HIV infection receiving both tenofovir disoproxil fumarate and didanosine in the TORO studies. Clin Infect Dis 2005;41 (6):901-5.
8623 Karrer U, Ledergerber B, Furrer H, Elzi L, Battegay M, Cavassini M, et al. Dose- dependent influence of didanosine on immune recovery in HIV-infected patients treated with tenofovir. AIDS 2005;19 (17):1987-94.
8715 Heffelfinger JD, Hanson DL, Voetsch AC, McNaghten AD, Sullivan PS. Renal impairment associated with the use of tenofovir [poster 779]. 13th Conference on Retroviruses and Opportunistic Infections; 2006 February 5-9; Denver, Colo, USA.
9023 Winston A, Amin J, Mallon P, Marriott D, Carr A, Cooper DA, et al. Minor changes in calculated creatinine clearance and anion-gap are associated with tenofovir disoproxil fumarate-containing highly active antiretroviral therapy. HIV Med 2006;7 (2):105-11.
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9161 Moreno S, Domingo P, Palacios R, Santos J, Falco V, Murillas J, et al. Renal Safety of Tenofovir Disoproxil Fumarate in HIV-1 Treatment-experienced Patients with Adverse Events Related to Prior NRTI Use: Data from a Prospective, Observational, Multicenter Study. J Acquir Immune Defic Syndr Hum Retrovirol 2006;42 (3):385-7.
9334 Buchacz K, Brooks JT, Tong T, Moorman AC, Baker RK, Holmberg SD, et al. Evaluation of hypophosphataemia in tenofovir disoproxil fumarate (TDF)-exposed and TDF-unexposed HIV-infected out-patients receiving highly active antiretroviral therapy. HIV Med 2006;7 (7):451-6.
10394 Buchacz K, Young B, Baker RK, Moorman A, Chmiel JS, Wood KC, et al. Renal Function in Patients Receiving Tenofovir With Ritonavir/Lopinavir or Ritonavir/Atazanavir in the HIV Outpatient Study (HOPS) Cohort. J Acquir Immune Defic Syndr 2006;43 (5):626-8.
10921 Nelson MR, Katlama C, Montaner JS, Cooper DA, Gazzard B, Clotet B, et al. The safety of tenofovir disoproxil fumarate for the treatment of HIV infection in adults: the first 4 years. AIDS 2007;21 (10):1273-81.
11031 Yeh RF, Gaver VE, Patterson KB, Rezk NL, Baxter-Meheux F, Blake MJ, et al. Lopinavir/ritonavir induces the hepatic activity of cytochrome P450 enzymes CYP2C9, CYP2C19, and CYP1A2 but inhibits the hepatic and intestinal activity of CYP3A as measured by a phenotyping drug cocktail in healthy volunteers. J Acquir Immune Defic Syndr 2006;42 (1):52-60.
11073 Feng J, Ly J, Myrick F, White K, Borroto-Esoda K, Miller M. Combination studies of tenofovir, emtricitabine, and efavirenz as inhibitors of HIV-1 reverse transcriptase [poster]. HIV DART 2006: Frontiers in Drug Development for Antiretroviral Therapies; 2006 December 10-14, 2006; Cancun, Mexico.
11111 Nizoral (ketoconazole) Tablet. US Prescribing Information. Janssen Pharmaceutica Products, L.P. Titusville, NJ. Revised: 08/2006.
12253 Ammassari A, Trotta MP, Murri R, Castelli F, NarcisoP,NotoP,et al. Correlates and predictors of adherence to highly active antiretroviral therapy: overview of published literature. J Acquir Immune Defic Syndr 2002;31 Suppl 3:S123-7.
12520 Venkatakrishnan K, von Moltke LL, Greenblatt DJ. Effects of the antifungal agents on oxidative drug metabolism: clinical relevance. Clin Pharmacokinet 2000;38 (2):111-80.
12548 Epivir® Tablets (lamivudine tablets). Prescribing Information. GlaxoSmithKline. Research Triangle Park, NC. Revised February 2008.
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12654 ZIAGEN® (abacavir sulfate) Tablets. ZIAGEN® (abacavir sulfate) Oral Solution. US Prescribing Information. GlaxoSmithKline. Research Triangle Park, NC. July 2008
12716 Hammer SM, Eron JJ, Jr., Reiss P, Schooley RT, Thompson MA, Walmsley S, et al. Antiretroviral treatment of adult HIV infection: 2008 recommendations of the International AIDS Society-USA panel. JAMA 2008;300 (5):555-70.
13252 Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28 (7):412-9.
13882 Korhonen T, Turpeinen M, Tolonen A, Laine K, Pelkonen O. Identification of the human cytochrome P450 enzymes involved in the in vitro biotransformation of lynestrenol and norethindrone. The Journal of steroid biochemistry and molecular biology 2008;110 (1-2):56-66.
13884 Zhang H, Cui D, Wang B, Han YH, Balimane P, Yang Z, et al. Pharmacokinetic drug interactions involving 17alpha-ethinylestradiol: a new look at an old drug. Clin Pharmacokinet 2007;46 (2):133-57.
14065 Gazzard BG. British HIV Association Guidelines for the treatment of HIV-1- infected adults with antiretroviral therapy 2008. HIV Med 2008;9 (8):563-608.
15207 Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. December 1, 2009; 1-161. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.
15280 Kirk O, Mocroft A, Reiss P, De Wit S, Sedlacek D, Beniowski M, et al. Chronic Kidney Disease and Exposure to ART in a Large Cohort with Long-term Follow- up: The EuroSIDA Study [Abstract 107LB]. 17th Conference on Retroviruses and Opportunistic Infections (CROI); 2010 February 16-19; San Francisco, CA.
15462 VIREAD® (tenofovir disoproxil fumarate) tablets. US Prescribing Information. Gilead Sciences, Inc. Foster City, CA. March 2010.
15541 Azijn H, Tirry I, Vingerhoets J, de Béthune M, Kraus G, Boven K, et al. TMC278, a Next-Generation Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI), Active against Wild-Type and NNRTI-Resistant HIV-1. Antimicrob Agents Chemother 2010;54 (2):718-27.
15807 SUSTIVA® (efavirenz) capsules and tablets. US Prescribing Information. Bristol- Myers Squibb Company. Princeton, NJ. March 2010.
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15845 Castillo R, Pedalino RP, El-Sherif N, Turitto G. Efavirenz-associated QT prolongation and Torsade de Pointes arrhythmia. Ann Pharmacother 2002;36 (6):1006-8.
15846 Chinello P, Lisena FP, Angeletti C, Boumis E, Papetti F, Petrosillo N. Role of antiretroviral treatment in prolonging QTc interval in HIV-positive patients. J Infect 2007;54 (6):597-602.
15851 Dharnidharka VR, Kwon C, Stevens G. Serum cystatin C is superior to serum creatinine as a marker of kidney function: a meta-analysis. Am J Kidney Dis 2002;40 (2):221-6.
15852 Dickinson L, Khoo S, Back D. Differences in the pharmacokinetics of protease inhibitors between healthy volunteers and HIV-infected persons. Curr Opin HIV AIDS 2008;3 (3):296-305.
15853 Eap CB, Bourquin M, Martin J, Spagnoli J, Livoti S, Powell K, et al. Plasma concentrations of the enantiomers of methadone and therapeutic response in methadone maintenance treatment. Drug and alcohol dependence 2000;61 (1):47- 54.
15857 AVANTI 2. Randomized, double-blind trial to evaluate the efficacy and safety of zidovudine plus lamivudine versus zidovudine plus lamivudine plus indinavir in HIV-infected antiretroviral-naive patients. AIDS 2000;14 (4):267-374.
15858 Gartland M. AVANTI 3: a randomized, double-blind trial to compare the efficacy and safety of lamivudine plus zidovudine versus lamivudine plus zidovudine plus nelfinavir in HIV-1-infected antiretroviral-naive patients. Antivir Ther 2001;6 (2):127-34.
15861 Hreiche R, Morissette P, Turgeon J. Drug-induced long QT syndrome in women: review of current evidence and remaining gaps. Gend Med 2008;5 (2):124-35.
15862 Jage J. [Methadone--pharmacokinetics and pharmacodynamics of an opiate]. Der Anaesthesist 1989;38 (4):159-66.
15865 Kharasch ED, Bedynek PS, Park S, Whittington D, Walker A, Hoffer C. Mechanism of ritonavir changes in methadone pharmacokinetics and pharmacodynamics: I. Evidence against CYP3A mediation of methadone clearance. Clin Pharmacol Ther 2008;84 (4):497-505.
15867 Larsson A, Malm J, Grubb A, Hansson LO. Calculation of glomerular filtration rate expressed in mL/min from plasma cystatin C values in mg/L. Scand J Clin Lab Invest 2004;64 (1):25-30.
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15870 Lucas D, Ferrara R, Gonzalez E, Bodenez P, Albores A, Manno M, et al. Chlorzoxazone, a selective probe for phenotyping CYP2E1 in humans. Pharmacogenetics 1999;9 (3):377-88.
15884 Swan SK. The search continues--an ideal marker of GFR. Clin Chem 1997;43 (6 Pt 1):913-4.
15885 Thummel KE, Wilkinson GR. In vitro and in vivo drug interactions involving human CYP3A. Annu Rev Pharmacol Toxicol 1998;38:389-430.
15886 Van Den Bout-Van Den Beukel CJ, Fievez L, Michels M, Sweep FC, Hermus AR, Bosch ME, et al. Vitamin D deficiency among HIV type 1-infected individuals in the Netherlands: effects of antiretroviral therapy. AIDS Res Hum Retroviruses 2008;24 (11):1375-82.
15889 Welage LS, Carver PL, Revankar S, Pierson C, Kauffman CA. Alterations in gastric acidity in patients infected with human immunodeficiency virus. Clin Infect Dis 1995;21 (6):1431-8.
15890 Zhang X, Lalezari JP, Badley AD, Dorr A, Kolis SJ, Kinchelow T, et al. Assessment of drug-drug interaction potential of enfuvirtide in human immunodeficiency virus type 1-infected patients. Clin Pharmacol Ther 2004;75 (6):558-68.
15969 Viramune® (nevirapine) tablets, 200 mg. US Prescribing Information. Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA. Revised January 2010.
15974 Videx EC (didanosine) Delayed-Release Capsules (125 mg, 200 mg, 250 mg, 400 mg). Prescribing Information (United States). Bristol-Myers Squibb Company, January 2010.
15985 Kaletra (Lopinavir/Ritonavir) Liquid Filled Capsule (133.3 mg lopinavir/33.3 mg ritonavir); Solution (80 mg lopinavir/20 mg ritonavir). Prescribing Information (United States). Abbott Laboratories. April 2010.
15986 Prezista (Darunavir) Film Coated Tablets (75 mg, 150 mg, 300 mg, 400 mg, and 600 mg). Prescribing Information (United States). Tibotec, April 2010.
15988 Mycobutin (Rifabutin) Capsule (150 mg). Prescribing Information (United States). Pfizer, October 2007.
15990 Viagra (Sildenafil Citrate) Film Coated Tablets (25 mg, 50 mg, 100 mg). Prescribing Information (United States). Pfizer, January 2010.
15991 Lipitor (Atorvastatin Sodium). Prescribing Information (United States) Tablets (10 mg, 20 mg, 40 mg, and 80 mg). Pfizer, June 2009.
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15992 Prilosec (Omeprazole). Delayed-Release Capsules (10 mg, 20 mg, and 40 mg); Delayed-Release Oral Suspension (2.5 mg, 10 mg). Prescribing Information (United States). Astra Zeneca, March 2008.
15993 PEPCID® (Famotidine) Tablets (20 mg, 40 mg). Prescribing Information (United States). Merck and Co., Inc., September 2009.
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CONFIDENTIAL Page 11 18AUG2010 SECTION 2.7 CLINICAL SUMMARY
SECTION 2.7.5—LITERATURE REFERENCES
EMTRICITABINE/RILPIVIRINE/TENOFOVIR DISOPROXIL FUMARATE SINGLE-TABLET REGIMEN
Gilead Sciences International Ltd
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CONFIDENTIAL AND PROPRIETARY INFORMATION Emtricitabine/Rilpivirine/Tenofovir Disoproxil Fumarate 2.7.5 Literature References Addendum FINAL
1. LITERATURE REFERENCES
24931 Centers for Disease Control and Prevention. Targeted tuberculin testing and treatment of latent tuberculosis infection. American Thoracic Society. MMWR Recomm Rep 2000;49 (RR-6):1-51.
24933 Norton BL, Holland DP. Current management options for latent tuberculosis: a review. Infection and drug resistance 2012;5:163-73.
24950 Mycobutin (Rifabutin) Capsule (150 mg) for oral administration. Summary of Product Characteristics (United Kingdom). Pfizer, March 2012.
24951 Walubo A. The role of cytochrome P450 in antiretroviral drug interactions. Expert Opin Drug Metab Toxicol 2007;3 (4):583-98.
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SECTION 5.2 TABULAR LISTING OF ALL CLINICAL STUDIES
EMTRICITABINE/RILPIVIRINE/ TENOFOVIR DISOPROXIL FUMARATE FIXED-DOSE COMBINATION
Gilead Sciences International Limited
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CONFIDENTIAL AND PROPRIETARY INFORMATION
Emtricitabine/Rilpivirine/Tenofovir Disoproxil Fumarate Section 5.2 Tabular Listing of All Clinical Studies Final
5.2. TABULAR LISTING OF ALL CLINICAL STUDIES
Test Product(s); Healthy Study Location Study Design Dosage Regimen; Subjects or Status; Study of Study Objectives(s) of and Type of Route of Number of Diagnosis of Duration of Type of Type of Study Identifier Report the Study Control Administration Subjects Patients Treatment Report BA FTC-110 Module To evaluate OL, A: 1 × 200-mg 12 subjects Healthy adult 3 single Complete; relative and randomized, FTC capsule, PO, (Synopsis) 5.3.1.1 subjects doses Final CSR absolute BA of 3-way fasted FTC crossover, B: 20 mL of FTC single 200-mg 10 mg/mL solution, doses PO, fasted administered C: 20 mL of FTC as IV solution, 10 mg/mL solution, oral solution, IV infused over or oral capsule 1 hour, fasted BA/BE FTC-109 Module Pilot study to OL, A: 2 × 100-mg 12 subjects Healthy adult 2 single Complete; evaluate the randomized, FTC capsules, PO, (Synopsis) 5.3.1.2 subjects doses Final CSR BE/BA of FTC 2-way fasted of the 100-mg crossover, B: 1 × 200-mg FTC and 200-mg single 200-mg capsule, PO, fasted capsules doses BA/BE FTC-111 Module To compare the OL, A: 2 × 100-mg 24 subjects Healthy adult 3 single Complete; (Synopsis) 5.3.1.2 BA of the 100- randomized, FTC capsules, PO, subjects doses Final CSR mg and 200-mg 3-way fasted capsules and the crossover, B: 1 × 200-mg FTC effect of food on single 200-mg capsule, PO, fasted BA of FTC dose, food C: 1 × 200-mg FTC administered as effect capsule, PO, fed a 200-mg capsule
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Test Product(s); Healthy Study Location Study Design Dosage Regimen; Subjects or Status; Study of Study Objectives(s) of and Type of Route of Number of Diagnosis of Duration of Type of Type of Study Identifier Report the Study Control Administration Subjects Patients Treatment Report BA/BE GS-00-914 Module To determine the Single-center, TDF (commercial 40 subjects, Healthy subjects 3 single Complete; (Synopsis) 5.3.1.2 PK profile of a 3-period, formulation) 36 completed doses Final CSR single dose of randomized, 300-mg single dose the clinical OL, BE and (taken under fasting formulation of food effect conditions and after TDF under a standardized fasted high-fat breakfast). conditions, and TDF (clinical the original formulation) 4 u commercial 75-mg single dose formulation (taken under fasting under both conditions) fasted and under fed conditions. To determine the BE of the clinical and commercial formulations under fasted conditions
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Test Product(s); Healthy Study Location Study Design Dosage Regimen; Subjects or Status; Study of Study Objectives(s) of and Type of Route of Number of Diagnosis of Duration of Type of Type of Study Identifier Report the Study Control Administration Subjects Patients Treatment Report BA/BE GS-US-104- Module To establish BE OL, A: 1 u 300-mg 44 subjects Healthy subjects 4 single Complete; 0172 5.3.1.2 between the randomized, TDF tablet and 1 u (26 males; 18 doses Final CSR (Synopsis) FTC/TDF tablet 4-treatment, 200-mg FTC females) and concurrent single-center, capsule, PO, fasted 39 completed administration of 4-way B: 1 u combination the TDF tablet crossover tablet (300-mg and FTC capsule TDF/ 200-mg FTC), PO, fasted C: 1 u combination tablet (300 mg TDF/ 200 mg FTC), PO with high-fat meal D: 1 u combination tablet (300 mg TDF/ 200 mg FTC), PO with light meal
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Test Product(s); Healthy Study Location Study Design Dosage Regimen; Subjects or Status; Study of Study Objectives(s) of and Type of Route of Number of Diagnosis of Duration of Type of Type of Study Identifier Report the Study Control Administration Subjects Patients Treatment Report BA/BE GS-US-264- Module To evaluate the Randomized, A (reference): a 48 enrolled Healthy adult 3 single Complete; 0101 5.3.1.2 safety and BE of OL, single- 200-mg capsule of A: 45 subjects doses; 1 Final CSR (Synopsis) 2 FDC tablets center, single- FTC, a 25-mg B: 46 each of (each containing dose, 3-way tablet of RPV, and C: 46 Treatment FTC 200 mg, crossover a 300-mg tablet of A, B, and C, RPV 25 mg, and study TDF taken on Days 1, TDF 300 mg) concurrently, PO, 15, and 29 compared with a fed 200-mg strength B and C (tests): 2 capsule of FTC, unique FDC a 25-mg tablet of tablets, each RPV, and a 300- containing FTC mg tablet of 200 mg, RPV 25 TDF taken mg, and TDF 300 concurrently mg, PO, fed under fed conditions
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Test Product(s); Healthy Study Location Study Design Dosage Regimen; Subjects or Status; Study of Study Objectives(s) of and Type of Route of Number of Diagnosis of Duration of Type of Type of Study Identifier Report the Study Control Administration Subjects Patients Treatment Report BA/BE GS-US-264- Module To evaluate the Randomized A (reference): a 36 enrolled Healthy adult 3 single Complete; 0103 safety and BE of OL, single- 5.3.1.2 200-mg capsule of A: 35 subjects doses; 1 Final CSR 2 FDC tablets center, single- FTC, a 25-mg each of (each containing dose, 3-way tablet of RPV, and B: 34 Treatment FTC 200 mg, crossover a 300-mg tablet of C: 35 A, B, and C, RPV 25 mg, and Phase 1 study TDF taken on Days 1, TDF 300 mg) concurrently, PO, 15, and 29 compared with a fed 200-mg strength B and C (tests): 2 capsule of FTC, unique FDC a 25-mg tablet of tablets, each RPV, and a 300- containing FTC mg tablet of 200 mg, RPV 25 TDF taken mg, and TDF 300 concurrently mg, PO, fed under fed conditions
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Test Product(s); Healthy Study Location Study Design Dosage Regimen; Subjects or Status; Study of Study Objectives(s) of and Type of Route of Number of Diagnosis of Duration of Type of Type of Study Identifier Report the Study Control Administration Subjects Patients Treatment Report Healthy FTC-106 Module ADME of OL, single- Day 1: 200-mg 6 enrolled Healthy adult 10 days Complete; Subject PK 5.3.3.1 [14C]-FTC, mass dose and 8-day FTC single dose, 5 completed male subjects Final CSR (Synopsis) and Initial balance by repeated doses PO, fasted Tolerability urinary and fecal of FTC (with a Days 310: 200-mg recovery, PK of single once daily FTC FTC- [14C]FTC dose) capsules, PO, fed triphosphate in or fasted PBMCs Day 11: 200 mg FTC solution containing 250-PCi [14C]FTC, PO, fasted Patient PK and Burroughs Module Safety and PK Randomized, Single escalating 18 enrolled HIV-infected 6 total Complete; Initial Wellcome 5.3.3.2 food effect on single-blind, oral doses of FTC (12 active adult subjects doses, each Draft CSR Tolerability 143-001 PK for FTC single-dose, administered as 6 placebo) given placebo- capsules: 100, 200, 1 week (Synopsis) controlled, 400 (r food), 800, apart escalating and 1200 mg, PO doses (100 to Placebo, PO 1200 mg) Patient PK and FTC-101 Module Repeated-dose OL, dose- Multiple escalating 41 subjects: HIV-infected, 14 days Complete; Initial 5.3.3.2 safety, tolerance, escalation, 5 oral doses of FTC 1: N = 9 therapy-naive Final CSR (Synopsis) Tolerability PK, antiviral cohort, 14 days administered as 2: N = 8 adult subjects activity of repeated capsules for 14 3: N = 8 doses of days: 4: N = 8 monotherapy 1: 25 mg BID 5: N = 8 2: 100 mg BID 3: 200 mg BID 4: 100 mg QD 5: 200 mg QD
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Test Product(s); Healthy Study Location Study Design Dosage Regimen; Subjects or Status; Study of Study Objectives(s) of and Type of Route of Number of Diagnosis of Duration of Type of Type of Study Identifier Report the Study Control Administration Subjects Patients Treatment Report Patient PK and FTC-102 Module Safety, antiviral Randomized, A: FTC 25 mg QD 81 subjects HIV-infected, 10 days Complete; Initial (Synopsis) 5.3.3.2 activity, dose OL, 3TC- B: FTC 100 mg A: N = 19 therapy-naive Final CSR Tolerability defining, controlled, QD B: N = 21 adults comparison with 3 doses of C: FTC 200 mg C: N = 19 3TC FTC, 10-day QD D: N = 21 repeated doses D: 3TC 150 mg of BID monotherapy PK Intrinsic FTC-107 Module Safety and PK OL, parallel 1 single 200-mg 29 subjects Adult subjects A single Complete; Factors (Synopsis) 5.3.3.3 profiles in group, single- FTC dose enrolled and with varying dose, except Final CSR subjects with dose of FTC in administered in completed degrees of renal for subjects Analysis & various degrees adult subjects capsule formulation Group I: function with in Group V, Simulations of renal with varying to: N = 6 and without who Report insufficiency degrees of --Group I (normal Group II: hemodialysis received a (for potential renal renal function, N = 6 second dose dosage insufficiency estimated CLCr Group III: N = adjustment) and without and ! 80 mL/min) 6 effect of with --Group II (mild Group IV: hemodialysis on hemodialysis renal impairment, N = 5 elimination of CLCr = 50í80 Group V: FTC in subjects mL/min) N = 6 with end-stage --Group III renal disease (moderate renal impairment, not requiring dialysis, CLCr = 30í49 mL/min) --Group IV (severe renal impairment,
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Test Product(s); Healthy Study Location Study Design Dosage Regimen; Subjects or Status; Study of Study Objectives(s) of and Type of Route of Number of Diagnosis of Duration of Type of Type of Study Identifier Report the Study Control Administration Subjects Patients Treatment Report
CLCr 30 mL/min) --Group V (end- stage renal disease, requiring hemodialysis) For Group V subjects, a second 200-mg FTC dose was administered a1.5 h before the start of a 3-hour hemodialysis PK Intrinsic GS-01-919 Module To evaluate the Multicenter, TDF 300 mg 41 subjects Healthy adult Single dose Complete; Factors (Synopsis) 5.3.3.3 safety and PK of single-dose, enrolled; subjects and Final CSR TFV following OL, fixed- 40 subjects renally impaired single-dose sequence study completed. adult subjects administration of TDF 300 mg in subjects with normal renal function and varying degrees of renal function impairment, including subjects undergoing hemodialysis. To develop
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Test Product(s); Healthy Study Location Study Design Dosage Regimen; Subjects or Status; Study of Study Objectives(s) of and Type of Route of Number of Diagnosis of Duration of Type of Type of Study Identifier Report the Study Control Administration Subjects Patients Treatment Report dosing guidelines for renal function impairment PK Intrinsic GS-01-931 Module To evaluate the Multicenter, TDF 300 mg tablet, 24 subjects Healthy subjects Single dose Complete; Factors A/B 5.3.3.3 safety and PK of single-dose, PO, single dose enrolled; and subjects Final CSR (Synopsis) TFV following OL, parallel- 24 subjects with moderate single-dose TDF group study completed. and severe 300 mg in hepatic subjects with impairment normal hepatic (Child-Pugh- function and Turcotte varying degrees Classification B of hepatic and C, impairment respectively) To develop dosing guidelines for renal function impairment PK Intrinsic GS-104- Module To evaluate OL, TDF 300-mg tablet 8 enrolled HIV-1 infected 48 weeks Complete; Factors 0235 5.3.3.3 safety and multicenter, every 7 days, FTC 4 completed subjects with Abbreviate tolerability of single-group 200-mg capsule (Synopsis) stable renal d CSR TFV after study every 96 hours, impairment administration of EFV 600-mg tablet TDF 300 mg in QD, PO, or combination FTC/TDF with FTC 200 mg/300 mg 200 mg for (Truvada) tablet
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Test Product(s); Healthy Study Location Study Design Dosage Regimen; Subjects or Status; Study of Study Objectives(s) of and Type of Route of Number of Diagnosis of Duration of Type of Type of Study Identifier Report the Study Control Administration Subjects Patients Treatment Report 48 weeks in every 24, 48, or HIV-infected 72 hours, EFV patients with 600 mg QD, various degrees depending on of renal creatinine impairment clearance, PO Safety, (only tx-naive tolerability of subjects received FTC; efficacy of EFV; tx- TDF; PK of TFV experienced and FTC subjects who switched to FTC + TDF could have remained on their NNRTI or PI)
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Test Product(s); Healthy Study Location Study Design Dosage Regimen; Subjects or Status; Study of Study Objectives(s) of and Type of Route of Number of Diagnosis of Duration of Type of Type of Study Identifier Report the Study Control Administration Subjects Patients Treatment Report PK Extrinsic FTC-103 Module Assess safety Randomized, Cohort 1: 3 single 13 subjects Healthy adult 3 single Complete; Factors (Synopsis) 5.3.3.4 and potential PK OL, single- crossover doses of: enrolled, subjects doses Final CSR interactions of dose, 2-cohort, -- FTC 200 mg Cohort 1: FTC with other 3-way alone, PO N = 6 NRTIs (ZDV, crossover --ZDV 300 mg Cohort 2: d4T) alone, PO N = 7 --FTC 200 mg + 12 subjects ZDV 300 mg, PO completed Cohort 2: 3 single crossover doses of: --FTC 200 mg alone, PO --d4T 40 mg alone, PO --FTC 200 mg + d4T 40 mg, PO
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Test Product(s); Healthy Study Location Study Design Dosage Regimen; Subjects or Status; Study of Study Objectives(s) of and Type of Route of Number of Diagnosis of Duration of Type of Type of Study Identifier Report the Study Control Administration Subjects Patients Treatment Report PK Extrinsic FTC-104 Module Assess safety Randomized, Cohort 1: 3 single 24 subjects Healthy adult 3 single Complete; Factors (Synopsis) 5.3.3.4 and potential PK OL, single- crossover PO doses enrolled and subjects doses Final CSR interactions of dose, 2-cohort, of: completed FTC with 3-way --FTC 200 mg Cohort 1: protease crossover alone N = 12 inhibitor (IDV) study --IDV 800 mg Cohort 2: and NNRTI alone N = 12 (MKC-442, --FTC 200 mg +
EMV) IDV 800 mg Cohort 2: single crossover PO doses of: --FTC 200 mg alone --EMV 750 mg alone --FTC 200 mg + EMV 750 mg PK Extrinsic FTC-108 Module Assess safety Randomized, 3 single crossover 12 subjects Healthy adult 3 single Complete; and potential PK OL, single- Factors (Synopsis) 5.3.3.4 doses of: subjects doses Final CSR interactions of dose, 3-way --FTC 200 mg FTC with crossover alone concomitant study in --FCV 500 mg antiviral drug healthy adult alone (ie, FCV) with subjects --FTC 200 mg + extensive renal FCV 500 mg excretion
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Test Product(s); Healthy Study Location Study Design Dosage Regimen; Subjects or Status; Study of Study Objectives(s) of and Type of Route of Number of Diagnosis of Duration of Type of Type of Study Identifier Report the Study Control Administration Subjects Patients Treatment Report PK Extrinsic FTC-114 Module To determine OL, single- B: TDF 300 mg 19 subjects Healthy adult 21 days Complete; Factors (Synopsis) 5.3.3.4 safety and center, QD for 7 days enrolled; subjects Up to Final CSR whether the PK randomized, 3- A: FTC 200 mg 17 subjects 14 days parameters of way crossover QD for 7 days completed cumulative TDF or FTC are study of TDF C: TDF 300 mg treatment affected and FTC and FTC 200 mg with FTC following their coadministered QD QD, and up coadministration for 7 days to 14 days PO cumulative with 300 mg TDF QD, with both drugs coadministe red QD for 7 days PK Extrinsic FTC-115 Module Safety and OL, A: FTC 200 mg 30 subjects Healthy adult 7 days Complete; tolerability of randomized, 3- Factors (Synopsis) 5.3.3.4 QD, PO for 7 days enrolled, 27 subjects Final CSR treatment; Effect way crossover B: ZDV 300 mg subjects of ZDV on FTC BID, PO for 7 days completed PK after C: FTC 200 mg concurrent QD + ZDV 300 mg multidose BID, PO for 7 days administration. Effect of FTC on ZDV PK after concurrent multidose administration
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Test Product(s); Healthy Study Location Study Design Dosage Regimen; Subjects or Status; Study of Study Objectives(s) of and Type of Route of Number of Diagnosis of Duration of Type of Type of Study Identifier Report the Study Control Administration Subjects Patients Treatment Report PK Extrinsic GS-01-932 Module To evaluate the OL, fixed- TDF 300 mg 28 subjects Healthy adult 14 days Complete; Factors (Synopsis) 5.3.3.4 potential for an sequence, tablets, PO on Days enrolled; subjects with TDF Final CSR interaction drug-drug 215 with a light 25 subjects Single between TDF interaction and meal completed. administra- and enteric- drug-drug-food tion of ddI ddI EC (Videx coated ddI (ddI interaction EC on Days EC) 400 mg EC), and to study of TDF 1, 8, and 9. capsules, PO, on determine if the and ddI EC Days 1 and 8 administration of food in (fasted) and on Day combination 9 with a light meal with the 2 had an effect on their PK PK Extrinsic GS-02-984 Module To evaluate the OL, 1- TDF 300-mg 28 subject Healthy adult Group 1: 9 Complete; PK of reduced- sequence enrolled; Factors (Synopsis) 5.3.3.4 tablets, PO, on subjects days with Final CSR dose ddI crossover, Day 2 (Group 1, 28 subjects TDF; single (250 mg) and drug-drug fed), on Days 3-9 completed administra- TDF with interaction and (all, fed), on tion of ddI staggered drug-drug-food Day 10 (all, fasted), EC on Days administration interaction on Days 11-15 1, 8, 9, and and study of TDF (Group 2, fed) 10 simultaneous and ddI EC, ddI (Videx EC) Group 2: 13 administration and abacavir 250-mg enteric- days with (with/without (exploratory) coated beadlet TDF; single food) relative to formulation administra- ddI 400 mg. To capsule, PO, on tion of ddI evaluate PK of Days 8 and 10 (all, EC on Days abacavir and fasted), on Day 9 1, 8, 9, and TDF after
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Test Product(s); Healthy Study Location Study Design Dosage Regimen; Subjects or Status; Study of Study Objectives(s) of and Type of Route of Number of Diagnosis of Duration of Type of Type of Study Identifier Report the Study Control Administration Subjects Patients Treatment Report coadministration (all, fed), 10; single with food ddI (Videx EC) administra- 400-mg enteric- tion of coated beadlet abacavir formulation sulfate on capsule, PO, on Days 2 and Day 1 (all, fasted) 15. abacavir sulfate (Ziagen) 300 mg tablet, PO, on Day 2 (Group 2, fed) and on Day 15 (Group 2, fed) PK Extrinsic GS-01-943 Module To determine 36-day, OL, TDF 300-mg tablet 27 subjects Healthy subjects 36 days Complete; Factors (Synopsis) 5.3.3.4 whether the PK randomized, once daily, PO, on enrolled; Final CSR parameters of multidose, Days 1-21 23 subjects TDF or crossover, (Group I) or completed LPV/RTV are 3-period, drug- Days 1-7 and affected drug Days 22-35 following interaction (Group II). coadministration study of TDF LPV/RTV 400/100 with a meal and Kaletra mg (3 u 133.3 (LPV/ mg/33.3-mg) RTV) capsules BID, PO, on Days 8-35 (all) PK Extrinsic GS-01-930 Module To determine the OL, TDF 300-mg 24 subjects Normal, healthy Days 1–29 Complete; Factors 5.3.3.4 effect of TDF on fixed-sequence tablets once daily, enrolled; females Ortho Final CSR the PK of drug-drug PO, on Days 23-29 4 never currently taking Tri-Cyclen
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Test Product(s); Healthy Study Location Study Design Dosage Regimen; Subjects or Status; Study of Study Objectives(s) of and Type of Route of Number of Diagnosis of Duration of Type of Type of Study Identifier Report the Study Control Administration Subjects Patients Treatment Report (Synopsis) norgestimate and interaction Norgestimate/ received TDF Ortho Days 23-29 ethinyl estradiol study of TDF ethinyl estradiol Tri-Cyclen for TDF in female and (Ortho Tri-Cyclen at least subjects norgestimate/ Dialpak) tablets 3 months prior ethinyl once daily, PO, on to study entry estradiol Days 1-29 (Ortho Tri- Cyclen) PK Extrinsic GS-01-929 Module To determine the OL, fixed- TDF 300-mg 13 subjects Methadone- 16 days Complete; effect of TDF on sequence drug- Factors (Synopsis) 5.3.3.4 tablets once daily, enrolled; maintained Final CSR the steady-state drug PO, on Days 2-15 13 subjects subjects PK of interaction Methadone completed methadone, study of TDF hydrochloride, including the R- and methadone 40 mg (minimum and hydrochloride dose) to 110 mg S-enantiomers, (maximum dose) in opiate-main- liquid formulation tained subjects (10 mg/mL) once daily, PO PK Extrinsic GS-01-940 Module To evaluate OL, TDF 300-mg 24 subjects Healthy subjects 8 days Complete; whether the PK fixed-sequence enrolled, Factors (Synopsis) 5.3.3.4 tablets once daily, TDF on Final CSR of TFV or ADV drug-drug PO, on Days 2-8 22 subjects Days 2-8 are affected by interaction ADV 10 mg, PO, completed ADV on coadministration study on Days 1 and 8 days 1 and 8 of multiple doses of TDF and single doses of ADV, and to examine safety
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Test Product(s); Healthy Study Location Study Design Dosage Regimen; Subjects or Status; Study of Study Objectives(s) of and Type of Route of Number of Diagnosis of Duration of Type of Type of Study Identifier Report the Study Control Administration Subjects Patients Treatment Report following co- administration of TFV and ADV PK Extrinsic GS-02-1037 Module Evaluate OL, fixed Ribavirin 600 mg 23 subjects Healthy subjects 24 days Complete; sequence, enrolled, Factors (Synopsis) 5.3.3.4 whether multiple (3 u 200-mg TDF on Final CSR doses of TDF multidose TDF tablets), PO, on 22 subjects days 17–24 had an effect on (Viread ) and Days 1 and 22 completed ribavirin on the PK profile of single-dose TDF 300-mg Days 1 and single dose of ribavirin 22 tablets once daily, ribavirin, and to (Rebetol ), PO, on Days 17-24 examine safety drug-drug following interaction coadministration study of TFV and ribavirin PK Extrinsic GS-02-1038 Module To study the OL, single- TDF (Viread) 25 subjects Healthy adult 20 days Complete; effect of group, enrolled and Final Factors (Synopsis) 5.3.3.4 300-mg tablets subjects rifampicin on the multidose, once daily, PO, 24 subjects Abbrevi- PK of TDF 2-period, with breakfast, on received TDF ated CSR To compare the single-center Days 1 to 20 and rifampicin study PK of rifampicin Rifampicin 23 subjects + TDF versus completed (Rifadin) 600 mg historical (2 300-mg controls u tablets), PO, with To evaluate the breakfast, on Days safety of TDF 11 to 20 when combined with rifampicin
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Test Product(s); Healthy Study Location Study Design Dosage Regimen; Subjects or Status; Study of Study Objectives(s) of and Type of Route of Number of Diagnosis of Duration of Type of Type of Study Identifier Report the Study Control Administration Subjects Patients Treatment Report PK Extrinsic GS-US-104- Module To evaluate OL, single- TDF 300-mg tablet 40 subjects Healthy subjects 39 days Complete; Factors 0236 5.3.3.4 whether the PK and once daily, PO, on enrolled, Final CSR (Synopsis) parameters of multiple-dose, Days 2-24 32 subjects TFV, SQV, or drug-drug SQV mesylate completed RTV are interaction 1000 mg affected after study (5 u 200-mg hard coadministration capsules), PO, once of TDF and daily on Days 1, 2, RTV-boosted 9, 10, and 39 or SQV mesylate BID on Days 11-38 (SQV/r) under steady-state RTV 100-mg soft conditions gel, PO, once daily on Days 10 and 39 or BID on Days 11-38 PK Extrinsic GS-US-104- Module To evaluate Randomized, TDF 300 mg QD 32 Healthy subjects 35 days Complete; Factors 0237 5.3.3.4 whether the PK OL, and NFV mesylate Final CSR (Synopsis) parameters of 3-treatment, 1250 mg (5 250-mg TFV or NFV are crossover tablets) BID, orally, affected study in combination following the coadministration TDF 300 mg QD of TDF and NFV and NFV mesylate mesylate 1250 mg (5 250-mg compared with tablets) BID, orally, administration of administered each as a single separately agent
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Test Product(s); Healthy Study Location Study Design Dosage Regimen; Subjects or Status; Study of Study Objectives(s) of and Type of Route of Number of Diagnosis of Duration of Type of Type of Study Identifier Report the Study Control Administration Subjects Patients Treatment Report PK Extrinsic GS-00-909 Module To evaluate the 2-center, 3- TDF alone, TDF, n = 103 Healthy subjects 43 to 99 Complete; Factors (Synopsis) 5.3.3.4 PK parameters period, open- reference treatment TDF + 3TC, n days Final CSR of TDF, 3TC, label, alone, and TDF + = 18 ddI, IDV, randomized, reference TDF + ddI, n ABT-378/r multiple-dose, treatment: = 15 (LPV/r), and crossover, drug TDF 300 mg/day u TDF + IDV, n EFV when interaction 7 days = 15 administered study TDF + LPV/r, 3TC 150 mg BID u alone and in n = 24 pairs containing 7 days TDF + EFV, n TDF ddI 250 mg/day = 31 (weight 60 kg) or 90 subjects 400 mg/day completed the (weight t 60 kg) study IDV 800 mg every 8 hours u 7 days LPV/r 400 mg/100 mg BID u 14 days EFV 600 mg/day u 14 days PK Extrinsic GS-US-174- Module To evaluate the OL, FTC/TDF N=31 Healthy adult Three 7-day Complete; Factors 0105 5.3.3.4 effect of randomized, 3- 200/300 mg fixed- randomized subjects treatment Final CSR way crossover, (Synopsis) coadministration dose tablets once N=21 periods drug-drug of tacrolimus daily, PO, for evaluated for interaction (TCL) on the 7 days FTC/TDF PK steady-state PK study TCL 0.1 mg/kg/day N=22 of emtricitabine (as 0.5-mg or 1-mg evaluated for
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Test Product(s); Healthy Study Location Study Design Dosage Regimen; Subjects or Status; Study of Study Objectives(s) of and Type of Route of Number of Diagnosis of Duration of Type of Type of Study Identifier Report the Study Control Administration Subjects Patients Treatment Report and tenofovir capsules as TCL PK (administered as appropriate), PO, the combination for 7 days of emtricitabine Both therapies and tenofovir taken together for disoproxil 7 days fumarate) and vice versa in healthy volunteers Human PD GS-96-701 Module To evaluate the Multicenter, TFV 1 mg/kg IV TFV N = 16: HIV-1 infected 1 day of Complete; (Synopsis) 5.3.4 safety, PK, and randomized, over 1 hour on TFV 1 mg/kg, subjects with treatment Final CSR anti-HIV activity DB, placebo- Day 1 and on n = 8 CD4 cell counts followed by of single and controlled Days 8-14 TFV 3 mg/kg, t 200 7-day multiple doses of 3 washout study TFV 3 mg/kg IV n = 8 cells/mm , IV TFV in HIV over 1 hour on plasma HIV followed by infection Day 1 and on Placebo, RNA level 7 days day Days 8-14 N = 4 t 10,000 of treatment copies/mL
Placebo IV over 1 hour on Day 1 and on Days 8-14 Human PD GS-97-901 Module To investigate Multicenter Parts A & B, Day 1 TDF, N = 46: HIV-1 infected Blinded Complete; (Synopsis) 5.3.4 the safety, Parts A & B: and Days 8-35: TDF 75 mg, subjects with phase (Parts Final CSR tolerance, PK, randomized, CD4 cell count TDF 75, 150, 300, n = 12 A & B): and anti-HIV-1 DB, placebo- 3 or 600 mg as TDF 150 mg, t 200 cells/mm 35 days activity of TDF controlled, 75-mg tablets or n = 8 and plasma HIV (single dose, as monotherapy dose escalation placebo once daily, TDF 300 mg, RNA levels t then 7-day
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Test Product(s); Healthy Study Location Study Design Dosage Regimen; Subjects or Status; Study of Study Objectives(s) of and Type of Route of Number of Diagnosis of Duration of Type of Type of Study Identifier Report the Study Control Administration Subjects Patients Treatment Report or in Part C: single- PO (Cohorts 0-3) n = 8 10, 000 observation, combination arm, OL or TDF 600 mg, copies/mL then 28-day with hydoxyurea Extended TDF 75-mg tablet n = 10 dose period) in the treatment dosing: OL once daily or TDF + OL phase of HIV-1 placebo + hydroxyurea, (Part C): infection hydroxyurea n = 8 12 months 500-mg capsule Placebo, Extended BID, PO (Cohort 6) N = 13 dosing: Placebo + 12 months hydroxyurea, or until Part C, Cohort 6, study up to 12 months of n = 2 termination treatment: or drug TDF 75-mg tablet commerci- once daily ally + hydroxyurea available 500 mg BID, PO Controlled FTC-301A Module To compare Randomized d4T (40 mg BID if N = 571 ART-naive 48 weeks or Complete: Efficacy and (1:1), DB, (48-Week 5.3.5.1 safety and t 60 kg; 30 mg received subjects with longer 24-week double- Safety Synopsis) efficacy of FTC BID if 60 kg) treatment HIV-1 RNA interim dummy, with that of d4T capsule + ddI n = 286 for t 5000 CSR (no multicenter, when used (400 mg once daily FTC group copies/mL synopsis within a triple active- provided) if t 60 kg; 250 mg n = 285 for drug controlled once daily if (26 August equivalence d4T group combination 60 kg) tablets + 2002); study in ART- N = 513 containing ddI EFV 600 mg 48-week naive subjects completed and EFV (3 200-mg final CSR u 24 weeks capsules) once (synopsis daily, PO, N = 444 provided)
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Test Product(s); Healthy Study Location Study Design Dosage Regimen; Subjects or Status; Study of Study Objectives(s) of and Type of Route of Number of Diagnosis of Duration of Type of Type of Study Identifier Report the Study Control Administration Subjects Patients Treatment Report coadministered completed (18 with either FTC 48 weeks December 200-mg capsule or 2002) placebo capsule once daily, PO Controlled FTC-302 Module To compare Randomized Arm 1: FTC Total subjects HIV-1 infected, 48 weeks Complete; Efficacy and safety and (1:1), DB, (Synopsis) 5.3.5.1 200 mg/day (2 u to receive treatment-naive Final CSR Safety efficacy of FTC double- 100-mg capsules) treatment: adults with and 3TC within dummy, PO + d4T (30 mg N = 468 (234 HIV-1 RNA t a triple drug multicenter BID if 60 kg or in each arm) 5000 copies/mL combination 40 mg BID if Total subjects and CD4+ cell containing d4T t 60 kg) capsules to complete counts t 200 and NVP or EFV 3 PO + NVP 200-mg 48 weeks: cells/mm tablet once daily N = 347 (167 for 14 days, then in Arm 1 and 200-mg tablet BID 180 in Arm 2 PO (n = 194) or
EFV 600 mg (3 u 200-mg capsules) once daily PO (n = 40)
Arm 2: 3TC 150-mg tablet BID PO + d4T (30 mg BID if 60 kg or 40 mg BID if t 60 kg) capsules PO + NVP 200-mg tablet
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Test Product(s); Healthy Study Location Study Design Dosage Regimen; Subjects or Status; Study of Study Objectives(s) of and Type of Route of Number of Diagnosis of Duration of Type of Type of Study Identifier Report the Study Control Administration Subjects Patients Treatment Report once daily for 14 days, then 200-mg tablet BID PO (n = 191) or EFV 600 mg (3 u 200-mg capsules) once daily PO (n = 43) Controlled FTC-303 Module To compare FTC Randomized Arm 1: patients Arm 1: N = HIV-1 infected 48 weeks Complete; Efficacy and to 3TC in HIV-1 (2:1) OL, Final CSR (CSR 5.3.5.1 switch from 3TC to 294 adult subjects, infected patients multicenter, (10 June Safety Synopsis) FTC while Arm 2: N = 3TC-experienced, with HIV-1 equivalence continuing on 146 stable HIV-1 2002) RNA d 400 study current background RNA PK copies/mL on a therapy, or substudy stable (t 12 Arm 2: patients report (10 weeks) ART continuing on June 2002) regimen current 3TC- First containing 3TC, containing Addendum d4T, or ZDV, regimen; PO (TLOVR) and a PI or (27 August NNRTI 2002) Controlled GS-98-902 Module To evaluate Phase 2, Group 1: TDF 189 subjects HIV-1 infected 48 weeks Complete; Efficacy and safety and randomized, (48-Week 5.3.5.1 75 mg QD, PO enrolled in subjects who followed by 48-week tolerability of 3 DB, placebo- Safety Synopsis) Group 2: TDF blinded phase: had received a OL phase CSR (20 doses of TDF controlled, 150 mg QD , PO 54, 51, 56, stable ARV for 80 to April 2001)
administered multicenter Group 3: TDF and 28 regimen of d 4 100 weeks Final CSR (Final CSR with other ARV study for 48 300 mg QD, PO enrolled into ARV agents for (18 January Synopsis) agents for up to weeks, Group 4: Placebo, Groups 1, 2, 8 weeks prior to 2002) 48 weeks to followed by an PO 3, and 4, enrollment and Interim
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Test Product(s); Healthy Study Location Study Design Dosage Regimen; Subjects or Status; Study of Study Objectives(s) of and Type of Route of Number of Diagnosis of Duration of Type of Type of Study Identifier Report the Study Control Administration Subjects Patients Treatment Report treatment- optional OL, In OL phase, respectively. who had plasma Extension experienced, non- subjects received Of these, 135 HIV-1 RNA Report (03 HIV-1 infected randomized, TDF 300 mg QD, (71%) level April subjects single-arm PO subjects t 400 copies/m 2001) treatment continued in L and d 100,000 48-week phase of TDF OL phase copies/mL Virology within 15 days Report (26 prior to January randomization 2001) Final Extension Phase Virology Report (02 January 2002) Controlled GS-99-907 Module To evaluate Randomized, TDF 300 mg QD or 552 enrolled, HIV-1 infected 48 weeks Complete; Efficacy and (24-week 5.3.5.1 safety and DB, placebo- placebo QD, PO 550 subjects subjects (DB phase 24-week Safety synopsis) efficacy of TDF controlled, received at t 400 and 24 weeks, CSR (18 300 mg in intensification least 1 dose of d 100,000 OL to 48 April 2001) (Final CSR treatment- study study drug; copies/mL HIV- weeks) Final 48- synopsis) experienced PK examined Single dose: n 1 RNA levels week CSR subjects on following = 14 (18 March stable ARV single dose and 12-48 weeks: No restriction 2002) therapy during chronic n = 7 to 14 on CD4 PK Evaluate PK in treatment over substudy substudy 12 to 48 weeks report (18 March 2002)
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Test Product(s); Healthy Study Location Study Design Dosage Regimen; Subjects or Status; Study of Study Objectives(s) of and Type of Route of Number of Diagnosis of Duration of Type of Type of Study Identifier Report the Study Control Administration Subjects Patients Treatment Report 48-week Virology Report (02 April 2002) Controlled GS-99-903 Module Evaluate Randomized, D4T + 3TC + EFV 600 subjects HIV infected, 144 weeks Ongoing; Efficacy and efficacy and DB (48-week 5.3.5.1 + TDF placebo, PO TDF: 299 ARV-naive 48-week safety of TDF in equivalence Safety synopsis) TDF + 3TC + EFV d4T: 301 subjects CSR (19 a triple- study (144-week + d4T placebo, PO Entry criteria: August combination synopsis) HIV-1 RNA ! 2002) regimen in HIV- 5000 copies/mL 144-week (192-week infected ARV- synopsis) No restriction CSR (19 naive subjects on CD4 April 2004) 192-week CSR (13 November 2008) Controlled GS-01-934 Module To assess Randomized, Group 1: TDF+FTC+E ARV-naive, 144 weeks; Completed; Efficacy and (48-week 5.3.5.1 noninferiority of OL, parallel, To Week 96: FV: HIV-1 infected amended to 48-week Safety synopsis) TDF and FTC in multicenter, TDF 300 mg QD + n = 257 subjects with continue CSR (29 (144-week combination active- FTC 200 mg QD + Combivir + plasma HIV-1 treatment up April 2005) synopsis) with EFV controlled EFV 600 mg QD, EFV: RNA > 10,000 to 288 144-week relative to study PO n = 254 copies/mL weeks CSR (02 Combivir in Weeks 96–144: May 2007) combination EFV/TDF tablet with EFV in the (200/300 mg) QD + treatment of EFV 600 mg QD, HIV-1 infected PO ARV-naive Group 2: subjects, as Combivir
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Test Product(s); Healthy Study Location Study Design Dosage Regimen; Subjects or Status; Study of Study Objectives(s) of and Type of Route of Number of Diagnosis of Duration of Type of Type of Study Identifier Report the Study Control Administration Subjects Patients Treatment Report determined by (3TC/AZT) the achievement 150/300 mg BID + and maintenance EFV 600 mg QD, of confirmed PO HIV-1 RNA < 400 copies/mL through Week 48 defined by the FDA TLOVR algorithm Controlled M02-418 Module To study safety, Phase 3, OL, 800 mg/200 mg 190 subjects ARV-naive 96 weeks Complete; Efficacy and (Final 96- 5.3.5.1 tolerability, PK, randomized, LPV/RTV QD with randomized HIV-infected Interim 48- and antiviral multicenter Safety week TDF and FTC, PO and treated patients with week CSR activity of once- study HIV RNA synopsis) 400 mg/100 mg (no daily dosing of LPV/RTV BID ! 1000 synopsis LPV/RTV in with TDF and FTC, copies/mL, no provided) combination PO CD4 count (07 June with TDF and restriction 2004); FTC in the Final 96- treatment of week CSR ARV-naive (07 July HIV-infected 2005) patients Controlled GS-MC- Module To investigate Phase 3, FTC/TDF 250 subjects Adults, with 48 weeks Complete; Efficacy and 164-0111 5.3.5.1 the effect of randomized, (200 mg/300 mg) were HIV-1 who had Final CSR Safety (synopsis) treatment with OL, with EFV (600 mg) randomized been maintained Truvada on multicenter, QD without regard into the study; on stable ARV hemoglobin and active- to meals 234 subjects therapy of EFV lipid profiles in controlled were treated, given with ZDV
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Test Product(s); Healthy Study Location Study Design Dosage Regimen; Subjects or Status; Study of Study Objectives(s) of and Type of Route of Number of Diagnosis of Duration of Type of Type of Study Identifier Report the Study Control Administration Subjects Patients Treatment Report virologically study ZDV (250 mg in 117 in each plus 3TC for at suppressed UK or 300 mg in group least 6 months subjects taking Ireland) plus 3TC and who had EFV who were (150 mg) , PO; or viral loads < 50 switched from Combivir (ZDV/ copies/mL on an NRTI 3TC, last 2 backbone 300 mg/150 mg) consecutive containing ZDV BID with EFV tests and < 400 plus 3TC, and to (600 mg) QD, PO copies/mL for determine > 3 months whether the simplified regimen of FTC and TDF was associated with a reduced rate of AEs, as well as improved adherence and acceptability among other measures of quality of life. Controlled GS-ES-164- Module To explore Phase 4, Subjects continued 80 subjects HIV-1 infected 72 weeks Complete; Efficacy and 0154 5.3.5.1 changes in limb multicenter, on current NRTI- analyzed subjects Final Safety (RECOMB fat by DEXA randomized, backbone regimen TVD group: n abbreviated Study) measurements, OL and as the control group = 39 CSR (synopsis) after substitution controlled, or switched to ZDV + of the ZDV + study receive TVD (FTC lamivudine lamivudine dual 200 mg/TDF
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Test Product(s); Healthy Study Location Study Design Dosage Regimen; Subjects or Status; Study of Study Objectives(s) of and Type of Route of Number of Diagnosis of Duration of Type of Type of Study Identifier Report the Study Control Administration Subjects Patients Treatment Report NRTI-backbone 300 mg) , PO. All group: n = 41 by TVD, versus subjects continued maintaining the to receive third original ZDV- agent of their containing HAART regimen, regimen without including a PI or any change, NNRTI through 48 weeks Uncontrolled GS-99-910 Module To observe the OL, TDF, 300 mg QD, 575 enrolled; All active Until Complete; Safety (synopsis) 5.3.5.2 long-term safety multicenter orally, with food 573 received subjects commercial Final CSR effects of TDF, at least 1 dose participating in availability in combination of TDF an ongoing trial or program with other of TDF (GS-97- termination ARVs, in 901, GS-98- by Gilead patients who had 902, and GS-99- Sciences completed prior 907) without TDF studies treatment- limiting toxicity were eligible for enrollment Uncontrolled GS-US-164- Module To characterize Prospective, FTC/TDF 402 treated HIV-1 infected, 24 weeks Complete; Efficacy and 0107 5.3.5.2 the risks, single-arm, 200/300 mg/day, virologically Final CSR Safety (synopsis) effectiveness, OL, switch PO suppressed and benefits of study subjects on a switching from a stable regimen Combivir (BID) of EFV taken /EFV (QD) with Combivir regimen to an all once-daily
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Test Product(s); Healthy Study Location Study Design Dosage Regimen; Subjects or Status; Study of Study Objectives(s) of and Type of Route of Number of Diagnosis of Duration of Type of Type of Study Identifier Report the Study Control Administration Subjects Patients Treatment Report regimen of Truvada/EFV. Uncontrolled GS-DE-164- Module To assess Phase 3, FTC/TDF 52 subjects Virologically 48 weeks Complete; Efficacy and 0106 5.3.5.2 efficacy and prospective, (200 mg/300 mg) enrolled suppressed Final CSR Safety (synopsis) safety of non- QD with or without (HIV-1 RNA treatment switch randomized, food, PO concentration from a regimen single-group, < 50 copies/ with ZDV and OL, 48-week mL), HIV 3TC plus a third pilot study infected adults partner to a receiving ZDV- once-daily and 3TC- regimen of FDC containing of TDF and FTC HAART (for plus a third > 3 months) once-daily partner Uncontrolled GS-US-164- Module To assess the 48-week, FTC/TDF 102 subjects HIV-1 infected, 48 weeks Complete; Efficacy and 0115 5.3.5.2 safety, prospective, (200 mg/300 mg) were enrolled, ARV treatment- Synoptic Safety (synopsis) tolerability, single-arm, OL plus ATV 300 mg 100 were naive adults Report efficacy, PK and pilot study (given as 2 150-mg treated with plasma adherence of a capsules) plus RTV HIV-1 RNA once-daily 100 mg QD, PO levels regimen of > 1000 copies/ fixed-dose FTC/ mL and TDF (200 mg/ adequate renal 300 mg) and function (CRCl ATV 300 mg >50 mL/min) (given as 2 150-mg capsules)
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Test Product(s); Healthy Study Location Study Design Dosage Regimen; Subjects or Status; Study of Study Objectives(s) of and Type of Route of Number of Diagnosis of Duration of Type of Type of Study Identifier Report the Study Control Administration Subjects Patients Treatment Report boosted with RTV 100 mg Other Studies PC-264- Module To assess Virology study C209/C215: RPV Pooled RPV HIV-1 infected, 48 weeks Complete; 2005 5.3.5.4 resistance for the at Week 48, 25 mg + FTC/TDF group: ARV treatment- Virology (summary) Truvada comparing or EFV 600 mg + N=550; naive subjects Study (FTC/TDF) pooled data FTC/TDF, PO Pooled EFV with HIV-1 Report subset in 2 of from 2 studies All subjects in control group: RNA levels Tibotec’s Phase in RPV versus C209 received N=546 t 5000 III trials EFV group FTC/TDF. Only copies/mL, (TMC278- (both groups those subjects in susceptible to TiDP6-C209 and also received C215 who received their TMC278- FTC/TDF) FTC/TDF were background TiDP6-C215) included. regimen, and no NNRTI mutations 3TC, lamivudine; ABT-378, lopinavir; ADME, absorption, distribution, metabolism, excretion; ADV, adefovir dipivoxil; AE, adverse event; ART, antiretroviral therapy; AZT, azidothymidine (also known as zidovudine [ZDV]); BA, bioavailability; BE, bioequivalence; BID, twice daily; CHMP, Committee for Human Medicinal Products; CNS, central nervous system; CLCr, creatinine clearance; CSR, clinical study report; d4T, stavudine; ddI, didanosine; DB, double blind; DEXA, dual-energy x-ray absorptiometry; DF, disoproxil fumarate; EC, enteric-coated; EFV, efavirenz; EMV, emivirine; FCV, famciclovir; FDA, Food and Drug Administration; FDC, fixed-dose combination; FTC, emtricitabine; HAART, highly active antiretroviral therapy; HIV, human immunodeficiency virus; HIV-1, human immunodeficiency virus-1; IDV, indinavir; IU, international units; IV, intravenous; LPV, lopinavir; NFV, nelfinavir; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; NVP, nevirapine; OL, open label; PBMC, peripheral blood mononuclear cell; PI, protease inhibitor; PK, pharmacokinetic; PO, oral; PSUR, periodic safety update report; QD, once daily; RNA, ribonucleic acid; RPV, rilpivirine; RTV, ritonavir; SQV, saquinavir; TDF, tenofovir disoproxil fumarate; TFV, tenofovir; TLOVR, time to loss of virologic response; TVD, Truvada; tx, treatment; UK, United Kingdom; ZDV, zidovudine
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Trial Naming Conventions Throughout the development of TMC278 several different naming conventions were used for trials. The first part of the trial identifier was one of the following, depending on when the trial was conducted: ! R278474-CDE- (used for the earlier trials) ! R278474- ! TMC278- ! TMC278-TiDP6- (used for the most recent trials) All trials were given a suffix of a unique 3-digit number preceded by the letter C (for ‘Clinical’), e.g., C201 or C209. The exception to this rule was the naming of trials R278474-CDE-101, R278474-CDE-102 and R278474-CDE-103, which did not include the letter C in the suffix. The Phase III and Phase I pooled analyses are also referred to by a suffix of a unique 3-digit number preceded by C, the first number always being 9 (i.e., the Phase III pooled analysis, TMC278-TiDP6-C904, is referred to as C904 and the Phase I pooled analysis, TMC278-TiDP6-C906, is referred to as C906).
Clinical Trials
During early development, TMC278 was referred to as R278474. This document will identify the compound only as TMC278. The International Nonproprietary Name and the United States Adopted Name is rilpivirine HCl. In the early clinical trials, TMC278 was formulated as the free base in solution (R278474), but later the oral tablet formulation was developed in which TMC278 was present as an HCl salt (R314585). As a result, in later trials, TMC278 formulations were referred to as containing an amount of TMC278 as base equivalent (eq). In the Summary of Clinical Safety, for consistency, the following convention is used throughout: TMC278 X mg means either a dose of X mg when the base was used or X mg eq when the salt was used.
Approved, Issued Date: 18-Jun-2010 TMC278– Module 5.2 Tabular Listing of all Clinical Trials Tibotec – Confidential Information 2
5.3.1 Reports of Biopharmaceutic Studies 5.3.1.1 Bioavailability Study Reports Status Dosage Regimen Type of Report Trial Trial Design Subjects Route of Administration Trial Report Location Phase (Country) Primary Trial Objectives N Duration of Treatment in CTD Modules I R278474-C102 Randomized, open label, 3-way Healthy Treatment A: single dose of TMC278 100 mg in solution Completed crossover, food effect, single volunteers (Belgium) Treatment B: single dose of TMC278 100 mg as capsule Full Report dose trial 24 Treatment C: single dose of TMC278 100 mg as tablet 5.3.1.1 Compare the oral bioavailability of the reference solution Panel 1: Treatment A under fed conditions, Treatment B under formulation of single dose fed conditions, and Treatment B under fasted conditions TMC278 with 2 experimental solid formulations (tablets and Panel 2: Treatment A under fed conditions, Treatment C under capsules) of single dose fed conditions, and Treatment C under fasted conditions TMC278, and assess the effect Solution, tablets and capsules - oral of food on the oral bioavailability of the 3 x 1 day, separated by 2 washout periods of 14 days each 2 experimental solid formulations of single dose TMC278
N: number of enrolled subjects.
Study Report Location in Study Number Analytical Report Title CTD Modules R278474/017 LC-MS/MS Determination of R278474 in Human Heparin Plasma Originating from Clinical Trial R278474-C102 5.3.1.1 LC-MS/MS: liquid chromatography-mass spectrometry/mass spectrometry.
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5.3.1 Reports of Biopharmaceutic Studies, Cont’d 5.3.1.1 Bioavailability Study Reports Status Dosage Regimen Type of Report Trial Trial Design Subjects Route of Administration Trial Report Location Phase (Country) Primary Trial Objectives N Duration of Treatment in CTD Modules I TMC278-TiDP6-C137 Randomized, open label, 4-way Healthy Treatment A: single dose of TMC278 75 mg under fed Completed crossover, single dose trial volunteers conditions (after a standard breakfast) (France) Full report Determine the effect of different 20 Treatment B: single dose of TMC278 75 mg under fasted 5.3.1.1 types of meals on the oral conditions bioavailability of TMC278 after Treatment C: single dose of TMC278 75 mg under fed a single dose, formulated as the conditions (after a high fat breakfast) Phase III tablet Treatment D: single dose of TMC278 75 mg under fed conditions (after a nutritional drink rich in proteins [Ensure® HP]) Tablets – oral 4 x 1 day, separated by 3 washout periods of 14 days each N: number of enrolled subjects.
Study Report Location in Study Number Analytical Report Title CTD Modules R278474/041 LC-MS/MS Determination of TMC278 in Human Heparin Plasma Samples Originating From Clinical Trial 5.3.1.1 TMC278-TiDP6-C137 LC-MS/MS: liquid chromatography-mass spectrometry/mass spectrometry.
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5.3.1 Reports of Biopharmaceutic Studies, Cont’d 5.3.1.2 Comparative Bioavailability and Bioequivalence Study Reports Status Dosage Regimen Type of Report Trial Trial Design Subjects Route of Administration Trial Report Location Phase (Country) Primary Trial Objectives N Duration of Treatment in CTD Modules I TMC278-C117 Randomized, open label, 2-way Healthy Treatment C: single dose of TMC278 100 mg Phase III tablet Completed crossover, single dose trial volunteers formulation (Belgium) Full Report Compare the oral bioavailability 32 Treatment D: single dose of TMC278 100 mg Phase IIb tablet 5.3.1.2 of the 2 reference Phase IIb formulation tablet formulations with the Treatment E: single dose of TMC278 150 mg Phase III tablet newly developed Phase III formulation tablet formulation Treatment F: single dose of TMC278 150 mg Phase IIb tablet formulation Panel 2: Treatment C under fed conditions, Treatment D under fed conditions Panel 3: Treatment E under fed conditions, Treatment F under fed conditions Tablets – oral 2 x 1 day, separated by a washout period of 13 days N: number of enrolled subjects. Note: Panel 1(including Treatments A and B, relating to a single dose of TMC278 25 mg [Phase III and Phase IIb tablet, respectively]) was removed from the trial design by protocol amendment 1 before the start of dosing.
Study Report Location in Study Number Analytical Report Title CTD Modules R278474/037 LC-MS/MS Determination of TMC278 (R278474) in Human Heparin Plasma Originating from Clinical Trial 5.3.1.2 TMC278-C117 LC-MS/MS: liquid chromatography-mass spectrometry/mass spectrometry.
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5.3.1 Reports of Biopharmaceutic Studies, Cont’d 5.3.1.2 Comparative Bioavailability and Bioequivalence Study Reports Status Dosage Regimen Type of Report Trial Trial Design Subjects Route of Administration Trial Report Location Phase (Country) Primary Trial Objectives N Duration of Treatment in CTD Modules I TMC278-TiDP38-C145 Randomized, open label, 3-way Healthy Treatment A1: single dose of TMC278 25 mg in solution Completed crossover, single dose trial volunteers (The Netherlands) Treatment B1: single dose of TMC278 25 mg in solution Full report Compare the oral bioavailability 36 Treatment A2: single dose of TMC278 25 mg in suspension 5.3.1.2 of 3 concept pediatric formulations of TMC278 Treatment B2: single dose of TMC278 25 mg in suspension (solution, suspension, granules) Treatment A3: single dose of TMC278 25 mg in granule to that of the adult 25 mg Phase III tablet formulation, and Treatment B3: single dose of TMC278 25 mg in granule to assess the food effect for each concept formulation Treatment C: single dose of TMC278 25 mg as tablet Panel 1: Treatment A1 under fed conditions, Treatment B1 under fasted conditions Panel 2: Treatment A2 under fed conditions, Treatment B2 under fasted conditions Panel 3: Treatment A3 under fed conditions, Treatment B3 under fasted conditions Panels 1, 2, and 3: Treatment C under fed conditions Solution, suspension, granules, and tablets – oral 3 x 1 day, separated by 2 washout periods of 14 days each N: number of enrolled subjects. Study Report Location in Study Number Analytical Report Title CTD Modules TMC278/049 LC-MS/MS Determination of TMC278 in Human Heparin Plasma Samples Originating From Clinical Trial 5.3.1.2 TMC278-TiDP38-C145 LC-MS/MS: liquid chromatography-mass spectrometry/mass spectrometry.
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5.3.1 Reports of Biopharmaceutic Studies, Cont’d 5.3.1.3 In vitro- In vivo Correlation Study Reports Status Dosage Regimen Type of Report Trial Trial Design Subjects Route of Administration Trial Report Location in Phase (Country) Primary Trial Objectives N Duration of Treatment CTD Modules Not applicable
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5.3.1 Reports of Biopharmaceutic Studies, Cont’d 5.3.1.4 Reports of Bioanalytical and Analytical Methods for Human Studies Study Report Location Study Number Analytical Report Title in CTD Modules PRD BA28 Validation (Full) of an LC-MS/MS Method for the Determination of R278474 in Human Heparin Plasma 5.3.1.4 BA28 Validation of an LC-MS/MS method for the determination of R278474 in human heparin plasma (Amendment 1 to 5.3.1.4 BA28) BA28 Validation of an LC-MS/MS method for the determination of R278474 in human heparin plasma (Amendment 2 to 5.3.1.4 BA28) BA218 Validation (Full) of an LC-MS/MS Method for the Determination of R278474 in Human Heparin Plasma, including 5.3.1.4 Amendment 1 BA218 Validation of an LC-MS/MS method for the determination of R278474 in human heparin plasma (Amendment 2 to 5.3.1.4 BA218) BA218 Validation of an LC-MS/MS method for the determination of R278474 in human heparin plasma (Amendment 3 to 5.3.1.4 BA218) ABL6187 The Validation of the Determination of TMC278 in Human Plasma Using LC-MS/MS 5.3.1.4 PRD-BA1071 Validation (Full) of an LC-MS/MS Method for the Determination of TMC278 (JNJ-16150108) in Human Heparin 5.3.1.4 Plasma ABL2241 Validation of the determination of efavirenz in human plasma using LC-MS/MS 5.3.1.4 ABL3230 Validation of the determination of nevirapine in human plasma using LC-MS/MS 5.3.1.4 PBRL-RD-688 Validation of a method for the determination of tenofovir in human plasma samples 5.3.1.4 PBRL-RD-688 Validation of a method for the determination of tenofovir in human plasma samples (Amendment 1 to PBRL-RD-688) 5.3.1.4 ABL6037 Partial validation of the determination of tenofovir in human urine using HPLC with fluorescence detection 5.3.1.4 PPD LCMS B202 Quantitation of ketoconazole in human plasma via HPLC with MS/MS detection 5.3.1.4 PPD LCMS B202 Quantitation of ketoconazole in human plasma via HPLC with MS/MS detection (Addendum to LCMS B202) 5.3.1.4 ABL2184 Validation of the determination of lopinavir in human plasma using LC/MS-MS 5.3.1.4 ABL3021 Validation of the combined determination of TMC114 and ritonavir in human plasma using LC-MS/MS 5.3.1.4
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5.3.1 Reports of Biopharmaceutic Studies, Cont’d 5.3.1.4 Reports of Bioanalytical and Analytical Methods for Human Studies Study Report Location Study Number Analytical Report Title in CTD Modules ABL5150 The cross-validation of the determination of TMC114 and ritonavir in human plasma using an API-4000 LC-MS/MS 5.3.1.4 system ABL6044 The cross-validation of the determination of TMC114 and ritonavir in human heparin plasma by LC-MS/MS using 5.3.1.4 D4-TMC114 and D6-ritonavir as internal standard ABL4267 The validation of the determination of didanosine in human heparin plasma by LC-MS/MS 5.3.1.4 PBRL-RD-667 Validation of a method for the determination of rifampicin and 25-desacetyl rifampicin in human plasma samples 5.3.1.4 PBRL-RD-715 Validation of a method for the determination of paracetamol, paracetamol glucuronide and paracetamol sulphate in 5.3.1.4 human plasma samples PBRL-RD-715 Validation of a method for the determination of paracetamol, paracetamol glucuronide and paracetamol sulphate in 5.3.1.4 human plasma samples (Amendment 1 to PBRL-RD-715) R319064/R115891/BA502 Validation (full) of an LC-MS/MS method for the determination of R319064 (TMC114) and R115891 (ritonavir) in 5.3.1.4 human heparin plasma PPD P749 Determination of omeprazole, 5-hydroxyomeprazole, and omeprazole sulphone in human plasma by LC/MS/MS 5.3.1.4 PBRL-RD-722 Validation of a method for the determination of atorvastatin and five metabolites in human plasma samples 5.3.1.4 ABL2083 Validation of the determination of ethinyl estradiol (EE) using LC/MS/MS by LC/MS/MS 5.3.1.4 ABL2083 Validation of the determination of ethinyl estradiol (EE) using LC/MS/MS by LC/MS/MS (Amendment 1 to ABL2083) 5.3.1.4 ABL3200 The cross-validation of the determination of ethinyl estradiol (EE) in human plasma using an API-4000 LC-MS/MS 5.3.1.4 system ABL4125 The partial revalidation of the determination of ethinyl estradiol (EE) in human heparin plasma over the range of 5.3.1.4 3.00-600 pg/mL using LC-MS/MS ABL6212 The validation of the determination of norethindrone in human plasma using GC-MS 5.3.1.4 PPD LCMS 323 Quantitation of methadone in human plasma via HPLC with MS/MS detection 5.3.1.4 PPD LCMSC 323.1 Quantitation of methadone enantiomers in human plasma via HPLC with MS/MS detection (February 2009) 5.3.1.4
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5.3.1 Reports of Biopharmaceutic Studies, Cont’d 5.3.1.4 Reports of Bioanalytical and Analytical Methods for Human Studies Study Report Location Study Number Analytical Report Title in CTD Modules PPD LCMSC 323.1 Quantitation of methadone enantiomers in human plasma via HPLC with MS/MS detection (May 2009) 5.3.1.4
LCMSC 323.1 Quantitation of methadone enantiomers in human plasma via HPLC with MS/MS detection (Addendum 1 to LCMSC 5.3.1.4 323.1) LCMSC 323.1 Quantitation of methadone enantiomers in human plasma via HPLC with MS/MS detection (Addendum 2 to LCMSC 5.3.1.4 323.1) PPD LCMS 231 Quantitation of sildenafil and desmethyl sildenafil in human plasma via HPLC with MS/MS detection (full validation, 5.3.1.4 human plasma containing tripotassium EDTA) PPD LCMS 231.1 Quantitation of sildenafil and desmethyl sildenafil in human plasma via HPLC with MS/MS detection (partial 5.3.1.4 validation, human plasma containing sodium heparin) PPD LCMS 231.1 Quantitation of sildenafil and desmethyl sildenafil in human plasma via HPLC with MS/MS detection (Addendum 1 to 5.3.1.4 PPD LCMS 231.1) PPD LCMS 231.1 Quantitation of sildenafil and desmethyl sildenafil in human plasma via HPLC with MS/MS detection (Addendum 2 to 5.3.1.4 PPD LCMS 231.1) ABL 2104 Validation of the combined determination of rifabutin and its metabolite 25-O-desacetylrifabutin in human plasma 5.3.1.4 using LC-MS/MS ABL 6237 The cross validation of the determination of rifabutin and 25-O-desacetylrifabutin in human plasma using API4000 5.3.1.4 LC-MS/MS PBRL-RD-680 Validation of a method for the determination of moxifloxacin in human plasma samples 5.3.1.4 PPD LCMSC 255 Quantitation of norethindrone and ethinylestradiol in human plasma containing sodium heparin via HPLC with MS/MS 5.3.1.4 detection PPD LCMSC 255.5 Quantitation of norethindrone and ethinylestradiol in human plasma containing dipotassium EDTA via HPLC with 5.3.1.4 MS/MS detection PPD RHK2 Quantification of chlorzoxazone and 6-hydroxychlorzoxazone in human plasma via HPLC with MS/MS detection 5.3.1.4 PPD RHK3 Quantification of chlorzoxazone and 6-hydroxychlorzoxazone in human plasma via HPLC with MS/MS detection 5.3.1.4
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5.3.1 Reports of Biopharmaceutic Studies, Cont’d 5.3.1.4 Reports of Bioanalytical and Analytical Methods for Human Studies Study Report Location Study Number Analytical Report Title in CTD Modules PPD RHK9 Quantification of chlorzoxazone and 6-hydroxychlorzoxazone in human plasma via HPLC with MS/MS detection 5.3.1.4 ABL 7044 Validation of the determination of famotidine in human plasma using LC-MS/MS 5.3.1.4 PPD LCMSB 276 Quantitation of moxifloxacin in human plasma via HPLC with MS/MS detection 5.3.1.4 PPD LC346 Quantitation of efavirenz in human plasma via HPLC with UV detection (May 2002) 5.3.1.4 PPD LC346 Quantitation of efavirenz in human plasma via HPLC with UV detection (June 2002) 5.3.1.4 PPD LC346 Quantitation of efavirenz in human plasma via HPLC with UV detection (Addendum 1 to PPD LC346) 5.3.1.4
PPD LC346 Quantitation of efavirenz in human plasma via HPLC with UV detection (Addendum 2 to PPD LC346) 5.3.1.4 PPD LC346 Quantitation of efavirenz in human plasma via HPLC with UV detection (Addendum 3 to PPD LC346) 5.3.1.4 ABL 3101 The validation of zidovudine and zidovudine-glucuronide in human plasma samples, using LC-MS/MS 5.3.1.4 ABL 8096 Cross validation of the determination of zidovudine and zidovudine-glucuronide in human plasma samples, using 5.3.1.4 LC-MS/MS EDTA: ethylene diamine tetra acetate; EE: ethinyl estradiol; GC-MS: gas chromatography-mass spectrometry; HPLC: high performance liquid chromatography; LC-MS/MS: liquid chromatography-mass spectrometry/mass spectrometry; MS/MS: mass spectrometry/mass spectrometry; UV: ultraviolet.
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5.3.2 Reports of Studies Pertinent to Pharmacokinetics using Human Biomaterials 5.3.2.1 Plasma Protein Binding Study Reports Refer to Module 4.2.2.3/TMC278-NC112 (FK527)
5.3.2 Reports of Studies Pertinent to Pharmacokinetics using Human Biomaterials, Cont’d 5.3.2.2 Reports of Hepatic Metabolism and Drug Interaction Studies Refer to Module 4.2.2.4/TMC278-NC102 Refer to Module 4.2.2.4/TMC278-TiDP6-NC157 Refer to Module 4.2.2.4/TMC278-NC141 Refer to Module 4.2.2.4/R278474-PRD-FK4123 Refer to Module 4.2.2.4/TMC278-NC186 Refer to Module 4.2.2.4/TMC278-NC283 Refer to Module 4.2.2.6/TMC278-NC194
5.3.2 Reports of Studies Pertinent to Pharmacokinetics using Human Biomaterials, Cont’d 5.3.2.3 Reports of Studies Using Other Human Biomaterials Refer to Module 4.2.2.2/TMC278-NC104
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5.3.3 Reports of Human Pharmacokinetic Studies 5.3.3.1 Healthy Subject Pharmacokinetics and Initial Tolerability Study Reports Status Dosage Regimen Type of Report Trial Trial Design Subjects Route of Administration Trial Report Location in Phase (Country) Primary Trial Objectives N Duration of Treatment CTD Modules I R278474-CDE-101 Randomized, double-blind, Healthy male Treatment A: single dose of TMC278 (12.5, 25, or 50 mg) or Completed placebo-controlled, ascending, volunteers placebo, under fed conditions (Belgium) Full report single dose trial 27 Solution – oral 5.3.3.1 Evaluate the safety, 1 day tolerability, pharmacokinetics, and ex vivo pharmacodynamics of single ascending doses of TMC278 N: number of enrolled subjects.
Study Report Location in Study Number Analytical Report Title CTD Modules R278474/004 LC-MS/MS Determination of R278474 in Human Heparin Plasma Originating from Clinical Trial R278474-CDE-101 5.3.3.1 LC-MS/MS: liquid chromatography-mass spectrometry/mass spectrometry.
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5.3.3 Reports of Human Pharmacokinetic Studies, Cont’d 5.3.3.1 Healthy Subject Pharmacokinetics and Initial Tolerability Study Reports Status Dosage Regimen Type of Report Trial Trial Design Subjects Route of Administration Trial Report Location in Phase (Country) Primary Trial Objectives N Duration of Treatment CTD Modules I R278474-CDE-102 Randomized, double-blind, Healthy male Treatment A: once daily dose of TMC278 (25, 75, or 150 mg) Completed placebo-controlled, ascending, volunteers or placebo, under fed conditions (The Netherlands) Full report multiple dose trial 27 Solution – oral 5.3.3.1 Evaluate the safety, 14 days tolerability, pharmacokinetics, and ex vivo pharmacodynamics of multiple ascending doses of TMC278 N: number of enrolled subjects.
Study Report Location in Study Number Analytical Report Title CTD Modules R278474/008 LC-MS/MS Determination of R278474 in Human Heparin Plasma Originating from Clinical Trial R278474-CDE-102 5.3.3.1 LC-MS/MS: liquid chromatography-mass spectrometry/mass spectrometry.
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5.3.3 Reports of Human Pharmacokinetic Studies, Cont’d 5.3.3.1 Healthy Subject Pharmacokinetics and Initial Tolerability Study Reports Status Dosage Regimen Type of Report Trial Trial Design Subjects Route of Administration Trial Report Location in Phase (Country) Primary Trial Objectives N Duration of Treatment CTD Modules I R278474-CDE-103 Randomized, double-blind, Healthy male Treatment A: single dose of TMC278 (50, 100, or 200 mg) or Completed placebo-controlled, ascending, volunteers placebo, under fed conditions (The Netherlands) Full report single dose trial 36 Solution – oral 5.3.3.1 Evaluate the safety, 1 day tolerability, pharmacokinetics, and ex vivo pharmacodynamics of single ascending doses of TMC278 N: number of enrolled subjects.
Study Report Location in Study Number Analytical Report Title CTD Modules R278474/007 LC-MS/MS Determination of R278474 in Human Heparin Plasma Originating from Clinical Trial R278474-CDE-103 5.3.3.1 LC-MS/MS: liquid chromatography-mass spectrometry/mass spectrometry.
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5.3.3 Reports of Human Pharmacokinetic Studies, Cont’d 5.3.3.1 Healthy Subject Pharmacokinetics and Initial Tolerability Study Reports Status Dosage Regimen Type of Report Trial Trial Design Subjects Route of Administration Trial Report Location in Phase (Country) Primary Trial Objectives N Duration of Treatment CTD Modules I TMC278-C103 Randomized, open label, Healthy Treatment A: once daily dose of TMC278 25 mg, under fed Completed parallel group, multiple dose volunteers conditions (Belgium) Full report ranging trial 48 Treatment B: once daily dose of TMC278 50 mg, under fed 5.3.3.1 Evaluate the safety, conditions tolerability and Treatment C: once daily dose of TMC278 100 mg, under fed pharmacokinetics of the solid conditions formulation Treatment D: once daily dose of TMC278 150 mg, under fed conditions Tablets – oral 14 days N: number of enrolled subjects.
Study Report Location in Study Number Analytical Report Title CTD Modules R278474/021 LC-MS/MS Determination of R278474 in Human Heparin Plasma Originating from Clinical Trial TMC278-C103 5.3.3.1 LC-MS/MS: liquid chromatography-mass spectrometry/mass spectrometry.
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5.3.3 Reports of Human Pharmacokinetic Studies, Cont’d 5.3.3.1 Healthy Subject Pharmacokinetics and Initial Tolerability Study Reports Status Dosage Regimen Type of Report Trial Trial Design Subjects Route of Administration Trial Report Location in Phase (Country) Primary Trial Objectives N Duration of Treatment CTD Modules I TMC278-C119 Open label, mass balance, Healthy male Single dose of TMC278 150 mg 14C-labeled solution under fed Completed single dose trial volunteers conditions (Belgium) Full report Characterize absorption, 6 Solution – oral 5.3.3.1 distribution, excretion, and the 1 day overall metabolic profile of a single dose of 14C-labeled TMC278 N: number of enrolled subjects.
Study Report Location in Study Number Analytical Report Title CTD Modules R278474/027 LC-MS/MS Determination of R278474 (TMC278) in Human Heparin Plasma Originating from Clinical Trial 5.3.3.1 TMC278-C119 LC-MS/MS: liquid chromatography-mass spectrometry/mass spectrometry.
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5.3.3 Reports of Human Pharmacokinetic Studies, Cont’d 5.3.3.1 Healthy Subject Pharmacokinetics and Initial Tolerability Study Reports Status Dosage Regimen Type of Report Trial Trial Design Subjects Route of Administration Trial Report Location in Phase (Country) Primary Trial Objectives N Duration of Treatment CTD Modules I TMC278-TiDP15- Randomized, double-blind, Healthy Panel 1: single 1 x 2 mL vehicle, or saline Completed C146 placebo-controlled, single volunteers Synopsis dose trial Panel 2: single 2 x 2 mL or vehicle (Belgium) 60 2.7.6 Evaluate the safety and Panel 3: single 3 x 2 mL or vehicle tolerability of TMC278LA for Panel 4: single 2 x 1 mL vehicle, or saline single dose subcutaneous or intramuscular injections Panel 5: single 2 x 2 mL or vehicle Panel 6: single 2 x 3 mL or vehicle Panel 7: single 2 x 2 mL or saline Panel 1-3: injectable suspension for TMC278LA and vehicle, solution for saline - subcutaneous Panel 4-6: injectable suspension for TMC278LA and vehicle, solution for saline - intramuscular Panel 7: injectable suspension for TMC278LA and solution for saline - intramuscular (deltoid) 1 day LA: long acting.
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5.3.3 Reports of Human Pharmacokinetic Studies, Cont’d 5.3.3.1 Healthy Subject Pharmacokinetics and Initial Tolerability Study Reports Status Dosage Regimen Type of Report Trial Trial Design Subjects Route of Administration Trial Report Location in Phase (Country) Primary Trial Objectives N Duration of Treatment CTD Modules I TMC278- TiDP15- Randomized, double-blind, Healthy Panel 1: a single dose of TMC278LA 600 mg (2 mL in 1 IS) or Completed C150 placebo-controlled, single volunteers vehicle or saline Synopsis dose and multiple dose trial 3 successive doses (at 1-month intervals) of (Germany) 20 TMC278LA 300 mg (1 mL in 1 IS) or vehicle or 2.7.6 Evaluate the safety and saline tolerability of TMC278LA Panel 2: a single dose of TMC278LA 1200 mg (2 mL in each of 2 ISs) or vehicle or saline 3 successive doses (at 1-month intervals) of 600 mg (2 mL in 1 IS) TMC278LA or vehicle or saline Nanosuspension for TMC278LA and vehicle, solution for saline - intramuscular 4 doses with a 1-month interval between doses IS: injection site: LA: long acting.
Approved, Issued Date: 18-Jun-2010 TMC278– Module 5.2 Tabular Listing of all Clinical Trials Tibotec – Confidential Information 19
5.3.3 Reports of Human Pharmacokinetic Studies, Cont’d 5.3.3.2 Patient Pharmacokinetics and Initial Tolerability Study Reports Status Dosage Regimen Type of Report Trial Trial Design Subjects Route of Administration Trial Report Location in Phase (Country) Primary Trial Objectives N Duration of Treatment CTD Modules Not applicable
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5.3.3 Reports of Human Pharmacokinetic Studies, Cont’d 5.3.3.3 Intrinsic Factor Study Reports Status Dosage Regimen Type of Report Trial Trial Design Subjects Route of Administration Trial Report Location in Phase (Country) Primary Trial Objectives N Duration of Treatment CTD Modules I TMC278-TiDP6-C130 Open label, parallel group, 32 Once daily dose of TMC278 25 mg, under fed conditions Completed controlled, sequential, (Belgium) 16 subjects Panel 1: 8 subjects with mild hepatic impairment and Full report multiple dose trial with mild or 8 healthy volunteers 5.3.3.3 Determine the single dose and moderate Panel 2: 8 subjects with moderate hepatic impairment and steady-state (multiple dose) hepatic 8 healthy volunteers pharmacokinetics and short impairment term safety and tolerability of 16 healthy Tablets – oral TMC278 in subjects with mild volunteers 11 days or moderate hepatic impairment compared to matched healthy control volunteers N: number of enrolled subjects.
Study Report Location in Study Number Analytical Report Title CTD Modules TMC278/050 LC-MS/MS Determination of TMC278 in Human Heparin Plasma Samples Originating From Clinical Trial 5.3.3.3 TMC278-TiDP6-C130 LC-MS/MS: liquid chromatography-mass spectrometry/mass spectrometry.
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5.3.3 Reports of Human Pharmacokinetic Studies, Cont’d 5.3.3.4 Extrinsic Factor Study Reports Status Dosage Regimen Type of Report Trial Trial Design Subjects Route of Administration Trial Report Location in Phase (Country) Primary Trial Objectives N Duration of Treatment CTD Modules I R278474-C101 Open label, parallel group, HIV-1 Treatment A: single dose of TMC278 50 mg under fed Completed add-on single dose trial infected male conditions, as add on to an EFV (600 mg once daily) (United Kingdom) Full report subjects containing ARV regimen Determine the single dose 5.3.3.4 pharmacokinetics of 15 Treatment B: single dose of TMC278 50 mg under fed TMC278 in HIV-1 infected conditions, as add on to a NVP (200 mg twice daily) subjects containing ARV regimen Solution (TMC278) – oral 1 day ARV: antiretroviral; EFV: efavirenz; HIV: human immunodeficiency virus; N: number of enrolled subjects; NVP: nevirapine.
Study Report Location in Study Number Analytical Report Title CTD Modules ABL4159 The Determination of Efavirenz in Human Plasma Samples, Derived From Tibotec Clinical Trial R278474-C101, Using 5.3.3.4 LC-MS/MS ABL4160 The Determination of Nevirapine in Human Plasma Samples, Derived From Tibotec Clinical Trial R278474-C101, 5.3.3.4 Using LC-MS/MS R278474/010 LC-MS/MS Determination of TMC278 in Human Heparin Plasma Samples Originating From Clinical Trial 5.3.3.4 R278474-C101 LC-MS/MS: liquid chromatography-mass spectrometry/mass spectrometry.
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5.3.3 Reports of Human Pharmacokinetic Studies, Cont’d 5.3.3.4 Extrinsic Factor Study Reports Status Dosage Regimen Type of Report Trial Trial Design Subjects Route of Administration Trial Report Location in Phase (Country) Primary Trial Objectives N Duration of Treatment CTD Modules I TMC278-C104 Randomized, open label, Healthy Treatment A: once daily dose of TMC278 150 mg, under fed Completed 2-sequence, crossover, volunteers conditions (The Netherlands) Full report multiple dose, drug 16 Treatment B: once daily dose of TDF 300 mg plus once daily interaction trial 5.3.3.4 dose of TMC278 150 mg, under fed conditions Determine the effect of Panel 1: Treatment A, on Days 1-8, followed by Treatment B, steady-state (multiple dose) on Days 1-16 (TDF plus TMC278 on Days 9-16) TMC278 concentrations on the steady-state Panel 2: Treatment A, on Days 1-8, followed by Treatment B, pharmacokinetics and on Days 1-16 (TDF plus TMC278 on Days 1-8) urinary excretion of Tablets (TMC278 and TDF) – oral tenofovir and the effect of steady-state tenofovir 8 days for Treatment A and 16 days for Treatment B, concentrations on the separated by a washout period of 14 days steady-state pharmacokinetics of TMC278 TDF: tenofovir disoproxil fumarate; N: number of enrolled subjects.
Study Report Location in Study Number Analytical Report Title CTD Modules ABL6034 The Determination of Tenofovir in Human Urine Samples, Derived From Tibotec Clinical Trial TMC278-C104, Using 5.3.3.4 HPLC with Fluorescence Detection BA429 LC-MS/MS Determination of Tenofovir in Human Plasma Samples Originating From Clinical Trial TMC278-C104 5.3.3.4 R278474/022 LC-MS/MS Determination of R278474 in Human Heparin Plasma Originating from Clinical Trial TMC278-C104 5.3.3.4 HPLC: high performance liquid chromatography; LC-MS/MS: liquid chromatography-mass spectrometry/mass spectrometry.
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5.3.3 Reports of Human Pharmacokinetic Studies, Cont’d 5.3.3.4 Extrinsic Factor Study Reports Status Dosage Regimen Type of Report Trial Trial Design Subjects Route of Administration Trial Report Location in Phase (Country) Primary Trial Objectives N Duration of Treatment CTD Modules I TMC278-C105 Randomized, open label, Healthy Treatment A: once daily dose of TMC278 150 mg, under fed Completed 2-way crossover, multiple volunteers conditions (France) Full report dose, drug interaction trial 16 Treatment B: twice daily dose of 400/100 mg 5.3.3.4 Determine the effect of lopinavir/ritonavir plus once daily dose of TMC278 150 mg, steady-state (multiple dose) under fed conditions TMC278 concentrations on Tablets (TMC278) and capsules (lopinavir/ritonavir) – oral the steady-state pharmacokinetics of 10 days for Treatment A and 20 days for Treatment B lopinavir/ritonavir and the (Days 1-20 for lopinavir/ritonavir plus TMC278 on effect of steady-state Days 11-20), separated by a washout period of 14 days lopinavir/ritonavir concentrations on the steady-state pharmacokinetics of TMC278 N: number of enrolled subjects.
Study Report Location in Study Number Analytical Report Title CTD Modules ABL6025 TMC278-C105-The Determination of Lopinavir in Human Plasma Samples, Derived From Tibotec Clinical Trial 5.3.3.4 TMC278-C105, Using LC-MS/MS ABL6026 TMC278-C105-The Determination of Ritonavir in Human Plasma Samples, Derived From Tibotec Clinical Trial 5.3.3.4 TMC278-C105, Using LC-MS/MS R278474/029 LC-MS/MS Determination of R278474 in Human Heparin Plasma Originating from Clinical Trial TMC278-C105 5.3.3.4 LC-MS/MS: liquid chromatography-mass spectrometry/mass spectrometry.
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5.3.3 Reports of Human Pharmacokinetic Studies, Cont’d 5.3.3.4 Extrinsic Factor Study Reports Status Dosage Regimen Type of Report Trial Trial Design Subjects Route of Administration Trial Report Location in Phase (Country) Primary Trial Objectives N Duration of Treatment CTD Modules I TMC278-C106 Randomized, open label, Healthy Treatment A: once daily dose of TMC278 150 mg, under fed Completed 2-sequence, multiple dose, volunteers conditions (USA) Full report drug interaction trial Treatment B: once daily dose of ddI 400 mg, under fasted 26 conditions, plus once daily dose of TMC278 150 mg, under 5.3.3.4 Determine the effect of fed conditions steady-state (multiple dose) TMC278 concentrations on Panel 1: Treatment A, on Days 1-7, followed by Treatment B the steady-state on Days 1-14 (ddI plus TMC278 on Days 8-14) pharmacokinetics of ddI and Panel 2: Treatment A, on Days 1-7, followed by Treatment B the effect of steady-state ddI on Days 1-14 (ddI plus TMC278 on Days 1-7) concentrations on the steady-state A sub-study was performed, after all subjects had completed pharmacokinetics of the main trial, in which 10 additional subjects were TMC278 randomized to Treatment B in order to replace samples that were lost during shipment. Tablets (TMC278) and capsules (ddI) – oral 7 days for Treatment A and 14 days for Treatment B, separated by a washout period of 14 days. 14 days for the repeat Treatment B (sub-study) ddI: didanosine; N: number of enrolled subjects. Continued
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5.3.3 Reports of Human Pharmacokinetic Studies, Cont’d 5.3.3.4 Extrinsic Factor Study Reports Study Report Location in Study Number Analytical Report Title CTD Modules ABL5217 The Determination of ddI in Human Plasma Samples, Derived From Tibotec Clinical Trial TMC278-C106, Using 5.3.3.4 LC-MS/MS R278474/039 LC-MS/MS Determination of TMC278 in Human Heparin Plasma Samples Originating From Clinical Trial 5.3.3.4 TMC278-C106 ddI: didanosine; LC-MS/MS: liquid chromatography-mass spectrometry/mass spectrometry.
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5.3.3 Reports of Human Pharmacokinetic Studies, Cont’d 5.3.3.4 Extrinsic Factor Study Reports Status Dosage Regimen Type of Report Trial Trial Design Subjects Route of Administration Trial Report Location in Phase (Country) Primary Trial Objectives N Duration of Treatment CTD Modules I R278474-C108 Randomized, open label, Healthy Treatment A: once daily dose of TMC278 150 mg, under fed Completed 3-way crossover, multiple volunteers conditions (Belgium) Full report dose, drug interaction trial 16 Treatment B: once daily dose of rifampin 600 mg, under fed 5.3.3.4 Determine the effect of conditions steady-state (multiple dose) Treatment C: once daily doses of TMC278 150 mg plus TMC278 concentrations on rifampin 600 mg, under fed conditions the steady-state pharmacokinetics of Solution (TMC278) and capsules (rifampin) – oral rifampin and its active 3 x 7 days, separated by 2 washout periods of 14 days each metabolite 25-desacetylrifampin, and the effect of steady-state rifampin concentrations on the steady-state pharmacokinetics of TMC278 N: number of enrolled subjects.
Study Report Location in Study Number Analytical Report Title CTD Modules Rifampin/001 LC-UV Determination of Rifampicin and 25-Desacetyl Rifampicin in Human Plasma Samples Originating From 5.3.3.4 Clinical Trial TMC278-C108 R278474/018 LC-MS/MS Determination of R278474 in Human Heparin Plasma Originating from Clinical Trial TMC278-C108 5.3.3.4 LC-MS/MS: liquid chromatography-mass spectrometry/mass spectrometry; LC-UV: liquid chromatography-ultraviolet.
Approved, Issued Date: 18-Jun-2010 TMC278– Module 5.2 Tabular Listing of all Clinical Trials Tibotec – Confidential Information 27
5.3.3 Reports of Human Pharmacokinetic Studies, Cont’d 5.3.3.4 Extrinsic Factor Study Reports Status Dosage Regimen Type of Report Trial Trial Design Subjects Route of Administration Trial Report Location in Phase (Country) Primary Trial Objectives N Duration of Treatment CTD Modules I TMC278-C109 Randomized, open label, Healthy Treatment A: single dose of paracetamol 500 mg, under fed Completed 2-way crossover, multiple volunteers conditions (Belgium) Full report dose, drug interaction trial 16 Treatment B: once daily dose of TMC278 150 mg plus a 5.3.3.4 Determine the effect of single dose of paracetamol 500 mg, under fed conditions steady-state (multiple dose) Tablets (TMC278 and paracetamol) – oral TMC278 concentrations on the pharmacokinetics of 1 day for Treatment A and 11 days for Treatment B paracetamol and the effect of (Days 1-11 for TMC278 plus paracetamol on Day 11), paracetamol on the separated by a washout period of 14 days steady-state pharmacokinetics of TMC278 N: number of enrolled subjects.
Study Report Location in Study Number Analytical Report Title CTD Modules Paracetamol/001 LC-UV Determination of Paracetamol, Paracetamol Glucuronide and Paracetamol Sulphate in Human Plasma Samples 5.3.3.4 Originating From Clinical Trial TMC278-C109 R278474/028 LC-MS/MS Determination of R278474 (TMC278) in Human Heparin Plasma Originating from Clinical Trial 5.3.3.4 TMC278-C109 LC-MS/MS: liquid chromatography-mass spectrometry/mass spectrometry; LC-UV: liquid chromatography-ultraviolet.
Approved, Issued Date: 18-Jun-2010 TMC278– Module 5.2 Tabular Listing of all Clinical Trials Tibotec – Confidential Information 28
5.3.3 Reports of Human Pharmacokinetic Studies, Cont’d 5.3.3.4 Extrinsic Factor Study Reports Status Dosage Regimen Type of Report Trial Trial Design Subjects Route of Administration Trial Report Location in Phase (Country) Primary Trial Objectives N Duration of Treatment CTD Modules I TMC278-C112 Randomized, open label, Healthy Treatment A: once daily dose of TMC278 150 mg, under fed Completed 2-way crossover, multiple volunteers conditions (Belgium) Full report dose, drug interaction trial 16 Treatment B: once daily dose of 5.3.3.4 Determine the effect of TMC114/ritonavir 800/100 mg plus once daily dose of steady-state (multiple dose) TMC278 150 mg, under fed conditions TMC278 concentrations on Tablets (TMC278 and TMC114) and capsules (ritonavir) – the pharmacokinetics of oral TMC114/ritonavir and the effect of steady-state 11 days for Treatment A and 22 days for Treatment B TMC114/ritonavir (Days 1-22 for TMC114/ritonavir plus TMC278 on concentrations on the Days 12-22), separated by a washout period of 14 days steady-state pharmacokinetics of TMC278 N: number of enrolled subjects.
Study Report Location in Study Number Analytical Report Title CTD Modules R278474/033 LC-MS/MS Determination of TMC278 (R278474) in Human Heparin Plasma Originating from Clinical Trial 5.3.3.4 TMC278-C112 LC-MS/MS Determination of TMC114 and ritonavir in Human Heparin Plasma Samples Originating From Clinical R319064/023 5.3.3.4 Trial TMC278-C112 LC-MS/MS: liquid chromatography-mass spectrometry/mass spectrometry.
Approved, Issued Date: 18-Jun-2010 TMC278– Module 5.2 Tabular Listing of all Clinical Trials Tibotec – Confidential Information 29
5.3.3 Reports of Human Pharmacokinetic Studies, Cont’d 5.3.3.4 Extrinsic Factor Study Reports Status Dosage Regimen Type of Report Trial Trial Design Subjects Route of Administration Trial Report Location in Phase (Country) Primary Trial Objectives N Duration of Treatment CTD Modules I TMC278-C114 Randomized, open label, Healthy Treatment A: once daily dose of TMC278 150 mg, under fed Completed 2-way crossover, multiple volunteers conditions (Belgium) Full report dose, drug interaction trial 16 Treatment B: once daily dose of omeprazole 20 mg plus once 5.3.3.4 Determine the effect of daily dose of TMC278 150 mg, under fed conditions single dose and steady-state Tablets (TMC278 and omeprazole) – oral (multiple dose) TMC278 concentrations on the 11 days for Treatment A and 22 days for Treatment B steady-state (Days 1-22 for omeprazole plus TMC278 on Days 12-22), pharmacokinetics of separated by a washout period of 14 days omeprazole and its metabolites 5-hydroxyomeprazole and omeprazole sulfone, and the effect of steady-state omeprazole concentrations on the single dose and steady-state pharmacokinetics of TMC278 N: number of enrolled subjects.
Study Report Location in Study Number Analytical Report Title CTD Modules ABL6191 The Determination of TMC278 in Human Plasma Samples, Using LC-MS/MS, Derived From Tibotec Clinical Trial 5.3.3.4 TMC278-C114 Omeprazole/002 LC-MS/MS Determination of Omeprazole, 5-hydroxyomeprazole, and Omeprazole Sulphone in Human Sodium 5.3.3.4 Heparin Plasma Originating from Clinical Trial TMC278-C114 LC-MS/MS: liquid chromatography-mass spectrometry/mass spectrometry.
Approved, Issued Date: 18-Jun-2010 TMC278– Module 5.2 Tabular Listing of all Clinical Trials Tibotec – Confidential Information 30
5.3.3 Reports of Human Pharmacokinetic Studies, Cont’d 5.3.3.4 Extrinsic Factor Study Reports Status Dosage Regimen Type of Report Trial Trial Design Subjects Route of Administration Trial Report Location in Phase (Country) Primary Trial Objectives N Duration of Treatment CTD Modules I TMC278-C116 Randomized, open label, Healthy Treatment A: once daily dose of atorvastatin 40 mg, under fed Completed 2-way crossover, multiple volunteers conditions (Germany) Full report dose, drug interaction trial 16 Treatment B: once daily dose of TMC278 150 mg plus once 5.3.3.4 Determine the effect of daily dose of atorvastatin 40 mg, under fed conditions steady-state (multiple dose) Tablets (TMC278 and atorvastatin) – oral TMC278 concentrations on the steady-state 4 days for Treatment A and 15 days for Treatment B pharmacokinetics of (Days 1-15 for TMC278 plus atorvastatin on Days 12-15), atorvastatin, atorvastatin separated by a washout period of 14 days lactone, and the active metabolites 2-hydroxyatorvastatin and 4-hydroxyatorvastatin, and the effect of steady-state atorvastatin concentrations on the steady-state pharmacokinetics of TMC278 N: number of enrolled subjects. Study Report Location in Study Number Analytical Report Title CTD Modules Atorvastatin/001 LC-MS/MS Determination of Atorvastatin, 2- and 4-hydroxyatorvastatin and Atorvastatin Lactone in Human Plasma 5.3.3.4 Samples Originating From Clinical Trial TMC278-C116 R278474/030 LC-MS/MS Determination of R278474 in Human Heparin Plasma Originating from Clinical Trial TMC278-C116 5.3.3.4 R278474/030-A-1 LC-MS/MS Determination of R278474 in Human Heparin Plasma (Amendment 1 to TMC278-C116-CPCD-BSS-PRD) 5.3.3.4 LC-MS/MS: liquid chromatography-mass spectrometry/mass spectrometry.
Approved, Issued Date: 18-Jun-2010 TMC278– Module 5.2 Tabular Listing of all Clinical Trials Tibotec – Confidential Information 31
5.3.3 Reports of Human Pharmacokinetic Studies, Cont’d 5.3.3.4 Extrinsic Factor Study Reports Status Dosage Regimen Type of Report Trial Trial Design Subjects Route of Administration Trial Report Location in Phase (Country) Primary Trial Objectives N Duration of Treatment CTD Modules I TMC278-C120 Open label, single-sequence, Healthy Treatment A: once daily doses of ethinylestradiol 35 ∀g and Completed multiple dose, drug female norethindrone 1.0 mg, under fed conditions (United Kingdom) Full report interaction trial volunteers Treatment B: once daily doses of ethinylestradiol 35 ∀g and 5.3.3.4 Determine the effect of 16 norethindrone 1.0 mg plus once daily dose of steady-state (multiple dose) TMC278 150 mg, under fed conditions TMC278 concentrations on the steady-state Tablets (TMC278 and ethinylestradiol plus norethindrone) – pharmacokinetics of oral ethinylestradiol, and on the 2 x 21 days: 21 days for Treatment A and 21 days for steady-state Treatment B (Days 1-21 for ethinylestradiol and pharmacokinetics of norethindrone plus TMC278 on Days 1-15), separated by a norethindrone 7-day pill-free period N: number of enrolled subjects.
Study Report Location in Study Number Analytical Report Title CTD Modules ABL6146 The Determination of Ethinyl Estradiol in Human Plasma Samples, Derived From Tibotec Clinical Trial 5.3.3.4 TMC278-C120, Using LC-MS/MS ABL6147 The Determination of Norethindrone in Human Plasma Samples, Derived From Tibotec Clinical Trial TMC278-C120, 5.3.3.4 Using GC-MS ABL6190 The Determination of TMC278 in Human Plasma Samples, Using LC-MS/MS, Derived From Tibotec Clinical Trial 5.3.3.4 TMC278-C120 GC-MS: gas chromatography-mass spectrometry; LC-MS/MS: liquid chromatography-mass spectrometry/mass spectrometry.
Approved, Issued Date: 18-Jun-2010 TMC278– Module 5.2 Tabular Listing of all Clinical Trials Tibotec – Confidential Information 32
5.3.3 Reports of Human Pharmacokinetic Studies, Cont’d 5.3.3.4 Extrinsic Factor Study Reports Status Dosage Regimen Type of Report Trial Trial Design Subjects Route of Administration Trial Report Location in Phase (Country) Primary Trial Objectives N Duration of Treatment CTD Modules I TMC278-TiDP6-C121 Open label, single-sequence, Healthy Once daily dose of TMC278 25 mg plus methadone Completed multiple dose, drug volunteers individualized maintenance therapy (once daily dose of 60 to (The Netherlands) Full report interaction trial 150 mg), under fed conditions 13 5.3.3.4 Determine the effect of Tablets (TMC278 and methadone) – oral steady-state (multiple dose) 26 days: TMC278 on Days 1-11 in addition to methadone TMC278 concentrations on individualized maintenance therapy on Days -14 to 12 the steady-state pharmacokinetics of R- and S-methadone N: number of enrolled subjects.
Study Report Location in Study Number Analytical Report Title CTD Modules TMC278/051 LC-MS/MS Determination of TMC278 in Human Heparin Plasma Originating from Clinical Trial TMC278-TiDP6- 5.3.3.4 C121 LC-MS/MS Determination of (R)-methadone and (S)-methadone in Human EDTA Plasma Originating From Clinical Methadone/001 5.3.3.4 Trial TMC278-TiDP6-C121 EDTA: ethylene diamine tetra acetate; LC-MS/MS: liquid chromatography-mass spectrometry/mass spectrometry.
Approved, Issued Date: 18-Jun-2010 TMC278– Module 5.2 Tabular Listing of all Clinical Trials Tibotec – Confidential Information 33
5.3.3 Reports of Human Pharmacokinetic Studies, Cont’d 5.3.3.4 Extrinsic Factor Study Reports Status Dosage Regimen Type of Report Trial Trial Design Subjects Route of Administration Trial Report Location in Phase (Country) Primary Trial Objectives N Duration of Treatment CTD Modules I TMC278-TiDP6-C123 Randomized, open label, Healthy male Treatment A: single dose of sildenafil 50 mg, under fed Completed 2-way crossover, multiple volunteers conditions (USA) Full report dose, drug interaction trial 16 Treatment B: once daily dose of TMC278 75 mg plus a single 5.3.3.4 Determine the effect of dose of sildenafil 50 mg, under fed conditions steady-state (multiple dose) Tablets (TMC278 and sildenafil) – oral TMC278 concentrations on the single dose 1 day for Treatment A and 12 days for Treatment B pharmacokinetics of (Days 1-12 for TMC278 plus sildenafil on Day 12), separated sildenafil and its active by a washout period of 14 days metabolite N-desmethyl sildenafil and the effect of single dose sildenafil concentrations on the steady-state pharmacokinetics of TMC278 N: number of enrolled subjects.
Study Report Location in Study Number Analytical Report Title CTD Modules TMC278/043 LC-MS/MS Determination of TMC278 in Human Heparin Plasma Samples Originating From Clinical Trial 5.3.3.4 TMC278-TiDP-C123 Sildenafil/BA1074 LC/MS/MS Determination of Sildenafil and Desmethylsildenafil in Human Sodium Heparin Plasma Originating From 5.3.3.4 Clinical Trial TMC278-TiDP-C123 LC-MS/MS: liquid chromatography-mass spectrometry/mass spectrometry.
Approved, Issued Date: 18-Jun-2010 TMC278– Module 5.2 Tabular Listing of all Clinical Trials Tibotec – Confidential Information 34
5.3.3 Reports of Human Pharmacokinetic Studies, Cont’d 5.3.3.4 Extrinsic Factor Study Reports Status Dosage Regimen Type of Report Trial Trial Design Subjects Route of Administration Trial Report Location in Phase (Country) Primary Trial Objectives N Duration of Treatment CTD Modules I TMC278-C125 Randomized, open label, Healthy Treatment A: once daily dose of TMC278 150 mg, under fed Completed 3-way crossover, multiple volunteers conditions (Belgium) Full report dose, drug interaction trial 18 Treatment B: once daily dose of rifabutin 300 mg, under fed 5.3.3.4 Determine the effect of conditions steady-state (multiple dose) Treatment C: once daily doses of TMC278 150 mg plus TMC278 concentrations on rifabutin 300 mg, under fed conditions the steady-state pharmacokinetics of Tablets (TMC278) and capsules (rifabutin) – oral rifabutin and its active 3 x 11 days, separated by 2 washout periods of 14 days each metabolite 25-O-desacetyl- rifabutin and the effect of steady-state rifabutin concentrations on the steady-state pharmacokinetics of TMC278 N: number of enrolled subjects.
Study Report Location in Study Number Analytical Report Title CTD Modules ABL6235 The Determination of Rifabutin and 25-O-desacetyl Rifabutin in Human Plasma Samples, Derived From Tibotec 5.3.3.4 Clinical Trial TMC278-C125, Using LC-MS/MS R278474/031 LC-MS/MS Determination of TMC278 (R278474) in Human Heparin Plasma Originating From Clinical Trial 5.3.3.4 TMC278-C125 LC-MS/MS: liquid chromatography-mass spectrometry/mass spectrometry.
Approved, Issued Date: 18-Jun-2010 TMC278– Module 5.2 Tabular Listing of all Clinical Trials Tibotec – Confidential Information 35
5.3.3 Reports of Human Pharmacokinetic Studies, Cont’d 5.3.3.4 Extrinsic Factor Study Reports Status Dosage Regimen Type of Report Trial Trial Design Subjects Route of Administration Trial Report Location in Phase (Country) Primary Trial Objectives N Duration of Treatment CTD Modules I TMC278-C127 Randomized, open label, Healthy Treatment A: once daily dose of TMC278 150 mg, under fed Completed 2-way crossover, multiple volunteers conditions (France) Full report dose, drug interaction trial 16 Treatment B: once daily doses of ketoconazole 400 mg plus 5.3.3.4 Determine the effect of TMC278 150 mg, under fed conditions steady-state (multiple dose) Tablets (TMC278 and ketoconazole) – oral TMC278 concentrations on the steady-state 11 days for Treatment A and 22 days for Treatment B pharmacokinetics of (Days 1-22 for ketoconazole plus TMC278 on Days 12-22), ketoconazole and the effect separated by a washout period of 14 days of steady-state ketoconazole concentrations on the steady-state pharmacokinetics of TMC278 N: number of enrolled subjects.
Study Report Location in Study Number Analytical Report Title CTD Modules ABL6189 The Determination of TMC278 in Human Plasma Samples, Using LC-MS/MS Originating From Clinical Trial 5.3.3.4 TMC278-C127 R41400/014 LC-MS/MS Determination of Ketoconazole in Human Sodium Heparin Plasma Originating From Clinical Trial 5.3.3.4 TMC278-C127 LC-MS/MS: liquid chromatography-mass spectrometry/mass spectrometry.
Approved, Issued Date: 18-Jun-2010 TMC278– Module 5.2 Tabular Listing of all Clinical Trials Tibotec – Confidential Information 36
5.3.3 Reports of Human Pharmacokinetic Studies, Cont’d 5.3.3.4 Extrinsic Factor Study Reports Status Dosage Regimen Type of Report Trial Trial Design Subjects Route of Administration Trial Report Location in Phase (Country) Primary Trial Objectives N Duration of Treatment CTD Modules I TMC278-TiDP6-C136 Open label, single-sequence, Healthy Treatment A: once daily doses of ethinylestradiol 35 ∀g and Completed multiple dose, drug female norethindrone 1.0 mg, under fed conditions (United Kingdom) Full report interaction trial volunteers Treatment B: once daily doses of ethinylestradiol 35 ∀g and 5.3.3.4 Determine the effect of 18 norethindrone 1.0 mg plus once daily dose of TMC278 25 mg, steady-state (multiple dose) under fed conditions TMC278 concentrations on the steady-state Tablets (TMC278 and ethinylestradiol plus norethindrone) – pharmacokinetics of oral ethinylestradiol and on the 2 x 21 days: 21 days for Treatment A and 21 days for steady-state Treatment B (Days 29-49 for ethinylestradiol and pharmacokinetics of norethindrone plus TMC278 on Days 29-43), separated by a norethindrone 7-day pill-free period N: number of enrolled subjects.
Study Report Location in Study Number Analytical Report Title CTD Modules TMC278/047 LC-MS/MS Determination of TMC278 in Human Heparin Plasma Samples Originating From Clinical Trial 5.3.3.4 TMC278-TiDP6-C136 Ethinylestradiol/001 LC-MS/MS Determination of Ethinyl Estradiol and Norethindrone in Human Dipotassium EDTA Plasma Originating 5.3.3.4 From Clinical Trial TMC278-TiDP6-C136 EDTA: ethylene diamine tetra acetate; LC-MS/MS: liquid chromatography-mass spectrometry/mass spectrometry.
Approved, Issued Date: 18-Jun-2010 TMC278– Module 5.2 Tabular Listing of all Clinical Trials Tibotec – Confidential Information 37
5.3.3 Reports of Human Pharmacokinetic Studies, Cont’d 5.3.3.4 Extrinsic Factor Study Reports Status Dosage Regimen Type of Report Trial Trial Design Subjects Route of Administration Trial Report Location in Phase (Country) Primary Trial Objectives N Duration of Treatment CTD Modules I TMC278-C139 Open label, multiple dose, Healthy Main study: single dose of chlorzoxazone 500 mg on Days 1, Completed drug interaction trial volunteers 4 and 15 or 19 and once daily dose of TMC278 150 mg on (USA) Full report Days 4-15 or 19 under fed conditions Determine the effect of 25 (16 under 5.3.3.4 single dose and steady-state the main Sub-study: single dose of chlorzoxazone 500 mg on Days 1, 4, (multiple dose) TMC278 protocol and 9 and 19 and once daily dose of TMC278 150 mg on Days 4-19 concentrations on the under the under fed conditions pharmacokinetics of sub-study Tablets (TMC278) and caplets (chlorzoxazone) – oral chlorzoxazone and protocol) 6-hydroxy-chlorzoxazone 13 or 17 days, excluding washout (2 days), (due to extreme after a single dose of weather conditions [hurricane] some subjects received chlorzoxazone, and the 4 additional days of TMC278 dosing) effect of single dose chlorzoxazone concentrations on the steady-state pharmacokinetics of TMC278 N: number of enrolled subjects.
Study Report Location in Study Number Analytical Report Title CTD Modules ABL6201 The Determination of TMC278 in Human Plasma Samples, Derived From Tibotec Clinical Trial TMC278-C139, Using 5.3.3.4 LC-MS/MS R278474/BA689 LC-MS/MS Determination of Chlorzoxazone and 6-hydroxychlorzoxazone in Human Sodium Heparin Plasma 5.3.3.4 Originating From Clinical Trial TMC278-C139 LC-MS/MS: liquid chromatography-mass spectrometry/mass spectrometry.
Approved, Issued Date: 18-Jun-2010 TMC278– Module 5.2 Tabular Listing of all Clinical Trials Tibotec – Confidential Information 38
5.3.3 Reports of Human Pharmacokinetic Studies, Cont’d 5.3.3.4 Extrinsic Factor Study Reports Status Dosage Regimen Type of Report Trial Trial Design Subjects Route of Administration Trial Report Location in Phase (Country) Primary Trial Objectives N Duration of Treatment CTD Modules I TMC278-C140 Randomized, open label, Healthy Treatment A: single dose of TMC278 150 mg under fed Completed 4-way crossover, single volunteers conditions (France) Full report dose, drug interaction trial 24 Treatment B: single dose of famotidine 40 mg, under fasted 5.3.3.4 Determine the effect of conditions, and a single dose of TMC278 150 mg 2 hours later single dose famotidine under fed conditions concentrations on the single Treatment C: single dose of TMC278 150 mg and a single dose pharmacokinetics of dose famotidine 40 mg 4 hours later, under fed conditions TMC278 in 3 different dosing regimens and Treatment D: single dose of famotidine 40 mg and a single investigate the relationship dose of TMC278 150 mg 12 hours later, under fed conditions between intragastric pH and Tablets (TMC278 and famotidine) – oral the pharmacokinetics of TMC278 4 x 1 day, separated by 3 washout periods of 14 days each N: number of enrolled subjects.
Study Report Location in Study Number Analytical Report Title CTD Modules R278474/036 LC-MS/MS Determination of TMC278 (R278474) in Human Heparin Plasma Originating From Clinical Trial 5.3.3.4 TMC278-C140 ABL7045 The Determination of Famotidine in Human Plasma Samples, Derived From Tibotec Clinical Trial TMC278-C140, 5.3.3.4 Using LC-MS/MS LC-MS/MS: liquid chromatography-mass spectrometry/mass spectrometry.
Approved, Issued Date: 18-Jun-2010 TMC278– Module 5.2 Tabular Listing of all Clinical Trials Tibotec – Confidential Information 39
5.3.3 Reports of Human Pharmacokinetic Studies, Cont’d 5.3.3.4 Extrinsic Factor Study Reports Status Dosage Regimen Type of Report Trial Trial Design Subjects Route of Administration Trial Report Location in Phase (Country) Primary Trial Objectives N Duration of Treatment CTD Modules I TMC278-TiDP6-C154 Randomized, open label, Healthy Treatment A: single dose of TMC278 25 mg under fed Ongoing/Available 4Q2010 4-way crossover, multiple volunteers conditions (Germany) Full report dose, drug interaction trial 16 Treatment B: single dose of omeprazole 20 mg, under fasted 5.3.3.4 Determine the effect of conditions, on Days 1-7 plus a single dose of TMC278 25 mg steady-state (multiple dose) on Day 6, under fed conditions omeprazole concentrations Treatment C: single dose of omeprazole 20 mg, under fasted on the pharmacokinetics of conditions, on Days 1-6 plus a single dose of TMC278 25 mg a single dose of TMC278, on Day 6, under fed conditions for 2 different dosing regimens; compare the Treatment D: single dose of omeprazole 20 mg, under fasted TMC278 pharmacokinetics conditions, on Days 1-7 plus a single dose of TMC278 50 mg after a single dose in the on Day 6, under fed conditions presence of steady-state omeprazole to the TMC278 Tablets (TMC278 and omeprazole) – oral pharmacokinetics after a 1 day for Treatment A, 7 days for Treatments B and D, and single dose of TMC278 6 days for Treatment C, separated by 3 washout periods of alone; and explore the 14 days each. For Treatments B, C and D, the intake of relationship between omeprazole could start as early as the 10th day of the washout intragastric pH and the period for TMC278 pharmacokinetics of TMC278 N: number of enrolled subjects
Approved, Issued Date: 18-Jun-2010 TMC278– Module 5.2 Tabular Listing of all Clinical Trials Tibotec – Confidential Information 40
5.3.3 Reports of Human Pharmacokinetic Studies, Cont’d 5.3.3.4 Extrinsic Factor Study Reports Status Dosage Regimen Type of Report Trial Trial Design Subjects Route of Administration Trial Report Location in Phase (Country) Primary Trial Objectives N Duration of Treatment CTD Modules I TMC278-HIV1001 Open label, single arm trial Healthy Treatment A: single dose of TMC278 25 mg on Days 1-14, Ongoing/Available 4Q2010 volunteers under fed conditions (United States) Determine the Full report pharmacokinetics of 20 Treatment B: single dose of EFV 600 mg on Days 1-14, under 5.3.3.4 TMC278 following a fasted conditions 2-week period receiving Treatment C: single dose of TMC278 25 mg on Days 1-28, EFV under fed conditions Tablets (TMC278 and EFV) – oral 14 days for Treatments A and B, separated by a washout period of 14 days, and 28 days for Treatment C (no washout period between Treatments B and C) EFV: efavirenz; N: number of enrolled subjects.
Approved, Issued Date: 18-Jun-2010 TMC278– Module 5.2 Tabular Listing of all Clinical Trials Tibotec – Confidential Information 41
5.3.3 Reports of Human Pharmacokinetic Studies, Cont’d 5.3.3.5 Population Pharmacokinetics Study Reports Refer to 5.3.5.1/TMC278-C204: population PK reports (48 weeks and 96 weeks) of the Phase IIb trial TMC278-C204 Refer to 5.3.5.3/0016435: population PK report (48 weeks) of the combined Phase III trials TMC278-TiDP6-C209/TMC278-TiDP6-C215 PK: pharmacokinetic.
Approved, Issued Date: 18-Jun-2010 TMC278– Module 5.2 Tabular Listing of all Clinical Trials Tibotec – Confidential Information 42
5.3.4 Reports of Human Pharmacodynamic Studies 5.3.4.1 Healthy Subject Pharmacodynamics and Pharmacokinetic/Pharmacodynamics Study Reports Status Dosage Regimen Type of Report Trial Trial Design Subjects Route of Administration Trial Report Location in Phase (Country) Primary Trial Objectives N Duration of Treatment CTD Modules I TMC278-TiDP6-C131 Randomized, double-blind, Healthy Treatment A: once daily doses of TMC278 75 mg and Completed double-dummy, placebo- and volunteers TMC278 placebo and a single dose of moxifloxacin placebo, (Belgium) Full report active-controlled, 3-way under fed conditions 41 crossover, multiple dose trial 5.3.4.1 Treatment B: once daily dose of TMC278 300 mg and a Evaluate the effect of single dose of moxifloxacin placebo, under fed conditions TMC278, compared to Treatment C: once daily dose of TMC278 placebo and a placebo, after a single dose single dose of moxifloxacin 400 mg, under fed conditions and at steady-state on the QT/QTcF interval Tablets (TMC278) and capsules (moxifloxacin) – oral 3 x 12 days: 12 days for Treatments A, B, and C (TMC278 or TMC278 placebo on Days 1-11 plus moxifloxacin or moxifloxacin placebo on Day 12), separated by 2 washout periods of 21 days each N: number of enrolled subjects.
Study Report Location in Study Number Analytical Report Title CTD Modules Cortisol/002 LC-MS/MS Determination of Cortisol and 6β-hydroxycortisol in Human Urine Samples Originating From Clinical Trial 5.3.4.1 TMC278-TiDP6-C131 Moxifloxacin/004 LC-MS/MS Determination of Moxifloxacin in Human Plasma Samples Originating From Clinical Trial 5.3.4.1 TMC278-TiDP6-C131 R278474/040 LC-MS/MS Determination of TMC278 (R278474) in Human Heparin Plasma Samples Originating From Clinical Trial 5.3.4.1 TMC278-TiDP6-C131 LC-MS/MS: liquid chromatography-mass spectrometry/mass spectrometry.
Approved, Issued Date: 18-Jun-2010 TMC278– Module 5.2 Tabular Listing of all Clinical Trials Tibotec – Confidential Information 43
5.3.4 Reports of Human Pharmacodynamic Studies, Cont’d 5.3.4.1 Healthy Subject Pharmacodynamics and Pharmacokinetic/Pharmacodynamics Study Reports Status Dosage Regimen Type of Report Trial Trial Design Subjects Route of Administration Trial Report Location in Phase (Country) Primary Trial Objectives N Duration of Treatment CTD Modules I TMC278-TiDP6-C151 Randomized, double-blind, Healthy Treatment A: once daily dose of TMC278 25 mg and a Completed double-dummy, placebo- and volunteers single dose of moxifloxacin placebo, under fed conditions (Belgium) Full report active-controlled, parallel 36 Treatment B: once daily dose of TMC278 placebo and a group, multiple dose trial 5.3.4.1 single dose of moxifloxacin 400 mg, under fed conditions Evaluate the effect of Tablets (TMC278) and capsules (moxifloxacin) – oral TMC278 at steady-state, compared to baseline, on the 12 days (TMC278 or TMC278 placebo on Days 1-11 and QT/QTcF interval moxifloxacin or moxifloxacin placebo on Day 12) N: number of enrolled subjects.
Study Report Location in Study Number Analytical Report Title CTD Modules TMC278/045 LC-MS/MS Determination of TMC278 in Human Heparin Plasma Samples Originating From Clinical Trial 5.3.4.1 TMC278-TiDP6-C151 Moxifloxacin/006 LC-MS/MS Determination of Moxifloxacin in Human Plasma Samples Originating From Clinical Trial 5.3.4.1 TMC278-TiDP6-C151 LC-MS/MS: liquid chromatography-mass spectrometry/mass spectrometry.
Approved, Issued Date: 18-Jun-2010 TMC278– Module 5.2 Tabular Listing of all Clinical Trials Tibotec – Confidential Information 44
5.3.4 Reports of Human Pharmacodynamic Studies, Cont’d 5.3.4.1 Healthy Subject Pharmacodynamics and Pharmacokinetic/Pharmacodynamics Study Reports Status Dosage Regimen Type of Report Trial Trial Design Subjects Route of Administration Trial Report Location in Phase (Country) Primary Trial Objectives N Duration of Treatment CTD Modules I TMC278-TiDP6-C152 Randomized, double-blind, Healthy Treatment A: once daily dose of TMC278 25 mg plus a Completed double-dummy, placebo- and volunteers single dose of moxifloxacin placebo, under fed conditions (USA) Full report active-controlled, crossover, 120 Treatment B: once daily dose of TMC278 placebo plus a multiple dose trial 5.3.4.1 single dose of moxifloxacin placebo, under fed conditions Evaluate the effect of Treatment C: once daily dose of TMC278 placebo plus a TMC278 at steady-state and single dose of 400 mg moxifloxacin, under fed conditions the effect of EFV at steady-state on the QT/QTcF Treatment D: once daily dose of EFV 600 mg, under fasted interval, in 2 randomized conditions panels Treatment E: once daily dose of EFV placebo, under fasted conditions TMC278 panel: Treatments A, B, and C EFV panel: Treatments D and E Tablets (TMC278 and EFV) and capsules (moxifloxacin) – oral For the TMC278 panel: 3 x 11 days (TMC278 or TMC278 placebo on Days 1-11 plus moxifloxacin or moxifloxacin placebo on Day 11), separated by 2 washout periods of 21 days each For the EFV panel: 2 x 11 days (EFV or EFV placebo on Days 1-11), separated by a washout period of 53 days I Refer to 5.3.5.3/0015283: PK/PD report pooled TQT Trials (TMC278-TiDP6-C131/C152)
EFV: efavirenz; N: number of enrolled subjects; PD: pharmacodynamic; PK: pharmacokinetic; TQT: thorough QT. Continued
Approved, Issued Date: 18-Jun-2010 TMC278– Module 5.2 Tabular Listing of all Clinical Trials Tibotec – Confidential Information 45
5.3.4 Reports of Human Pharmacodynamic Studies, Cont’d 5.3.4.1 Healthy Subject Pharmacodynamics and Pharmacokinetic/Pharmacodynamics Study Reports Study Report Location in Study Number Analytical Report Title CTD Modules TMC278/048 LC-MS/MS Determination of TMC278 in Human Heparin Plasma Samples Originating From Clinical Trial 5.3.4.1 TMC278-TiDP6-C152 Moxifloxacin/008 LC-MS/MS Determination of Moxifloxacin in Human Sodium Heparin Plasma Samples Originating From Clinical Trial 5.3.4.1 TMC278-TiDP6-C152 Efavirenz/001 HPLC Determination of Efavirenz in Human Sodium Heparin Plasma Samples Originating From Clinical Trial 5.3.4.1 TMC278-TiDP6-C152 HPLC: high performance liquid chromatography; LC-MS/MS: liquid chromatography-mass spectrometry/mass spectrometry.
5.3.4 Reports of Human Pharmacodynamic Studies, Cont’d 5.3.4.2 Patient Pharmacodynamics and Pharmacokinetic/Pharmacodynamics Study Reports Refer to 5.3.5.3/0016436: PK/PD report of the combined Phase III trials (TMC278-TiDP6-C209/C215) PD: pharmacodynamic; PK: pharmacokinetic.
Approved, Issued Date: 18-Jun-2010 TMC278– Module 5.2 Tabular Listing of all Clinical Trials Tibotec – Confidential Information 46
5.3.5 Reports of Efficacy and Safety Studies, Cont’d 5.3.5.1 Study Reports of Controlled Clinical Studies Pertinent to the Claimed Indication Status Dosage Regimen Type of Report Trial Trial Design Subjects Route of Administration Trial Report Location in Phase (Country) Primary Trial Objectives N Duration of Treatment CTD Modules IIa R278474-C201 Randomized, double-blind, HIV-infected, Panel 1: once daily dose of TMC278 25 mg or matching Completed placebo-controlled, treatment naïve placebo, under fed conditions (United Kingdom, Full report dose-escalation, male subjects Germany, Russia) Panel 2: once daily dose of TMC278 50 mg or matching proof-of-principle, multiple (with 5.3.5.1 placebo, under fed conditions dose trial documented absence of Panel 3: once daily dose of TMC278 100 mg or matching Evaluate the change from resistance) placebo, under fed conditions baseline in plasma viral load during treatment with 47 Panel 4: once daily dose of TMC278 150 mg or matching multiple dose (once daily) placebo, under fed conditions TMC278 as functional monotherapy Solution – oral 7 days HIV: human immunodeficiency virus; N: number of enrolled subjects.
Study Report Location in Study Number Analytical Report Title CTD Modules R278474/016 LC-MS/MS Determination of R278474 in Human Heparin Plasma Originating From Clinical Trial R278474-C201 5.3.5.1 LC-MS/MS: liquid chromatography-mass spectrometry/mass spectrometry.
Approved, Issued Date: 18-Jun-2010 TMC278– Module 5.2 Tabular Listing of all Clinical Trials Tibotec – Confidential Information 47
5.3.5 Reports of Efficacy and Safety Studies, Cont’d 5.3.5.1 Study Reports of Controlled Clinical Studies Pertinent to the Claimed Indication Status Dosage Regimen Type of Report Trial Trial Design Subjects Route of Administration Trial Report Location in Phase (Country) Primary Trial Objectives N Duration of Treatment CTD Modules IIb TMC278-C204 Randomized, partially HIV-infected, Once daily dose of TMC278 25, 75, or 150 mg, under fed Ongoing/Available blinded, active-controlled, treatment naïve conditions, or once daily dose of EFV 600 mg, under fasted 4Q2010 (Argentina, Austria, dose finding, multiple dose subjects conditions, for 96 weeks (each plus 2 investigator selected Brazil, China, Germany, Week 48 Report Body trial. All subjects could N[t]RTIs: AZT/3TC or TDF/FTC) France, United Kingdom, 368 enter an optional open label 5.3.5.1 Mexico, Puerto Rico, Once daily dose of TMC278 75 mg, under fed conditions, or trial extension up to Russia, Thailand, once daily dose of EFV 600 mg, under fasted conditions, up Population 240 weeks. After Uganda, USA, South to approximately Week 144 (each plus 2 investigator Pharmacokinetic Week 48 240 weeks, subjects on Africa) selected N[t]RTIs: AZT/3TC or TDF/FTC) Report TMC278 will have the option to enter into another Once daily dose of TMC278 25 mg, under fed conditions, 5.3.5.1 open label trial extension from approximately Week 144 onwards (plus 2 investigator selected N[t]RTIs: AZT/3TC or TDF/FTC) Week 96 Full Report Evaluate the dose-response relationship of antiviral Tablets (TMC278 and EFV) – oral 5.3.5.1 efficacy (plasma viral load Population 240 weeks (+ optional extension) < 50 HIV-1 RNA Pharmacokinetic Week 96 copies/mL, according to Report TLOVR algorithm) at 48 weeks treatment with 5.3.5.1 multiple dose TMC278 Week 192 Statistical Analyses 5.3.5.1 Serious Adverse Event Week 192 Report 5.3.5.3 AZT: zidovudine; EFV: efavirenz; FTC: emtricitabine; HIV: human immunodeficiency virus; N: number of enrolled subjects; N[t]RTIs: nucleoside[tide] reverse transcriptase inhibitors; RNA: ribonucleic acid; 3TC: lamivudine; TDF: tenofovir disoproxil fumarate; TLOVR: time to loss of virologic response. Continued
Approved, Issued Date: 18-Jun-2010 TMC278– Module 5.2 Tabular Listing of all Clinical Trials Tibotec – Confidential Information 48
5.3.5 Reports of Efficacy and Safety Studies, Cont’d 5.3.5.1 Study Reports of Controlled Clinical Studies Pertinent to the Claimed Indication Study Report Location in Study Number Analytical Report Title CTD Modules ABL8058 The Determination of Zidovudine and Zidovudine-glucuronide in Human Plasma Samples, Derived From Tibotec 5.3.5.1 Clinical Trial TMC278-C204, Using LC-MS/MS TMC278/032 LC-MS/MS Determination of TMC278 in Human Heparin Plasma Samples Originating From Clinical Trial 5.3.5.1 TMC278-C204 LC-MS/MS: liquid chromatography-mass spectrometry/mass spectrometry.
Approved, Issued Date: 18-Jun-2010 TMC278– Module 5.2 Tabular Listing of all Clinical Trials Tibotec – Confidential Information 49
5.3.5 Reports of Efficacy and Safety Studies, Cont’d 5.3.5.1 Study Reports of Controlled Clinical Studies Pertinent to the Claimed Indication Status Dosage Regimen Type of Report Trial Trial Design Subjects Route of Administration Trial Report Location in Phase (Country) Primary Trial Objectives N Duration of Treatment CTD Modules III TMC278-TiDP6-C209 Randomized, double-blind, HIV-infected, Once daily dose of TMC278 25 mg, under fed conditions, Ongoing/Available double-dummy, treatment naïve and once daily dose of EFV placebo, under fasted 3Q2010 (Argentina, Australia, active-controlled, multiple subjects conditions, (each plus TDF/FTC as background regimen), Austria, Brazil, Canada, Week 48 Full Report dose trial or Denmark, France, Italy, 694 Once daily dose of EFV 600 mg, under fasted conditions, 5.3.5.1 Mexico, Portugal, Puerto Demonstrate non-inferiority and once daily dose of TMC278 placebo, under fed Rico, Romania, Russia, of treatment with multiple Reports of SAEs conditions, (each plus TDF/FTC as background regimen) South Africa, Spain, dose TMC278 compared to 5.3.5.3 Sweden, Taiwan, control (EFV) in regard to Tablets (TMC278 and EFV) – oral Thailand, The the proportion of virologic 96 weeks Netherlands, United responders (plasma viral Kingdom, USA) load < 50 HIV-1 RNA copies/mL, according to TLOVR algorithm) at 48 weeks, with a maximum allowable difference of 12% A DEXA sub-study is currently ongoing, Week 96 results will be reported in a separate report. EFV: efavirenz; FTC: emtricitabine; HIV: human immunodeficiency virus; N: number of enrolled subjects; RNA: ribonucleic acid; TDF: tenofovir disoproxil fumarate; TLOVR: time to loss of virologic response.
Study Report Location in Study Number Analytical Report Title CTD Modules LC-MS/MS Determination of TMC278 in Human Heparin Plasma Samples Originating From Clinical Trial TMC278/054 (interim) 5.3.5.1 TMC278-TiDP6-C209 LC-MS/MS: liquid chromatography-mass spectrometry/mass spectrometry.
Approved, Issued Date: 18-Jun-2010 TMC278– Module 5.2 Tabular Listing of all Clinical Trials Tibotec – Confidential Information 50
5.3.5 Reports of Efficacy and Safety Studies, Cont’d 5.3.5.1 Study Reports of Controlled Clinical Studies Pertinent to the Claimed Indication Status Dosage Regimen Type of Report Trial Trial Design Subjects Route of Administration Trial Report Location in Phase (Country) Primary Trial Objectives N Duration of Treatment CTD Modules III TMC278-TiDP6-C215 Randomized, double-blind, HIV-infected, Once daily dose of TMC278 25 mg, under fed conditions, Ongoing/Available double-dummy, treatment naïve and once daily dose of EFV placebo, under fasted 3Q2010 (Australia, Belgium, active-controlled, multiple subjects conditions, (each plus 2 investigator selected N[t]RTIs: Brazil, Canada, Chile, Week 48 Full Report dose trial ABC/3TC, AZT/3TC, or TDF/FTC), China, Costa Rica, 680 or 5.3.5.1 France, Germany, India, Demonstrate non-inferiority Once daily dose of EFV 600 mg, under fasted conditions, Italy, Mexico, Panama, of treatment with multiple Reports of SAEs and once daily dose of TMC278 placebo, under fed Portugal, Puerto Rico, dose TMC278 compared to conditions, (each plus 2 investigator selected N[t]RTIs: 5.3.5.3 Russia, South Africa, control (EFV) in regard to ABC/3TC, AZT/3TC, or TDF/FTC) Spain, Thailand, United the proportion of virologic Kingdom, USA) responders (plasma viral Tablets (TMC278 and EFV) – oral load < 50 HIV-1 RNA 96 weeks copies/mL, according to TLOVR algorithm) at 48 weeks, with a maximum allowable difference of 12% A DEXA sub-study is currently ongoing, Week 96 results will be reported in a separate report. ABC: abacavir; AZT: zidovudine; EFV: efavirenz; FTC: emtricitabine; HIV: human immunodeficiency virus; N: number of enrolled subjects; N[t]RTIs: nucleoside[tide] reverse transcriptase inhibitors; RNA: ribonucleic acid; 3TC: lamivudine; TDF: tenofovir disoproxil fumarate; TLOVR: time to loss of virologic response.
Study Report Location in Study Number Analytical Report Title CTD Modules LC-MS/MS Determination of TMC278 in Human Heparin Plasma Samples Originating From Clinical Trial TMC278/056 (interim) 5.3.5.1 TMC278-TiDP6-C215 LC-MS/MS: liquid chromatography-mass spectrometry/mass spectrometry.
Approved, Issued Date: 18-Jun-2010 TMC278– Module 5.2 Tabular Listing of all Clinical Trials Tibotec – Confidential Information 51
5.3.5 Reports of Efficacy and Safety Studies, Cont’d 5.3.5.2 Study Reports of Uncontrolled Clinical Studies Status Dosage Regimen Type of Report Trial Trial Design Subjects Route of Administration Trial Report Location in Phase (Country) Primary Trial Objectives N Duration of Treatment CTD Modules IIa R278474-C202 Randomized, open label, HIV-1 infected Once daily dose of TMC278 25 mg, 50 mg, or 150 mg in Completed proof-of-principle, multiple subjects with combination with background regimen (N[t]RTIs, plus (Austria, France, Full report dose trial NNRTI enfuvirtide, if applicable), under fed conditions Germany, United experience 5.3.5.2 Kingdom, Italy, Russia) Evaluate the change from Solution (TMC278) – oral and/or genotypic baseline in plasma viral load evidence of 7 days during treatment with NNRTI multiple dose (once daily) resistance TMC278 as functional associated monotherapy mutations 36 HIV: human immunodeficiency virus; N: number of enrolled subjects; NNRTI: non-nucleoside reverse transcriptase inhibitor; N[t]RTIs: nucleoside[tide] reverse transcriptase inhibitors.
Study Report Location in Study Number Analytical Report Title CTD Modules R278474/023 LC-MS/MS Determination of R278474 in Human Heparin Plasma Originating From Clinical Trial R278474-C202 5.3.5.2 LC-MS/MS: liquid chromatography-mass spectrometry/mass spectrometry.
Approved, Issued Date: 18-Jun-2010 TMC278– Module 5.2 Tabular Listing of all Clinical Trials Tibotec – Confidential Information 52
5.3.5 Reports of Efficacy and Safety Studies, Cont’d 5.3.5.2 Study Reports of Uncontrolled Clinical Studies Status Dosage Regimen Type of Report Trial Design Subjects Route of Administration Trial Report Location in Phase Trial Primary Trial Objectives N Duration of Treatment CTD Modules II TMC278-TiDP38-C213 Open label, single arm trial HIV-1 infected Once daily dose of TMC278 25 mg, under fed conditions, Planned/Available 2Q2013 treatment naïve plus 2 investigator selected N(t)RTIs: AZT/3TC or ABC/3TC Determine the effect of Full report adolescents steady-state (multiple dose) Tablets (TMC278) – oral (≥ 12 to 5.3.5.2 pharmacokinetics and < 18 years) 48 weeks short-term safety and efficacy of TMC278 in 35 adolescents II TMC278-TiDP38-C220a Trial will be conducted in HIV-1 infected Dosage regimen, route of administration, and duration of Planned/Available 2Q2017 children < 12 years treatment naïve treatment will depend on the conduct and outcome of the Full report children TMC278-TiDP38-C213 trial Design will depend on the (< 12 years) 5.3.5.2 conduct and outcome of the Oral TMC278-TiDP38-C213 trial a Protocol not available. ABC: abacavir; AZT: zidovudine; HIV: human immunodeficiency virus; N: number of enrolled subjects; N(t)RTIs: nucleoside(tide) reverse transcriptase inhibitors; 3TC: lamivudine.
Approved, Issued Date: 18-Jun-2010 TMC278– Module 5.2 Tabular Listing of all Clinical Trials Tibotec – Confidential Information 53
5.3.5 Reports of Efficacy and Safety Studies, Cont’d 5.3.5.3 Reports of Analyses of Data From More Than One Study Type of Report Trial Report Location in Trial Trial Title CTD Modules TMC278-C906 Statistical Analysis: Clinical Safety: Phase I Summary of Clinical Safety 2.7.4 Statistical Analyses 5.3.5.3 TMC278-C904 - Statistical Analysis: Clinical Safety: Phase III Summary of Clinical Safety - Statistical Analysis: Clinical Efficacy: Phase III 2.7.4 Summary of Clinical Efficacy 2.7.3 Statistical Analyses 5.3.5.3 TMC278-0015283 Pharmacokinetic/pharmacodynamic modeling and simulation of the effect of TMC278 on QTcF prolongation, Pharmacokinetic/ based on pooled data from clinical trials TMC278-TiDP6-C131 and TMC278-TiDP6-C152 in healthy volunteers Pharmacodynamic Report 5.3.5.3 TMC278-0016435 TMC278 Phase III population pharmacokinetic modeling (48 weeks), empirical Bayesian feedback and covariate Population Pharmacokinetic analysis Report 5.3.5.3 TMC278-0016436 Modeling (GAM) of the 48-week decrease in viral load and increase in CD4 count to explore the relationship Population Pharmacokinetic/ with TMC278 exposure and other prognostic factors for the Phase III trials of TMC278 Pharmacodynamic Report 5.3.5.3 TMC278-Ongoing-Trials TMC278-TiDP6-C154, TMC278-C204, TMC278-TiDP6-C209, TMC278-TiDP6-C215, TMC278-HIV1001 Reports of SAEs 5.3.5.3
Approved, Issued Date: 18-Jun-2010 TMC278– Module 5.2 Tabular Listing of all Clinical Trials Tibotec – Confidential Information 54
5.3.5 Reports of Efficacy and Safety Studies, Cont’d 5.3.5.4 Other Study Reports Status Type of Report Trial Trial Title Trial Report Location in CTD Modules TMC278-IV1-AVMR Mechanism of action and in-vitro antiviral activity of TMC278 against wild type and Completed NNRTI-resistant HIV Virology Report Raw Data 5.3.5.4 TMC278-IV2-AVMR Mechanism of action and in-vitro antiviral activity of TMC278 against wild type and Completed NNRTI-resistant HIV (Part 2) Virology Report Raw Data 5.3.5.4 TMC278-C204-W96- Exploratory analysis of genotypic and phenotypic changes observed in the Completed AVMR TMC278-C204 clinical trial virological failures (rebound and never suppressed) by Virology Report Week 96 (primary endpoint) 5.3.5.4 TMC278-C204-W192- Exploratory analysis of genotypic and phenotypic changes observed in the Completed AVMR TMC278-C204 clinical trial virological failures (rebound and never suppressed) on or Virology Report before Week 192 5.3.5.4 TMC278-C209-C215- Exploratory analyses of genotypic and phenotypic changes observed in the Completed C904-W48-AVMR TMC278-TiDP6-C209 and TMC278-TiDP6-C215 clinical trials virological failures Virology Report (rebound and never suppressed) by Week 48 5.3.5.4 HIV: human immunodeficiency virus; NNRTI: non-nucleoside reverse transcriptase inhibitor. Continued
Approved, Issued Date: 18-Jun-2010 TMC278– Module 5.2 Tabular Listing of all Clinical Trials Tibotec – Confidential Information 55
5.3.5 Reports of Efficacy and Safety Studies, Cont’d 5.3.5.4 Other Study Reports Status Type of Report Trial Trial Title Trial Report Location in CTD Modules TMC278-C904-LLV- Exploratory analyses of genotypic and phenotypic characteristics of HIV-1 recombinant Completed AVMR clinical isolates obtained from a subset of subjects from the TMC278-TiDP6-C209 and Virology Report TMC278-TiDP6-C215 clinical trials having persistent low level viremia or displaying viral load blips on or before Week 48, when viral load is determined using the Taqman 5.3.5.4 assay NPR-20060022-VRR-V5 List of Non-Nucleoside Reverse Transcriptase Inhibitor Resistance-Associated Completed Mutations Virology Report 5.3.5.4 NPR-20060022-VRR-V6 List of Non-Nucleoside Reverse Transcriptase Inhibitor Resistance-Associated Completed Mutations Virology Report 5.3.5.4 HIV: human immunodeficiency virus.
Approved, Issued Date: 18-Jun-2010 TMC278– Module 5.2 Tabular Listing of all Clinical Trials Tibotec – Confidential Information 56
5.3.6 Reports of Post-marketing Experience Status Type of Report Trial Trial Title Trial Report Location in CTD Modules Not applicable
Approved, Issued Date: 18-Jun-2010 TMC278– Module 5.2 Tabular Listing of all Clinical Trials Tibotec – Confidential Information 57
5.3.7 Case Report Forms and Individual Patient Listings Status Type of Report Trial Trial Title Trial Report Location in CTD Modules Individual CRFs on all subjects for whom narratives are provided will be included in the NDA, not in the MAA NDA: New Drug Application; MAA: Marketing Authorization Application.
Approved, Issued Date: 18-Jun-2010 ࠦࡦࡊ㈩ว㍤ 1.13 EU ᛚᓟߦᦝᣂߪᚑߐࠇߚ⹜㛎ႎ๔ᦠ╬
EU ᛚᓟߦᦝᣂߪᚑߐࠇߚ⹜㛎ႎ๔ᦠ߮ᣣᧄߢ↳⺧ߐࠇߡߥຠ ⋡㧔Atripla㧕ߦ㑐ߒߡ Module 5 ߦㅊടߒߚ⹜㛎ႎ๔ᦠߩ߹ߣ
JEDI_DEV00 \ 0900fde980417d91 1.18 2013-11-13 20:55
1
2 ࠦࡦࡊ㈩ว㍤
⹜㛎࠺ࠩ ஜᐽⵍ㛎 ࠗࡦ ⠪ ⹜㛎ߩㅴⴕ⁁ ⹜㛎ߩ⒳ ⹜㛎ႎ๔ᦠ ⵍ㛎⮎߮ኻᾖ⮎ ⹜㛎⇟ภ ⹜㛎ߩ⋡⊛ ߮ ⵍ㛎⠪ᢙ ߪ ᴫ 㘃 ᷝઃ႐ᚲ ᛩਈᣇᴺ ᛩਈ⚻〝 ኻᾖߩ⒳ ᖚ⠪ߩ⸻ ႎ๔ᦠߩ⒳㘃 㘃 ᢿฬ 1㧕 5.3.3.1.1 8 ⮎‛േᘒ TMC278IFD4005 ᣣᧄੱஜᐽᚑੱߦ TMC278 㕖⋤ᬌ㧘 ᮡḰ⊛ߥᦺ㘩៨ขᓟ 10 ಽએౝߦ TMC278 ஜᐽⵍ㛎 ቢੌ 1.13 EU ోᕈ 25 mg ࠍ㘩ᓟߦන࿁⚻ญᛩਈ න࿁⚻ญ 25 mg ࠍන࿁⚻ญᛩਈ ⠪ ᴦ㛎✚ႎ๔ 㧔╙ IV ߒߚߣ߈ߩⴊẏਛ TMC278 ᛩਈ⹜㛎 ᦠ ⋧㧕 ߩ⮎‛േᘒࠍᬌ⸛ߔࠆޕ ⹜㛎ߩ⇛㧦 ᷝ 1 ⮎‛േᘒ TMC278-TiDP6- 5.3.3.4.35 omeprazole 20 mg ࠍ 1 ᣣ 1 ࿁ 㕖⋤ᬌ㧘 ᛩਈᣇᴺ A㧦 17 ஜᐽⵍ㛎 ቢੌ 㧔╙ I ⋧㧕 C1541㧕 ᛩਈਛߦ TMC278 25 mg ߮ ࡦ࠳ࡓ TMC278 25 mg ࠍන࿁⚻ญᛩਈ ⠪ ᴦ㛎✚ႎ๔ 50 mg ࠍන࿁⚻ญᛩਈߒߚߣ ൻ㧘4 ᦼ ᛩਈᣇᴺ B㧦 ᦠ ߈ߩ TMC278 ߩ⮎‛േᘒࠍ ࠢࡠࠬࠝ omeprazole 20 mg ࠍ 1 ᣣ 1 ࿁ 7 ᣣ㑆ᦺ㘩ߩ 1 ᬌ⸛ߔࠆޕ ࡃ⹜ ᤨ㑆೨ߦᛩਈߒ㧘6 ᣣ⋡ߩᦺߦ omeprazole ᛩ ⹜㛎ߩ⇛㧦 㛎 ਈߩ 1.5 ᤨ㑆ᓟߦ TMC278 25 mg ࠍන࿁⚻ญ ᷝ 2 ᛩਈ ᛩਈᣇᴺ C㧦 omeprazole 20 mg ࠍ 1 ᣣ 1 ࿁ 6 ᣣ㑆ᄛ㑆ߩⓨ ⣻ᤨߦᛩਈߒ㧘6 ᣣ⋡ߩᦺ㧔omeprazole ᛩਈ ߩ 12 ᤨ㑆ᓟ㧕ߦ TMC278 25 mg ࠍන࿁⚻ญ ᛩਈ ᛩਈᣇᴺ D㧦 omeprazole 20 mg ࠍ 1 ᣣ 1 ࿁ 7 ᣣ㑆ᦺ㘩ߩ 1 ᤨ㑆೨ߦᛩਈߒ㧘6 ᣣ⋡ߩᦺߦ omeprazole ᛩ ਈߩ 1.5 ᤨ㑆ᓟߦ TMC278 50 mg ࠍන࿁⚻ญ
ᛩਈ ᛚᓟߦᦝᣂߐࠇߚ⹜㛎ႎ๔ᦠ╬
ߕࠇߩᛩਈᣇᴺߦ߅ߡ߽ TMC278 ߪᮡḰ ⊛ߥᦺ㘩ࠍ៨ขᓟߦᛩਈߒߚ
JEDI_DEV00 \ 0900fde980417d91 \ 1.18 \ 2013-11-13 20:55 JEDI_DEV00 \ 0900fde980417d91 \ 1.18 \ 2013-11-13 20:55
3 ࠦࡦࡊ㈩ว㍤ ⹜㛎࠺ࠩ ஜᐽⵍ㛎 ࠗࡦ ⠪ ⹜㛎ߩㅴⴕ⁁ ⹜㛎ߩ⒳ ⹜㛎ႎ๔ᦠ ⵍ㛎⮎߮ኻᾖ⮎ ⹜㛎⇟ภ ⹜㛎ߩ⋡⊛ ߮ ⵍ㛎⠪ᢙ ߪ ᴫ 㘃 ᷝઃ႐ᚲ ᛩਈᣇᴺ ᛩਈ⚻〝 ኻᾖߩ⒳ ᖚ⠪ߩ⸻ ႎ๔ᦠߩ⒳㘃 㘃 ᢿฬ ⮎‛േᘒ TMC278HIV10011㧕 5.3.3.4.36 ஜᐽᚑੱߦ Efavirenz (EFV) 㕖⋤ᬌ⹜ ᛩਈᣇᴺ A㧦 20 ஜᐽⵍ㛎 ቢੌ 㧔╙ I ⋧㧕 600 mg ࠍ 2 ㅳ㑆ᓳᛩਈߒ 㛎 TMC278 25 mg ࠍ 1 ᣣ 1 ࿁ 14 ᣣ㑆ᓳ⚻ญᛩ ⠪ ᴦ㛎✚ႎ๔
ߚᓟߦ TMC278 ࠍ 1 ᣣ 1 ࿁ ਈߔࠆ ᦠ 1.13 EU ᓳᛩਈߒߚߣ߈ߩ⮎‛േ ᛩਈᣇᴺ B㧦 ᘒࠍᬌ⸛ߔࠆ EFV 600 mg ࠍ 1 ᣣ 1 ࿁ 14 ᣣ㑆ᓳ⚻ญᛩਈ ⹜㛎ߩ⇛㧦 ߔࠆ ᷝ 3 ᛩਈᣇᴺ C㧦 TMC278 ࠍ 1 ᣣ 1 ࿁ 28 ᣣ㑆ᓳ⚻ญᛩਈߔ ࠆ
ᛩਈᣇᴺ A ߣ B ߩ㑆ߦߪ 14㨪21 ᣣ㑆ߩભ⮎ ᦼ㑆ࠍ⸳ቯߒߚޕᛩਈᣇᴺ B ߣ C ߩ㑆ߦߪ ભ⮎ᦼ㑆ࠍ⸳ቯߒߥ߆ߞߚޕ ലᕈ TMC278-C2041㧕 5.3.5.1.2-4 3 ↪㊂ߩ TMC278 ࠍ 48 ㅳ㑆 㕖⋤ᬌ㧘 96㨪144 ㅳ㧦 TMC278: HIV-1 ᗵ ቢੌ ోᕈ ᛩਈߒߚߣ߈ߩ᛫࠙ࠗ࡞ࠬ ታ⮎ኻᾖ TMC278 ⟲ߪ TMC278 75mg ࠍ 1 ᣣ 1 ࿁⚻ 279 ᨴ∝ᖚ⠪ 240 ㅳߩႎ๔ 㧔╙ IIb ᵴᕈߩ↪㊂-ᔕ㑐ଥࠍ⹏ଔ 㧔96 ㅳએ ญᛩਈ㧘ኻᾖ⮎⟲ߪ EFV 600 mg ࠍ 1 ᣣ 1 ࿁ ኻᾖ⮎: ᦠ ⋧㧕 ߔࠆޕ 㒠㧕 ⚻ญᛩਈ㧘ਔ⟲ߢᴦ㛎⽿છකᏧ߇ㆬᛯߒߚ 89 N(t)RTI ࠍ૬↪ ⹜㛎ߩ⇛㧦 144㨪240 ㅳ㧦 ᷝ 4 TMC278 ⟲ TMC278 25 mg ࠍ 1 ᣣ 1 ࿁⚻ญ ᛩਈ㧘ᴦ㛎⽿છකᏧ߇ㆬᛯߒߚ N(t)RTI ࠍ૬ ↪
ᛚᓟߦᦝᣂߐࠇߚ⹜㛎ႎ๔ᦠ╬
4 ࠦࡦࡊ㈩ว㍤ ⹜㛎࠺ࠩ ஜᐽⵍ㛎 ࠗࡦ ⠪ ⹜㛎ߩㅴⴕ⁁ ⹜㛎ߩ⒳ ⹜㛎ႎ๔ᦠ ⵍ㛎⮎߮ኻᾖ⮎ ⹜㛎⇟ภ ⹜㛎ߩ⋡⊛ ߮ ⵍ㛎⠪ᢙ ߪ ᴫ 㘃 ᷝઃ႐ᚲ ᛩਈᣇᴺ ᛩਈ⚻〝 ኻᾖߩ⒳ ᖚ⠪ߩ⸻ ႎ๔ᦠߩ⒳㘃 㘃 ᢿฬ ోᕈ TMC278-C2041㧕 5.3.5.1.2-5 ╙ 3 ᑧ㐳ᦼ㧔240 ㅳએ㒠㧕ߩ 㕖⋤ᬌ 240 ㅳએ㒠㧦 166 HIV-1 ᗵ ቢੌ 㧔╙ IIb ⋡⊛㧦 㧔240 ㅳ TMC278 25 mg ࠍ 1 ᣣ 1 ࿁⚻ญᛩਈ㧘ᴦ㛎 ᨴ∝ᖚ⠪ 240 ㅳએ㒠ߩ
⋧㧕 ᧄ⹜㛎ߩᖚ⠪ߢ㧘╙ 2 㕖⋤ᬌ એ㒠㧕 ⽿છකᏧ߇ㆬᛯߒߚ N(t)RTI ࠍ૬↪ ᚑ❣ߩㅊടႎ 1.13 EU ᑧ㐳ᦼߢ 240 ㅳߩ TMC278 ๔ᦠ ᛩਈࠍቢੌߒ㧘ᴦ≮ߩലᨐ ߇ᜬ⛯ߒߡ߅ࠅ㧘߆ߟ TMC278 ߇߹ߛᏒ⽼ߐࠇߡ ߥߚ⊛ߪ᳃㑆ߩක ≮ᐲߦࠃࠆ㒾⸻≮ߩኻ ⽎ߣߥࠄߥ߆㧘ࠆߪ ߩᣇᴺ㧔ࠕࠢࠬࡊࡠࠣ ࡓ㧘ᐭߦࠃࠆࡊࡠࠣ ࡓ╬㧕ߢ߽ TMC278 ߇↪ ߢ߈ߥၞߦዬߒߡ ࠆᖚ⠪㧘ࠆߪ TMC278- TiDP6-C222 ⹜㛎߳ߩෳട߇ ࿎㔍ߥᖚ⠪ߦߟߡ㧘 TMC278 ߦࠃࠆᴦ≮ߩ⛮⛯ࠍ น⢻ߣߔࠆޕ
ലᕈ TMC278-TiDP6- 5.3.5.1.3-2 ᛫࠻ࡠ࠙ࠗ࡞ࠬ⮎ߦࠃࠆ ੑ㊀⋤ TMC278 ⟲ߪ TMC278 25 mg 1 ᣣ 1 ࿁⚻ญᛩ TMC278: HIV-1 ᗵ ቢੌ 1 ోᕈ C209 㧕 ᴦ≮⚻㛎ߩߥᚑੱ HIV-1 ᬌ㧘ࡦ ਈ㧘ኻᾖ⟲ߪ EFV 600 mg 1 ᣣ 1 ࿁⚻ญᛩ 346 ᨴ∝ᖚ⠪ 96 ㅳߩႎ๔ᦠ 㧔╙ III ᗵᨴ∝ⵍ㛎⠪ߦ߅ߌࠆ 48 ㅳ ࠳ࡓൻ㧘 ਈ㧘ਔ⟲ߢ TDF/FTC ࠍ૬↪ ኻᾖ⮎: ⋧㧕 ⋡ߩ࠙ࠗ࡞ࠬቇ⊛ലᨐ߇ᓧ ታ⮎ኻᾖ 344 ⹜㛎ߩ⇛㧦 ࠄࠇߚⵍ㛎⠪ߩഀวࠍᜰᮡ ᷝ 5 ᛚᓟߦᦝᣂߐࠇߚ⹜㛎ႎ๔ᦠ╬ ߣߒߡ㧘TMC278 25 mg 1 ᣣ 1 ࿁ᛩਈߩኻᾖ㧔EFV 600 mg 1 ᣣ 1 ࿁㧕ߦኻߔࠆ㕖ഠᕈࠍ 12%ߩ㕖ഠᕈ㒢⇇ߢⵣઃߌ ࠆޕ ലᕈ TMC278-TiDP6- 5.3.5.1.3-3 96 ㅳએ㒠ߩ⋡⊛㧦 㕖⋤ᬌ TMC278 ⟲ߪ TMC278 25 mg 1 ᣣ 1 ࿁⚻ญᛩ TMC278: HIV-1 ᗵ ቢੌ 1 ోᕈ C209 㧕 TMC278 ᛩਈࠍ 96 ㅳએ㒠߽ 㧔96 ㅳ ਈ㧘ኻᾖ⟲ߪ EFV 600 mg 1 ᣣ 1 ࿁⚻ญᛩ 268 ᨴ∝ᖚ⠪ 96 ㅳએ㒠ߩᚑ 㧔╙ III ⛮⛯ߒߚⵍ㛎⠪ߩലᕈ database ਈ㧘ਔ⟲ߢ TDF/FTC ࠍ૬↪ ኻᾖ⮎: ❣ߩㅊടႎ๔ ⋧㧕 ߮ోᕈࠍ⹏ଔߔࠆޕ lock એ 270 ᦠ 㒠㧕㧘 ࡦ࠳ࡓ ൻ㧘ታ⮎ ኻᾖ
JEDI_DEV00 \ 0900fde980417d91 \ 1.18 \ 2013-11-13 20:55 JEDI_DEV00 \ 0900fde980417d91 \ 1.18 \ 2013-11-13 20:55
5 ࠦࡦࡊ㈩ว㍤ ⹜㛎࠺ࠩ ஜᐽⵍ㛎 ࠗࡦ ⠪ ⹜㛎ߩㅴⴕ⁁ ⹜㛎ߩ⒳ ⹜㛎ႎ๔ᦠ ⵍ㛎⮎߮ኻᾖ⮎ ⹜㛎⇟ภ ⹜㛎ߩ⋡⊛ ߮ ⵍ㛎⠪ᢙ ߪ ᴫ 㘃 ᷝઃ႐ᚲ ᛩਈᣇᴺ ᛩਈ⚻〝 ኻᾖߩ⒳ ᖚ⠪ߩ⸻ ႎ๔ᦠߩ⒳㘃 㘃 ᢿฬ ലᕈ TMC278-TiDP6- 5.3.5.1.4-2 ᛫࠻ࡠ࠙ࠗ࡞ࠬ⮎ߦࠃࠆ ੑ㊀⋤ TMC278 ⟲ߪ TMC278 25 mg 1 ᣣ 1 ࿁⚻ญᛩ TMC278: HIV-1 ᗵ ቢੌ 1 ోᕈ C215 㧕 ᴦ≮⚻㛎ߩߥᚑੱ HIV-1 ᬌ㧘ࡦ ਈ㧘ኻᾖ⟲ߪ EFV 600 mg 1 ᣣ 1 ࿁⚻ญᛩ 340 ᨴ∝ᖚ⠪ 96 ㅳߩႎ๔ᦠ
㧔╙ III ᗵᨴ∝ⵍ㛎⠪ߦ߅ߌࠆ 48 ㅳ ࠳ࡓൻ㧘 ਈ㧘ਔ⟲ߢᴦ㛎⽿છකᏧ߇ㆬᛯߒߚ N(t)RTI ኻᾖ⮎: 1.13 EU ⋧㧕 ⋡ߩ࠙ࠗ࡞ࠬቇ⊛ലᨐ߇ᓧ ታ⮎ኻᾖ ࠍ૬↪ 338 ⹜㛎ߩ⇛㧦 ࠄࠇߚⵍ㛎⠪ߩഀวࠍᜰᮡ ᷝ 6 ߣߒߡ㧘TMC278 25 mg 1 ᣣ 1 ࿁ᛩਈߩኻᾖ㧔EFV 600 mg 1 ᣣ 1 ࿁㧕ߦኻߔࠆ㕖ഠᕈࠍ 12%ߩ㕖ഠᕈ㒢⇇ߢⵣઃߌ ࠆޕ
ലᕈ TMC278-TiDP6- 5.3.5.1.4-3 96 ㅳએ㒠ߩ⋡⊛㧦 㕖⋤ᬌ TMC278 ⟲ߪ TMC278 25 mg 1 ᣣ 1 ࿁⚻ญᛩ TMC278: HIV-1 ᗵ ቢੌ 1 ోᕈ C215 㧕 TMC278 ᛩਈࠍ 96 ㅳએ㒠߽ 㧔96 ㅳ ਈ㧘ኻᾖ⟲ߪ EFV 600 mg 1 ᣣ 1 ࿁⚻ญᛩ 274 ᨴ∝ᖚ⠪ 96 ㅳએ㒠ߩᚑ 㧔╙ III ⛮⛯ߒߚⵍ㛎⠪ߩലᕈ database ਈ㧘ਔ⟲ߢᴦ㛎⽿છකᏧ߇ㆬᛯߒߚ N(t)RTI ኻᾖ⮎: ❣ߩㅊടႎ๔ ⋧㧕 ߮ోᕈࠍ⹏ଔߔࠆޕ lock એ ࠍ૬↪ 263 ᦠ 㒠㧕㧘 ࡦ࠳ࡓ ൻ㧘ታ⮎ ኻᾖ ലᕈ GS-01-9342㧕 5.3.5.1.11-3 ᑧ㐳ᦼ㧔144㨪240 ㅳ㧕ߩ⋡ 㕖⋤ᬌ 144 ㅳએ㒠㧦 286 HIV-1 ᗵ ቢੌ ోᕈ ⊛㧦 EFV(600 mg)/ FTC (200 mg)/ TDF (300 mg)ࠍ 1 ᨴ∝ᖚ⠪ 168 ㅳߩ 㧔╙ III EFV/TDF/FTC ߩ 240 ㅳᛩਈ ᣣ 1 ࿁⚻ญᛩਈ Clinical ⋧㧕 ߦ߅ߌࠆ㐳ᦼᛩਈߩല Summary ᕈ㧘ోᕈ߮ᔋኈᕈࠍ⹏ ଔߒߚޕ ᛚᓟߦᦝᣂߐࠇߚ⹜㛎ႎ๔ᦠ╬ CBV1 ᣣ 2 ࿁߮ EFV1 ᣣ 1 ࿁ߩ૬↪ᛩਈ߆ࠄ㧘࿕ቯ↪ ㊂ߩ EFV/TDF/FTC ᛩਈ߳ߩ ಾࠅᦧ߃ߦ߅ߌࠆోᕈ㧘 ᔋኈᕈ㧘ലᕈ߮ࡌࡀࡈ ࠖ࠶࠻ࠍ⹏ଔߒߚޕ
6 ࠦࡦࡊ㈩ว㍤ ⹜㛎࠺ࠩ ஜᐽⵍ㛎 ࠗࡦ ⠪ ⹜㛎ߩㅴⴕ⁁ ⹜㛎ߩ⒳ ⹜㛎ႎ๔ᦠ ⵍ㛎⮎߮ኻᾖ⮎ ⹜㛎⇟ภ ⹜㛎ߩ⋡⊛ ߮ ⵍ㛎⠪ᢙ ߪ ᴫ 㘃 ᷝઃ႐ᚲ ᛩਈᣇᴺ ᛩਈ⚻〝 ኻᾖߩ⒳ ᖚ⠪ߩ⸻ ႎ๔ᦠߩ⒳㘃 㘃 ᢿฬ ലᕈ GS-01-9342㧕 5.3.5.1.11-4 ᑧ㐳ᦼ㨇144㨪240 ㅳ㧔৻ㇱ 㕖⋤ᬌ 144 ㅳએ㒠㧦 286 HIV-1 ᗵ ቢੌ ోᕈ ߩᣉ⸳ߢߪ 288 ㅳ߹ߢᑧ EFV(600 mg)/ FTC (200 mg)/ TDF (300 mg)ࠍ 1 ᨴ∝ᖚ⠪ 240 ㅳ㧔288
㧔╙ III 㐳㧕㨉ߩ⋡⊛㧦 ᣣ 1 ࿁⚻ญᛩਈ ㅳ㧕ߩႎ๔ᦠ 1.13 EU ⋧㧕 EFV/TDF/FTC ߩ 288 ㅳᛩਈ ߦ߅ߌࠆ㐳ᦼᛩਈߩല ᕈ㧘ోᕈ߮ᔋኈᕈࠍ⹏ ଔߒߚޕ CBV1 ᣣ 2 ࿁߮ EFV1 ᣣ 1 ࿁ߩ૬↪ᛩਈ߆ࠄ㧘࿕ቯ↪ ㊂ߩ EFV/TDF/FTC ᛩਈ߳ߩ ಾࠅᦧ߃ߦ߅ߌࠆోᕈ㧘 ᔋኈᕈ㧘ലᕈ߮ࡌࡀࡈ ࠖ࠶࠻ࠍ⹏ଔߒߚޕ
1㧕EU ᛚᓟߦᦝᣂߐࠇߚ⹜㛎ႎ๔ᦠ 2㧕ᣣᧄߢ↳⺧ߐࠇߡߥຠ⋡㧔Atripla㧕ߩ⹜㛎ႎ๔ᦠ ᛚᓟߦᦝᣂߐࠇߚ⹜㛎ႎ๔ᦠ╬
JEDI_DEV00 \ 0900fde980417d91 \ 1.18 \ 2013-11-13 20:55 R278474-C102 1
SYNOPSIS Trial Identification and Protocol Summary Company: Tibotec Pharmaceuticals Ltd. Drug Substance: R278474 Trade Name: Trial no.: R278474-C102 Indication: HIV-1 infection Clinical Phase: I Title: A Phase I, open-label, randomized, three-way cross-over trial in two panels of 12 subjects each to establish the relative oral bioavailability of two experimental solid formulations of R278474 versus the current oral solution formulation of R278474 and the effect of food on the bioavailability of these formulations. Investigator: Country: Belgium
Belgium Trial Period: Start: - -20 No. of Investigators: 1 End: - -20 No. of Subjects: 24 Objectives: The objectives of this Phase I trial were: to establish the relative oral bioavailability of R278474 administered as 2 experimental solid formulations relative to the oral solution under fed conditions; to evaluate the effect of food on the bioavailability of R278474 administered as 2 experimental solid formulations; to monitor the safety and tolerability of single doses of R278474 in healthy subjects. Design: This was a Phase I, open-label, randomized, three-way crossover trial in 2 panels of 12 healthy subjects to investigate the bioavailability of 2 experimental solid formulations of R278474 (Treatments B and C), relative to a reference oral solution formulation (Treatment A). The effect of food on the bioavailability of Treatments B and C was also studied. Per panel, each subject received 3 single doses, each equivalent to 100 mg R278474 base. One panel of subjects took single doses of Treatment A after a standardized breakfast, Treatment B after a standardized breakfast, and Treatment B in the fasted state, in a randomized order, and the other panel of subjects received Treatment C instead of Treatment B. Safety and tolerability was assessed on an ongoing basis. There was at least a 2-week washout period between all doses. Blood samples were obtained for pharmacokinetic analysis predose and up to 216 hours after each dose. Subject Selection Inclusion Criteria 1. Aged between 18 and 55 years, extremes included. 2. Smoking no more than 10 cigarettes, or 2 cigars, or 2 pipes per day (or non-smoking) for at least 3 months prior to selection. 3. Normal weight as defined by a Quetelet Index (Body Mass Index: weight in kg divided by the square of height in meters) of 18 to 30 kg/m2, extremes included. 4. Informed consent form signed voluntarily before first trial-related activity. 5. Cortisol of at least 550 nmol/L (19.9 Pg/dL) at any time at screening (i.e., morning cortisol, 30 or 60 minutes after 250 Pg adrenocorticotropic hormone [ACTH] stimulation). 6. Able to comply with protocol requirements. 7. Healthy on the basis of a pre-trial physical examination, medical history, electrocardiogram (ECG), vital signs, and the results of blood biochemistry and hematology tests and a urinalysis carried out within 2 weeks before the first dose. Exclusion Criteria 1. A positive HIV test at trial screening. 2. Female, except if postmenopausal for more than 2 years, or posthysterectomy or post tubal ligation (without reversal operation). 3. History or suspicion of alcohol, barbiturate, amphetamine, or narcotic drug use that in the investigator’s opinion could compromise the subject’s safety or ability to comply with trial procedures. 4. Hepatitis A infection (confirmed by Hepatitis A antibody IgM), or Hepatitis B infection (confirmed by Hepatitis B surface antigen), or Hepatitis C infection (confirmed by Hepatitis C virus antibody) at trial screening.
Clinical Research Report Synopsis Version: 1.0 Date: 21-Jun-2005 R278474-C102 2
Exclusion Criteria, continued 5. A positive urine drug test at trial screening. Urine was tested for the presence of amphetamines, benzodiazepines, cocaine, cannabinoids, and opioids. 6. Currently active or underlying gastrointestinal, cardiovascular, neurologic, psychiatric, metabolic, renal, hepatic, respiratory, inflammatory, or infectious disease. 7. Any current or previous adrenal illness. 8. Currently significant diarrhea, gastric stasis, or constipation that in the investigator’s opinion could influence drug absorption or bioavailability. 9. Any history of significant skin disease such as but not limited to drug rash or eruptions, drug allergies, food allergy, dermatitis, eczema, psoriasis, or urticaria. 10. Previously demonstrated clinically significant allergy or hypersensitivity to any of the excipients of the investigational medication. 11. Use of concomitant medication, including over the counter products and dietary supplements, except for ibuprofen up to 3 days before the first dose of trial medication. All other medication had to be discontinued at least 14 days before the first dose of trial medication. 12. Participation in an investigational drug trial within 30 days prior to the first intake of trial medication. 13. Donation of blood in the 60 days preceding the first intake of trial medication. 14. Subjects with the following laboratory abnormalities at screening as defined by the enhanced toxicity grading severity list: serum creatinine grade 1 or greater; pancreatic amylase or lipase grade 1 or greater; hemoglobin toxicity grade 1 or greater; platelet count grade 1 or greater; absolute neutrophil count grade 1 or greater; aspartate aminotransferase (AST) or alanine aminotransferase (ALT) grade 1 or greater; total bilirubin grade 1 or greater; any other toxicity grade 2 or above, including proteinuria (spot urine) > 1+ and gross hematuria. 15. Having previously participated in a trial with R278474, TMC120, or TMC125. Treatment Treatment A Treatment B Treatment C Concentration 25 mg/mL R278474 in 50 mg R278474 per 100 mg R278474 equivalent 100% PEG400 capsule with beads (110 mg R314585; HCl salt (100 mg base) (R278474:HPMC = 1:3) of R278474) per tablet (50 mg base) 100 mg base equivalent
Dosage Form (TF No.) Solution (F002) Capsules (F003) Tablets (F002)
Usage 4 mL p.o. 2 capsules p.o. 1 tablet p.o. Batch Number 04C15/F002 04C17/F003 04C22/F002 Dose Regimen A single dose, equivalent to 100 mg R278474 base, on Day 1 of each of the 3 sessions with a washout period of at least 2 weeks between administrations. Treatment A after a standardized breakfast (n=24), Treatment B or Treatment C after a standardized breakfast (n=12), and Treatment B or Treatment C in the fasted state (n=12). Duration of Treatment 3 x 1 day Duration of Trial 39 days (excluding screening and follow-up) Disallowed Medication During the entire trial, subjects were not allowed to use any medication other than the trial medication. All medication, including herbal medication and dietary supplements, had to be discontinued at least 14 days before administration of trial medication, except for ibuprofen. Ibuprofen was allowed up to 3 days before administration of trial medication. After that, the clinical investigator could permit the use of ibuprofen (until 5 days after trial medication intake at no more than 1 x 400 mg per day). In case of cutaneous event/rash (grade 1) and/or an allergic reaction (grade 1 and 2), the use of cetirizine, topical corticosteroids, or antipruritic agents in the recommended dosing scheme was permitted. In case of nausea (grade 1 and 2), the use of antiemetics was permitted. In case of diarrhea (grade 1 and 2), the use of loperamide was allowed.
Clinical Research Report Synopsis Version: 1.0 Date: 21-Jun-2005 R278474-C102 3
Assessments Screeninga Session I, II, and III Follow-upk
Day 1 Day 31, 32, or 33 Day 2 Day 7 14 days days 14 Day –1 Days 3-6 Days
d Predose Postdose Days 8-10 Days
Drug screening X Alcohol breath test X X Pharmacokinetics Blood sample Xd Xe Xf Xg Xh Xi Safety Adverse eventsb X X X X X X X X Concomitant meds X X X X X X X X Hemat & biochemc X Xd Xj X X X Urinalysis X Xd X X X Morning cortisol & X X ACTH stim test ECG & vital signs X Xd Xj X X X Skin exam X Physical exam X X X meds = medication; Hemat & biochem = hematology & biochemistry; ACTH = adrenocorticotropic hormone; stim = stimulation; ECG = electrocardiogram; exam = examination. a At screening, subject’s demographics and characteristics, medical and surgical history, concomitant diseases, HIV, and Hepatitis A, B and C test; a serum pregnancy test was also performed if applicable. b Adverse events were monitored continuously from signing of the informed consent to final trial related visit. c Biochemistry samples were taken fasting for at least 10 hours with the exception of the 4-hour post-dose sample on Day 1. d Within 2 hours before R278474 intake and (if applicable) before breakfast. e Samples taken at 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours postdose. f Samples taken at 24 and 32 hours postdose. g Samples taken at 48 hours (Day 3), 72 hours (Day 4), 96 hours (Day 5), and 120 hours (Day 6) postdose. h Sample taken at 144 hours postdose. i Samples taken at 168 hours (Day 8) and 216 hours (Day 10) postdose. j At 4 hours postdose. k In case of dropout, for other reasons than withdrawal of consent, additional blood and urine samples for safety were taken, additional ECG and vital signs were recorded, and a physical examination was performed at the time of dropout or the following morning, 7 days after dropout, and 30, 31, or 32 days after dropout. Additional blood samples for pharmacokinetics were also taken at the time of dropout or the following morning. In case of dropout, a morning cortisol and ACTH stimulation test was performed 7 days after dropout (in fasted subjects). Statistical Methods Descriptive statistics, frequency tabulations, graphical presentations, linear mixed effects modeling, Wilcoxon matched-pairs signed-ranks test.
Clinical Research Report Synopsis Version: 1.0 Date: 21-Jun-2005 R278474-C102 4
Main Features of the Subject Sample and Summary of the Results Panel 1 Panel 2 Baseline Characteristics - Treatments A and B Treatments B and C Subject Disposition (F002 and F003) (F003 and F002) Number of Subjects Entered (Male/Female) 12/0 12/0 Age (yrs): median (range) 42.0 (25 - 55) 35.5 (25 - 53) Dropouts 0 0
Pharmacokinetics Panel 1 Least Square Means Parameter N Treatment A-fed Treatment B-fed ratio % (B/A) 90% CI
Cmax (ng/mL) 12 386 399 103.2 93.7 – 113.7
AUClast (ng.h/mL) 12 14876 13294 89.4 81.9 – 97.5 AUCf (ng.h/mL) 12 15489 13870 89.6 82.3 – 97.5 Panel 2 Least Square Means Parameter N Treatment A-fed Treatment C-fed ratio % (C/A) 90% CI
Cmax (ng/mL) 12 370 310 83.8 73.9 – 95.0
AUClast (ng.h/mL) 12 12188 10124 83.1 72.8 – 94.8 AUCf (ng.h/mL) 12 12633 10526 83.3 73.0 – 95.1 Panel 1 Least Square Means Parameter N Treatment B-fed Treatment B-fasted ratio % (fed/fasted) 90% CI
Cmax (ng/mL) 12 399 248 160.7 112.6 – 229.2
AUClast (ng.h/mL) 12 13294 8771 151.6 117.6 – 195.3 AUCf (ng.h/mL) 12 13870 9141 151.7 117.9 – 195.3 Panel 2 Least Square Means Parameter N Treatment C-fed Treatment C-fasted ratio % (fed/fasted) 90% CI
Cmax (ng/mL) 12 310 181 171.3 129.2 – 227.0
AUClast (ng.h/mL) 12 10124 6931 146.1 124.7 – 171.1 AUCf (ng.h/mL) 12 10526 7286 144.5 124.1 – 168.2 N = number of subjects per treatment group; CI = confidence interval; Cmax = maximum plasma concentration; AUClast = area under the plasma concentration-time curve from time of administration until the last measurable or measured time point; AUCf = area under the plasma concentration-time curve from time of administration until infinity.
Clinical Research Report Synopsis Version: 1.0 Date: 21-Jun-2005 R278474-C102 5
Safety, Panel 1 Panel 2 (n = number of Trt Trt Whole Trt Trt Whole subjects with Trt A WO B-fed WO B-fasted WO Triala Trt A WO C-fed WO C-fasted WO Triala data) N = 12 N = 12 N = 12 N = 12 N = 12 N = 12 N = 12 N = 12 N = 12 N = 12 N = 12 N = 12 N = 12 N = 12 Adverse Events (AEs) Most frequently reported AEs (reported in > 1 subject), n (%) Headache 1 (8.3) 1 (8.3) 3 (25.0) 0 2 (16.7) 2 (16.7) 5 (41.7) 0 0 0 0 1 (8.3) 1 (8.3) 3 (25.0) Hot flush 0 3 (25.0) 0 1 (8.3) 0 0 3 (25.0) 0 0 0 1 (8.3) 0 0 2 (16.7) Catheter site 0 0 0 0 0 0 1 (8.3) 0 2 (16.7) 0 1 (8.3) 0 0 3 (25.0) hemorrhage Arthralgia 0 0 0 0 0 0 0 0 0 0 1 (8.3) 0 1 (8.3) 2 (16.7) Pharyngola- 0 0 0 0 0 0 0 0 0 0 1 (8.3) 0 1 (8.3) 2 (16.7) ryngeal pain n (%) with 1 or 1 (8.3) 6 (50.0) 3 (25.0) 4 (33.3) 2 (16.7) 3 (25.0) 9 (75.0) 1 (8.3) 4 (33.3) 3 (25.0) 6 (50.0) 2 (16.7) 5 (41.7) 11 (91.7) more AEs n (%) of 0 0 0 0 0 0 0 0 0 0 0 0 0 0 deaths n (%) with 1 or 0 0 0 0 0 0 0 0 0 0 0 0 0 0 more other SAEs n (%) of 0 0 0 0 0 0 0 0 0 0 0 0 0 0 treatment stopped due to AEs n (%) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 with 1 or more grade 3 or 4 AEs a Includes events that occurred at Screening. Trt = Treatment; WO = Washout; N = number of subjects per treatment group; SAE = serious AE. Adverse events for each treatment include only those occurring on the day of trial medication intake.
Clinical Research Report Synopsis Version: 1.0 Date: 21-Jun-2005 R278474-C102 6
Panel 1 Panel 2 Trt Trt WO Trt A Trt B-fed B-fasted Trt A Trt C-fed C-fasted Safety, continued N = 12 N = 12 N = 12 N = 12 N = 12 N = 12 N = 24 Clinical Laboratory Tests n (%) with 1 or more grade 3 or 0 0 1 (8.3) 1 (8.3) 0 0 1 (8.3)a 4 treatment-emergent laboratory abnormalities a Panel 2, Day 7 of Session I (Treatment C-fed). Laboratory Tests There were no consistent or clinically relevant treatment-emergent changes over time in median laboratory parameters. Three grade 4 abnormalities of hyperkalemia were reported, 1 subject in Panel 1 and 2 subjects in Panel 2. All grade 4 hyperkalemia were due to hemolysed samples. No grade 3 abnormalities were reported. Eight subjects had treatment-emergent grade 2 postdose laboratory abnormalities, 4 per panel. In general, the incidence of laboratory abnormalities was similar for the 6 treatment sequences and no trends or relationship to treatment were apparent. No subjects developed a laboratory abnormality that resulted in an AE. Urinalysis indicated occasional abnormalities. For 1 subject, polyuria (possibly related) was reported as a grade 1 AE on the day after R278474 intake in 2 of the 3 sessions (Treatment C-fed and fasted). No abnormalities in urinalysis were observed for this subject. One subject in Panel 2 had abnormal cortisol levels following treatment with R278474 (cortisol 0.55 Pmol/L). However, the abnormal values observed during Sessions I, II, and III actually constituted a better ‘response’ to ACTH stimulation than that observed at screening, even though the screening values were considered normal. All other subjects had normal adrenal function at all time points measured (screening and at Day 7 of each of the 3 treatment sessions). Cardiovascular Safety Minor median changes were reported for vital signs and ECG parameters and only a few were statistically significant. No trends or relationship to treatment were evident and no clinically significant changes in vital signs or ECG were reported. Physical Examination Three subjects reported a new abnormality at the follow-up visit (1 case of a swollen left ankle and 2 cases of retromandibular adenopathies bilateral). No skin abnormalities were reported at the follow-up visit. Conclusions x The results of the present trial demonstrate that the newly developed solid formulations of R278474 (capsule and tablet) both provide significant exposure to R278474 which is slightly lower compared to the reference oral solution of R278474. When administered as the tested experimental solid formulations, R278474 should be administered with food to improve the relative oral bioavailability. x In these healthy subjects, the administration of R278474 as 3 single oral 100 mg doses, formulations F002 (Treatment A), F003 (Treatment B), and F002 (Treatment C), was considered to be generally safe and tolerable. No apparent differences in AE reporting were observed between the 3 R278474 formulations and no apparent differences in AE reporting were noticed between the administration of the solid formulations (Treatments B and C) under fed or fasted conditions. No clinical grade 3 or 4 AEs were observed and no AEs leading to discontinuation or SAEs were reported.
Clinical Research Report Synopsis Version: 1.0 Date: 21-Jun-2005 TMC278-TiDP6-C137 CONFIDENTIAL 3 Clinical Research Report
SYNOPSIS Trial Identification and Protocol Summary
Company: Tibotec Pharmaceuticals Ltd. Drug Substance: TMC278 Trade Name: - Trial no.: TMC278-TiDP6-C137 Indication: HIV-1 infection Clinical Phase: I Title: The effect of food on the bioavailability of TMC278 after a single oral dose of 75 mg, formulated as the Phase III tablet, in healthy subjects Investigator: Country: France France Trial Period: Start: - -20 No. of Investigators: 1 End: - -20 No. of Subjects: 20 Objectives: The primary objective of this study was to determine the effect of different types of meals on the bioavailability of TMC278 after a single oral dose of 75 mg, formulated as the Phase III tablet, in healthy subjects. The secondary objective was to determine the short-term safety and tolerability of TMC278 after single dose administration under fasted and fed conditions in healthy subjects. Design: This was a Phase I, open-label, randomized 4-way crossover trial in healthy subjects to investigate the effect of different types of meals on the bioavailability of TMC278 after a single oral dose of 75 mg, formulated as the Phase III tablet. Twenty subjects received 4 different treatments in 4 sessions, separated by a washout period of at least 13 days. Subjects received, in a randomized fashion, a single dose of 75 mg TMC278 after a standard breakfast (Treatment A), under fasting conditions (Treatment B), after a high-fat breakfast (Treatment C), and after a nutritional drink rich in proteins (Treatment D). In each session, full pharmacokinetic profiles of TMC278 were obtained up to 168 hours post dose. Safety and tolerability evaluations were recorded at regular intervals throughout the trial period. Subject Selection Inclusion Criteria 1. Aged between 18 and 55 years, extremes included. 2. Non-smoking or smoking no more than 10 cigarettes, or 2 cigars, or 2 pipes per day for at least 3 months prior to selection. 3. Normal weight as defined by a Quetelet Index (Body Mass Index: weight in kg divided by the square of height in meters) of 18.0 to 30.0 kg/m2, extremes included. 4. Informed Consent Form (ICF) signed voluntarily before first trial-related activity. 5. Able to comply with protocol requirements. 6. Healthy on the basis of a medical evaluation that confirms the absence of any clinically relevant abnormality and includes a physical examination, medical history, electrocardiogram (ECG), vital signs, and the results of blood biochemistry and hematology tests and a urinalysis carried out at screening.
Clinical Research Report Synopsis
0296617, Final, 08-Dec-2008 14:08 TMC278-TiDP6-C137 CONFIDENTIAL 3 Clinical Research Report
Exclusion Criteria 1. A positive human immunodeficiency virus (HIV)-1 or HIV-2 test at trial screening. 2. Female, except if postmenopausal for more than 2 years, or post-hysterectomy, or post-tubal ligation (without reversal operation). 3. History or evidence of current use of alcohol, barbiturate, amphetamine, recreational, or narcotic drug(s), which in the investigator’s opinion would compromise subject’s safety and/or compliance with the trial procedures. 4. Hepatitis A, B, or C infection (confirmed by hepatitis A IgM antibody, hepatitis B surface antigen, or hepatitis C antibody, respectively) at screening. 5. A positive urine drug test at screening. Urine was tested to check the current use of methadone, barbiturates, amphetamines, benzodiazepines, cocaine, cannabinoids, and opioids. 6. Currently active or underlying gastrointestinal, cardiovascular, neurologic, psychiatric, metabolic, renal, hepatic, respiratory, inflammatory, or infectious disease. 7. Current or history of adrenal disorder. 8. Currently significant diarrhea, gastric stasis, or constipation that in the investigator’s opinion could influence drug absorption or bioavailability. 9. Any history of significant skin disease such as, but not limited to, drug rash or eruptions, drug allergies, food allergy, dermatitis, eczema, psoriasis, or urticaria. 10. Previously demonstrated clinically significant allergy or hypersensitivity to any of the excipients of the medication administered in this trial (i.e., TMC278). 11. Use of concomitant medication, including over-the-counter products, herbal medications, and dietary supplements. 12. Having previously participated in more than 1 trial (single or multiple dose) with TMC125 and/or TMC120, or having developed a rash, erythema, or urticaria while participating in a trial with the aforementioned compounds. 13. Having participated in a trial with TMC278 (formerly known as R278474). 14. Participation in an interventional drug trial within 60 days prior to the first administration of trial medication. 15. Donation of blood or plasma within the 60 days preceding the first administration of trial medication. 16. Subjects with the following laboratory abnormalities at screening as defined by the Division of Acquired Immunodeficiency Syndrome (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events (AEs) (“DAIDS grading table”) and in accordance with the normal ranges of the clinical laboratory: serum creatinine grade 1 or greater ( 1.1 x upper limit of laboratory normal range [ULN]); serum lipase grade 1 or greater ( 1.1 x ULN); hemoglobin toxicity grade 1 or greater ( 10.9 g/dL); platelet count grade 1 or greater ( 124.999/mm3); absolute neutrophil count grade 1 or greater ( 1300/mm3); aspartate aminotransferase or alanine aminotransferase grade 1 or greater ( 1.25 x ULN); total bilirubin grade 1 or greater ( 1.1 x ULN); any other toxicity grade 2 or above, including: proteinuria (spot urine) 2+ and microscopic hematuria > 10 red blood cells/high power field.
Clinical Research Report Synopsis
0296617, Final, 08-Dec-2008 14:08 TMC278-TiDP6-C137 CONFIDENTIAL 3 Clinical Research Report
Treatment Treatment A Treatment B Treatment C Treatment D Dosage 75 mg TMC278 75 mg TMC278 75 mg TMC278 75 mg TMC278 single dose single dose single dose single dose Dosage Form (TF No.) 75 mg tablet (F008) 75 mg tablet (F008) 75 mg tablet (F008) 75 mg tablet (F008) Usage 1 x 75 mg TMC278 1 x 75 mg TMC278 1 x 75 mg TMC278 1 x 75 mg TMC278 tablet orally after a tablet orally under tablet orally after a tablet orally after a standard breakfast fasting conditions high-fat breakfast nutritional drink rich on Day 1 on Day 1 on Day 1 in proteins on Day 1 Batch Number PD2115 PD2115 PD2115 PD2115 Dose Regimen Group 1: 75 mg TMC278 single dose in treatment sequence ADBC in 4 separate sessions. Group 2: 75 mg TMC278 single dose in treatment sequence BACD in 4 separate sessions. Group 3: 75 mg TMC278 single dose in treatment sequence CBDA in 4 separate sessions. Group 4: 75 mg TMC278 single dose in treatment sequence DCAB in 4 separate sessions. In all groups, a washout period of t 13 days separated each session from the next. Duration of Treatment 4 days (1 day per session, excluding washout). Duration of Trial At least 43 days (excluding screening and follow-up). Disallowed Medication All over-the-counter medication had to be discontinued at least 7 days before the first intake of trial medication and all prescribed medication had to be discontinued at least 14 days before the first intake of trial medication, except for ibuprofen and paracetamol (acetaminophen). Subjects were not to use any medication other than the trial medication up to 14 days after the last intake of trial medication, except for ibuprofen and paracetamol. Subjects were also not to use any herbal medications or dietary supplements including products containing Hypericum perforatum (e.g., St. John’s wort) from 14 days before the first intake of trial medication and up to 14 days after the last intake of trial medication. Ibuprofen or paracetamol could be used up to 3 days before the first intake of trial medication. After that, the clinical investigator could permit the use of ibuprofen (at no more than 400 mg per day) or paracetamol (at no more than 2 x 500 mg per day). In the event of cutaneous reaction/rash and/or an allergic reaction, the use of cetirizine (Zyrtec), levocetirizine (Xyzal), topical corticosteroids, or antipruritic agents in the recommended dosing scheme was permitted. In case of nausea, the use of antiemetics was permitted. In case of diarrhea, the use of loperamide was allowed.
Clinical Research Report Synopsis
0296617, Final, 08-Dec-2008 14:08 TMC278-TiDP6-C137 CONFIDENTIAL 3 Clinical Research Report
Assessments a Treatments A, B, C and Db Screening Follow-up c d Day 3 Day 4 Day 6 Day 8 Day 1 Day 2 32 days 32 days 21 days days 21 after last after 30, 31, or 30, 31, or d 5, 6 or 7 & 7 & or 5, 6 drug intake intake drug Pharmacokinetics Blood samplee Xf Xg Xg Xg Xg Xg Safety AEs + concomitant medicationh X X X X X X X X Hematology & biochemistryi X Xj Xk Xk X Urinalysis X Xj Xk Xk X ECG X Xj X Vital Signsl X Xm X Skin examination X Xn Xn X Physical examination X Xn Xn X a At screening, subject’s demographics, medical and surgical history, smoking habits, and concomitant diseases were recorded and an HIV-1 and HIV-2 test, hepatitis A, B, and C test and urine drug screening were performed; a serum pregnancy test was also performed for females. b Treatments were separated by a washout period of at least 13 days. c Subjects were admitted to the unit in the afternoon before Day 1. d First day of washout period. e For determination of TMC278. f Taken immediately before the intake of TMC278 predose, and 0.5, 1, 2, 3, 4, 5, 6, 9, 12, and 16 hours post dose. g Taken 24 hours post dose (Day 2), 48 hours post dose (Day 3), 72 hours post dose (Day 4), 120 hours post dose (Day 6), and 168 hours post dose (Day 8). h AEs and concomitant medications were monitored continuously from signing the ICF until the last trial-related activity. i Biochemistry samples were taken fasted for at least 10 hours. j Taken predose within 2 hours before the intake of TMC278. k Performed 24 hours post dose (Day 2) and 168 hours post dose (Day 8). l Blood pressure and pulse. m Recorded predose within 2 hours before the intake of TMC278 and 4 hours post dose. n Performed at predose (Day 1) and 168 hours post dose (Day 8). Statistical Methods Descriptive statistics, frequency tabulations, intent-to-treat analysis for safety analyses; descriptive statistics, linear mixed effects modeling, nonparametric test (Koch) (for time to maximum plasma concentration [tmax]) for pharmacokinetic analysis.
Clinical Research Report Synopsis
0296617, Final, 08-Dec-2008 14:08 TMC278-TiDP6-C137 CONFIDENTIAL 3 Clinical Research Report
Main Features of the Subject Sample and Summary of the Results
Baseline Characteristics - Group 1 Group 2 Group 3 Group 4 Subject Disposition (ADBC) (BACD) (CBDA) (DCAB) All Subjects N = 5 N = 5 N = 5 N = 5 N = 20 Number of Subjects entered (M/F) 3/2 5/0 5/0 5/0 18/2 Age: median (range), yrs 38.0 (36-55) 31.0 (21-50) 31.0 (23-34) 35.0 (31-54) 34.5 (21-55) Drop-Outs - withdrawal of 0 1 (20.0%) 1 (20.0%) 0 2 (40.0%) consent
Pharmacokinetics Standard Protein-rich of TMC278 Fasting conditions High-fat breakfast breakfast nutritional drink (test 1) (test 2) (mean rSD, tmax: (reference) (test 3) median [range]) n 19 19 19a 18
tmax, h 5.0 (2.0 - 9.0) 4.0 (2.0 - 24.0) 5.0 (3.0 - 9.0) 5.0 (4.0 - 9.0)
Cmax, ng/mL 296.4 ± 117.6 170.2 ± 65.61 279.8 ± 102.6 156.0 ± 59.66
AUClast, ng.h/mL 10340 ± 3894 6230 ± 2339 9717 ± 3535 5437 ± 2421
AUCf, ng.h/mL 11450 ± 4431 7202 ± 3024 10670 ± 4331 6094 ± 3047
t1/2term, h 47.98 ± 22.08 54.84 ± 28.25 43.05 ± 17.28 47.29 ± 22.89 Least square mean ratio (90% CI), % Test 1 vs reference Test 2 vs reference Test 3 vs reference n - 19 vs 19 19a vs 19 18 vs 19
Cmax - 54.45 (42.92 - 69.07) 92.20 (80.97 - 105.0) 50.17 (39.66 - 63.46)
AUClast - 57.27 (45.72 - 71.75) 92.21 (79.81 - 106.5) 50.25 (41.36 - 61.05)
AUCf - 59.02 (46.87 - 74.32) 90.94 (78.52 - 105.3) 50.55 (41.50 - 61.56) AUC = area under the plasma concentration-time curve CI = confidence interval Cmax = maximum plasma concentration tmax = time to maximum plasma concentration t1/2term = terminal elimination half-life a n=18 for AUClast, AUCf and t1/2term
Clinical Research Report Synopsis
0296617, Final, 08-Dec-2008 14:08 TMC278-TiDP6-C137 CONFIDENTIAL 3 Clinical Research Report
Safety Treatment A Treatment B Treatment C Treatment D All Subjects (n = number of subjects with data) N = 19 N = 19 N = 19 N = 18 N = 20 AEs n (%) with 1 or more AEs 3 (15.8) 1 (5.3) 2 (10.5) 0 5 (25.0) Diarrhea 0 1 (5.3) 0 0 1 (5.0) Gastroenteritis 0 0 1 (5.3) 0 1 (5.0) Puncture site pain 1 (5.3) 0 0 0 1 (5.0) Rhinitis 1 (5.3) 0 0 0 1 (5.0) Headache 0 0 1 (5.3) 0 1 (5.0) Hot flush 1 (5.3) 0 0 0 1 (5.0) n (%) deaths, serious adverse events, AEs leading to withdrawal, or grade 3 or 4 AEs 0 0 0 0 0 There was no predominance of AEs during each treatment and none of the reported AEs were experienced by > 1 subject. The only system organ class to contain > 1 subject experiencing an event was infections and infestations (gastroenteritis and rhinitis). No skin events of interest were experienced. The AE of hot flush experienced during Treatment A was considered possibly related to TMC278; all other AEs were considered doubtful or not related to TMC278. Most AEs were grade 1 in severity, with a small number of grade 2 events also experienced. Clinical Laboratory Tests All subjects experienced at least one treatment-emergent graded abnormality, most of which were grade 1 or 2. One grade 4 laboratory abnormality was experienced during the trial; hyponatremia by 1 subject (5.3%) during Treatment C. A total of 15 grade 3 treatment-emergent laboratory abnormalities were reported by 8 subjects (40.0%) during the trial. The majority of treatment-emergent, graded laboratory abnormalities were reported for phosphorous (grade 2 and 3 [6 subjects reported grade 3 abnormalities across on at least 1 occasion during the trial]), total cholesterol (grade 1 and 2), and direct low density lipoprotein (grade 1, 2, and one grade 3 abnormality). No differences in the frequency of laboratory abnormalities between the treatments were observed. Non-graded abnormalities were most frequently experienced for hematological parameters; however, the number of subjects affected was low (approximately 1 to 3 subjects per treatment for each parameter). There were no AEs reported for laboratory abnormalities. Cardiovascular Safety Results for vital signs indicated minor variations over time that were not considered clinically relevant. Nine subjects (45.0%) experienced treatment-emergent abnormalities in vital signs; however, the number of subjects experiencing abnormalities for each vital signs parameter was low (4 subjects, 20.0% or fewer per parameter). No subjects experienced any treatment-emergent abnormalities for QTcF or QRS. Three male subjects (15.0%) experienced increases in QTcB between 30 and 60 msec, 1 pre-dose, Treatment D (Session 3 for that subject), and 2 during follow-up; however, the resulting QTcB values were not abnormal (> 450 msec). Three subjects (15.0%) experienced treatment-emergent abnormalities for HR, and 1 subject for PR. There were no AEs reported for cardiovascular abnormalities. Physical Examination There were no safety concerns revealed by physical examination and no AEs were reported as a result of the physical examinations.
Clinical Research Report Synopsis
0296617, Final, 08-Dec-2008 14:08 TMC278-TiDP6-C137 CONFIDENTIAL 3 Clinical Research Report
Conclusions
The results of this study demonstrate that the exposure (expressed as Cmax, AUClast and AUCf to TMC278 was 40-50% lower when TMC278 was administered under fasting conditions or after a protein-rich nutritional drink, compared to TMC278 administered after a standard breakfast. Administration of TMC278 after a high-fat breakfast or after a standard breakfast resulted in similar exposures. TMC278 should therefore be administered with a meal to enhance the absorption and exposure. TMC278 was well-tolerated, and did not elicit any clinically relevant safety issues.
Clinical Research Report Synopsis
0296617, Final, 08-Dec-2008 14:08
FINAL CLINICAL STUDY REPORT
Study Title: Bioequivalence Study of Two, Fixed-dose, Combination Tablet Formulations Containing Emtricitabine, Rilpivirine, and Tenofovir Disoproxil Fumarate Compared to the Concurrent Administration of the Individual Components Name of Test Drug: Emtricitabine (FTC), rilpivirine (RPV), and tenofovir disoproxil fumarate (TDF) Dose and Formulation: x Fixed-dose combination (FDC) tablet containing emtricitabine 200 mg, rilpivirine 25 mg, and tenofovir disoproxil fumarate 300 mg (FTC/RPV/TDF) x 200-mg strength capsule of emtricitabine, 25-mg strength tablet of rilpivirine, and 300-mg strength tablet of tenofovir disoproxil fumarate (FTC+RPV+TDF) Indication: HIV-1 Infection Sponsor: Gilead Sciences, Inc. 333 Lakeside Drive Foster City, CA 94404 Study No.: GS-US-264-0103 Phase of Development: Phase 1 IND No.: 106,252 EudraCT No.: Not applicable Study Start Date: 20 (First Subject Screened) Study End Date: 20 (Last Subject Observation) Principal or Coordinating Investigator: USA Gilead Responsible Name: Medical Monitor: Telephone: Fax: Report Date: 27 July 2010
CONFIDENTIAL AND PROPRIETARY INFORMATION This study was conducted in accordance with the guidelines of Good Clinical Practice, including archiving of essential documents. Emtricitabine/Rilpivirine/Tenofovir Disoproxil Fumarate Fixed-Dose Combination Study GS-US-264-0103 Final Clinical Study Report Final
STUDY SYNOPSIS Study GS-US-264-0103: Gilead Sciences, Inc. 333 Lakeside Drive Foster City, CA 94404 United States of America
Title of Study: Bioequivalence Study of Two, Fixed-dose, Combination Tablet Formulations Containing Emtricitabine, Rilpivirine, and Tenofovir Disoproxil Fumarate Compared to the Concurrent Administration of the Individual Components Investigator:
Study Centers: Single Phase 1 center in the US ( )
Publications: None
Study Period: 20 (First subject screened) 20 (Last subject observation)
Phase of Development: Phase 1
Objectives: The primary objective of this study was as follows: x To evaluate the bioequivalence of two fixed-dose combination (FDC) tablets, each containing emtricitabine (FTC) 200 mg, rilpivirine (RPV) 25 mg, and tenofovir disoproxil fumarate (TDF) 300 mg (FTC/RPV/TDF), compared to a 200-mg strength capsule of FTC, a 25-mg strength tablet of RPV, and a 300-mg strength tablet of TDF taken concurrently under fed conditions The secondary objective of this study was as follows: x To evaluate the safety of FTC, RPV, and TDF when administered together, either as FDC tablets or individual dosage forms in healthy volunteers
Methodology: This was a Phase 1, randomized, open-label, single-center, single-dose, 3-way crossover study that evaluated the relative bioequivalence of two FDC tablets (FTC/RPV/TDF FDC test formulations 3 and 4, each containing FTC 200 mg, RPV 25 mg, and TDF 300 mg) compared to concurrent administration of the individual components under fed conditions. Eligible subjects were randomized to one of six treatment sequences and received 1 dose of study drug on the second day of three consecutive 14-day periods (i.e., study Days 1, 15, and 29). Periods 1 and 2 were followed by a 14-day washout. Following period 3 dosing, subjects returned to the study center 14 days after the last dose for a follow-up visit.
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Number of Subjects (Planned and Analyzed): Planned: 36 to get 24 evaluable Analyzed: Safety Pharmacokinetics (PK) 35 Treatment A (FTC+RPV+TDF reference) 34 FTC 34 Treatment B (FTC/RPV/TDF FDC test formulation 3) 34 RPV 35 Treatment C (FTC/RPV/TDF FDC test formulation 4) 34 TDF Diagnosis and Main Criteria for Inclusion: Eligible subjects were healthy males and nonpregnant, nonlactating females between 18 and 45 years of age (inclusive) with a body mass index (BMI) between 19 and 30 (inclusive), no significant medical history, normal renal function, and in good general health, as determined by the investigator at screening evaluation performed no more than 28 days prior to the scheduled first dose of study drug.
Duration of Treatment: Three single doses 14 days apart over 29 days
Test Product, Dose, Mode of Administration, and Lot No.: Treatment B (FTC/RPV/TDF FDC test formulation 3): A single dose of FDC tablet containing FTC 200 mg, RPV 25 mg (as 27.5 mg of the hydrochloride salt), and TDF 300 mg (Lot BY1001B1) administered orally in the morning and within 5 minutes of consuming a standardized meal. Treatment C (FTC/RPV/TDF FDC test formulation 4): A single dose of FDC tablet containing FTC 200 mg, RPV 25 mg (as 27.5 mg of the hydrochloride salt), and TDF 300 mg (Lot BY1002B1) administered orally in the morning and within 5 minutes of consuming a standardized meal.
Reference Therapy, Dose, Mode of Administration, and Lot No.: Treatment A (reference): A single dose of FTC 1 u 200-mg strength capsule (Lot 56766AF21), RPV 1 u 25-mg strength tablet (as 27.5 mg of the hydrochloride salt) (Lot 9CL1F), and TDF 1 u 300-mg strength tablet (Lot A117181A) administered together orally in the morning and within 5 minutes of consuming a standardized meal
Criteria for Evaluation: Efficacy: Not applicable; efficacy was not evaluated in this study. Pharmacokinetics: The following plasma PK parameters of FTC, RPV, and tenofovir (TFV) were computed: Cmax, Tmax, Clast, Tlast, Ȝz, AUClast, AUCinf, %AUCexp, and T1/2. Safety: Adverse events (AEs), routine clinical laboratory tests, complete and symptom- driven physical examinations, vital signs, electrocardiograms (ECGs), and concomitant medications were monitored throughout the study period.
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Statistical Methods: Efficacy: Not applicable; efficacy was not evaluated in this study. Pharmacokinetics: PK concentration data and parameters for FTC, RPV, and TFV are listed by subject and summarized by treatment using descriptive statistics. A parametric (normal theory) analysis of variance (ANOVA) using a mixed-effects model appropriate for the crossover design was fitted to the natural logarithmic transformation of FTC, RPV and TFV PK parameters AUCinf, AUClast, and Cmax for each treatment pair of interest. To evaluate the bioequivalence of FDC test formulation 3 and FDC test formulation 4 versus the reference treatment, 90% confidence intervals (CIs) were constructed for the ratio of geometric means (test/reference) of AUCinf, AUClast, and Cmax of FTC, RPV and TFV for each test/reference treatment pair. Bioequivalence was to be concluded if the 90% CI lay between the boundary of 80–125% for all primary parameters and for all components for each treatment pair of interest. Safety: All safety data collected on or after the date of the first dose of the test product up to 30 days after the last dose of study drug were listed by subject and summarized by treatment group using descriptive statistics.
SUMMARY – RESULTS: Subject Disposition and Demographics: Thirty-six eligible subjects were enrolled and randomized, 6 subjects in each of the 6 treatment sequences. Thirty-four of the 36 randomized subjects completed the study; 1 subject discontinued because of angioedema of the face, and 1 subject was terminated from the study for a protocol violation. Of the 36 enrolled subjects, 15 (41.7%) were male, 27 (75.0%) were white, and 9 (25.0%) were black. The mean age was 33 years (range, 19 to 45 years), mean BMI was 25.4 kg/m2 (range, 19.6 to 29.0 kg/m2), and the mean creatinine clearance was 128.0 mL/minute (range, 91.4 to 157.4 mL/minute). Efficacy Results: Not applicable; efficacy was not evaluated in this study.
Pharmacokinetic Results: Two FDC tablets were tested in this study. FTC, RPV, and TFV geometric least-squares (GLS) mean PK parameters and the statistical comparisons of GLS means ratios and associated 90% CIs, are presented in the summary table below.
GLS Mean GMR (%) FTC Test Formulation 3a Referencea Test/Reference 90% CI
AUCinf (ngh/mL) 9581.10 9594.63 99.86 97.67, 102.09
AUClast (ngh/mL) 9360.88 9366.29 99.94 97.77, 102.16
Cmax (ng/mL) 1714.21 1625.23 105.47 100.46, 110.74 Test Formulation 4a Referencea Test/Reference
AUCinf (ngh/mL) 9646.25 9594.63 100.54 98.34, 102.79
AUClast (ngh/mL) 9432.71 9366.29 100.71 98.52, 102.94
Cmax (ng/mL) 1753.57 1625.23 107.90 102.77, 113.28
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GLS Mean GMR (%) RPV Test Formulation 3a Referencea Test/Reference 90% CI
AUCinf (ngh/mL) 3166.87 2738.56 115.64 108.71, 123.01
AUClast (ngh/mL) 2854.58 2466.92 115.71 109.13, 122.69
Cmax (ng/mL) 109.57 94.56 115.87 108.21, 124.06 Test Formulation 4a Referencea Test/Reference
AUCinf (ngh/mL) 3211.23 2738.56 117.26 110.24, 124.73
AUClast (ngh/mL) 2888.99 2466.92 117.11 110.45, 124.17
Cmax (ng/mL) 115.02 94.56 121.63 113.59, 130.23
GLS Mean GMR (%) TFV Test Formulation 3a Referencea Test/Reference 90% CI
AUCinf (ngh/mL) 3264.17 3200.52 101.99 99.06, 105.00
AUClast (ngh/mL) 3053.10 2989.16 102.14 99.00, 105.38
Cmax (ng/mL) 315.41 284.13 111.01 104.19, 118.28 Test Formulation 4a Referencea Test/Reference
AUCinf (ngh/mL) 3333.11 3200.52 104.14 101.15, 107.22
AUClast (ngh/mL) 3110.38 2989.16 104.06 100.86, 107.35
Cmax (ng/mL) 323.41 284.13 113.83 106.83, 121.28 GLS = geometric least squares; GMR = geometric means ratio; CI = confidence interval reference = FTC+RPV+TDF: single doses of FTC 200-mg strength capsule, RPV 25-mg strength tablet (as 27.5 mg of the hydrochloride salt), and TDF 300-mg strength tablet test formulation 3: FTC/RPV/TDF, a single dose of FDC tablet (FTC 200 mg, RPV 25 mg, and TDF 300 mg) test formulation 4: FTC/RPV/TDF, a single dose of FDC tablet (FTC 200 mg, RPV 25 mg, and TDF 300 mg) a N = 34 The FTC/RPV/TDF FDC test formulation 3 demonstrated bioequivalence to the reference treatment of concurrent administration of the individual components (FTC+RPV+TDF) under fed conditions. The 90% CIs for the GLS mean ratios (test treatment/reference treatment) were contained within the bioequivalence bounds of 80% to 125% for FTC, RPV, and TFV for all primary pharmacokinetic parameters (AUCinf, AUClast, and Cmax). The FTC/RPV/TDF FDC test formulation 4 is not bioequivalent to the reference products as not all three of the components, specifically RPV Cmax, of the FDC formulation met the bioequivalence criterion.
CONFIDENTIAL Page 5 27JULY2010 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Fumarate Fixed-Dose Combination Study GS-US-264-0103 Final Clinical Study Report Final
Safety Results: 34/36 enrolled subjects received all planned doses of study drugs and completed the study. One subject received only FTC/RPV/TDF FDC test formulation 4 and discontinued because of angioedema of the face, and 1 subject received only the reference treatment and was terminated from the study for a protocol violation. Overall, treatment-emergent AEs were reported in 3/35 subjects (8.6%) for the reference treatment, 4/34 subjects (11.8%) for FTC/RPV/TDF FDC test formulation 3, and 4/35 subjects (11.4%) for FTC/RPV/TDF FDC test formulation 4. Testicular pain (n = 2, both on reference treatment) was the only AE reported in 1 subject for a treatment. All AEs except one (Grade 2 allergic rhinitis, on FTC/RPV/TDF FDC test formulation 3) were Grade 1. Treatment-emergent AEs that were considered related to study drug included diarrhea, musculoskeletal pain, pain in extremity, headache, dysuria, testicular pain, angioedema, papular rash, and hot flash. There was no death or other serious adverse event. One subject discontinued prematurely for Grade 1 angioedema of the right side of the face on study Day 1 following administration of the first dose of study treatment (FTC/RPV/TDF FDC test formulation 4). The investigator evaluated the AE as related to study drug. Overall, treatment-emergent graded laboratory abnormalities were reported in 10/35 subjects (28.6%) for the reference treatment, 9/34 subjects (26.5%) for FTC/RPV/TDF FDC test formulation 3, and 5/35 subjects (14.3%) for FTC/RPV/TDF FDC test formulation 4. Grade 1 hemoglobinemia in 1 subject was the only graded hematology lab test reported. Fasting hypercholesterolemia was the most frequent treatment-emergent graded laboratory abnormality (all Grade 1): 6/34 subjects (17.6%) for the reference treatment, 1/34 subjects (2.9%) for FTC/RPV/TDF FDC test formulation 3, and 2/35 subjects (5.7%) for FTC/RPV/TDF FDC test formulation 4. No notable change in clinical laboratory test value treatment means, or vital signs or physical findings was observed during the study. No pregnancy occurred in this study.
CONCLUSIONS: Pharmacokinetics: The FTC/RPV/TDF FDC test formulation 3 is bioequivalent to concurrent administration of the individual components under fed conditions. Safety: Single, oral doses of the reference treatment (FTC+RPV+TDF) and both FDC test formulations of FTC/RPV/TDF were well tolerated in this study.
CONFIDENTIAL Page 6 27JULY2010 TMC278-C117 1
SYNOPSIS Trial Identification and Protocol Summary
Company: Tibotec Pharmaceuticals Ltd. Drug Substance: TMC278 Trade Name: - Trial no.: TMC278-C117 Indication: HIV-1 infection Clinical Phase: I Title: A Phase I, open-label, randomized, 2-way, crossover trial to compare the oral bioavailability of the Phase III tablet formulation of TMC278 relative to that of the Phase IIb tablet formulations after single-dose intake with food in healthy subjects. Investigator: Country: Belgium
Belgium Trial Period: Start: - -20 No. of Investigators: 1 End: - -20 No. of Subjects: 32 Objectives: The primary objective of this trial was to compare the rate and extent of absorption of TMC278 administered as the newly developed Phase III tablet formulation versus the Phase IIb tablet formulations when administered as a single oral dose in healthy subjects after a standardized breakfast. The secondary objective was to determine the safety and tolerability of a single dose of a Phase III and different Phase IIb tablet formulations of TMC278. Design: This was a Phase I, open-label, randomized, 2-way, crossover trial in 32 healthy subjects to assess the rate and extent of absorption of TMC278 following single-dose administration of different tablet formulations in the presence of food. The implementation of protocol amendment 1 before the start of dosing removed Treatments A and B (relating to a dose of 25 mg TMC278) and Panel 1 from the study design. Subjects were randomly assigned to 1 of 2 parallel panels. In Panel 2 (n=16), subjects were randomized to receive a single oral dose of 100 mg TMC278 as 4 separate 25 mg tablets of the Phase III tablet formulation (Treatment C) or a single oral dose of 100 mg TMC278 as the 100 mg Phase IIb tablet formulation (Treatment D). In Panel 3 (n=16), subjects were randomized to receive a single oral dose of 150 mg TMC278 as the 150 mg Phase III tablet formulation (Treatment E) or a single oral dose of 150 mg TMC278 as 3 separate 50 mg tablets of the Phase IIb tablet formulation (Treatment F). In both panels, subjects received the alternate treatment after a 13-day washout period. All drug intakes occurred after 10-hour overnight fasting and within 10 minutes after completion of a standardized breakfast. Plasma pharmacokinetics of TMC278 were assessed up to 168 hours following each treatment. Safety and tolerability evaluations were recorded at regular intervals throughout the trial period. Subject Selection Inclusion Criteria 1. Male or female, aged between 18 and 55 years, extremes included. 2. Smoking no more than 10 cigarettes, or 2 cigars, or 2 pipes per day (or non-smoking) for at least 3 months prior to selection. 3. Normal weight as defined by a Quetelet Index (body mass index: weight in kg divided by the square of height in meters) of 18.0 to 30.0 kg/m2, extremes included. 4. Informed consent form (ICF) signed voluntarily before the first trial-related activity. 5. Able to comply with the protocol requirements. 6. Healthy on the basis of a medical evaluation that revealed the absence of any clinically relevant abnormality and included a physical examination, medical history, electrocardiogram (ECG), vital signs, and the results of blood biochemistry and hematology tests and a urinalysis carried out at screening.
Clinical Research Report Synopsis Version: 1.0 Date: 10-May-2007
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Exclusion Criteria 1. A positive human immunodeficiency virus (HIV)-1 or HIV-2 test at trial screening. 2. Female, except if postmenopausal since more than 2 years, or posthysterectomy or posttubal ligation (without reversal operation). 3. History or evidence of current use of alcohol, barbiturate, amphetamine, recreational or narcotic drug use which, in the investigator’s opinion, would compromise subject’s safety and/or compliance with the trial procedures. 4. Hepatitis A, B, or C infection (confirmed by hepatitis A antibody IgM, hepatitis B surface antigen, or hepatitis C virus antibody, respectively) at screening. 5. A positive urine drug test at trial screening. Urine was tested for the current use of amphetamines, barbiturates, benzodiazepines, cocaine, cannabinoids, methadone, and opioids. 6. Currently active or underlying gastrointestinal, cardiovascular, neurologic, psychiatric, metabolic, renal, hepatic, respiratory, inflammatory, or infectious disease. 7. Current or history of adrenal disorder. 8. History of tuberculosis or ocular herpes. 9. History of renal insufficiency (estimated creatinine clearance below 60 mL/min). 10. Currently significant diarrhea, gastric stasis, or constipation that in the investigator’s opinion could influence drug absorption or bioavailability. 11. Any history of significant skin disease such as, but not limited to, rash or eruptions, drug allergies, food allergy, dermatitis, eczema, psoriasis, or urticaria. 12. Previously demonstrated clinically significant allergy or hypersensitivity to any of the excipients of the investigational medication administered in this trial (i.e., TMC278). 13. Use of concomitant medication, including over-the-counter products, herbal medications, and dietary supplements. Over-the-counter medication had to be discontinued at least 7 days prior to the first intake of study medication and prescribed medication had to be discontinued at least 14 days prior to the first intake of study medication, except ibuprofen. 14. Having previously participated in more than 1 trial (single or multiple dose) with TMC125, TMC120, and/or TMC278 (formerly known as R278474) or developed a rash, erythema, or urticaria while participating in a trial with the aforementioned compounds. 15. Participation in an investigational drug trial within 60 days preceding the first intake of study medication. 16. Donation of blood or plasma within 60 days preceding the first intake of study medication. 17. Subjects with the following laboratory abnormalities at screening as defined by the Division of Acquired Immunodeficiency Syndrome (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events (AEs; “DAIDS grading table”) and in accordance with the normal ranges of the clinical laboratory: serum creatinine grade 1 or greater ( 1.1 x upper limit of normal range [ULN]); serum lipase grade 1 or greater ( 1.1 x ULN); hemoglobin grade 1 or greater ( 10.9 g/dL); platelet count grade 1 or greater ( 124.999/mm3); absolute neutrophil count grade 1 or greater ( 1.3 x 109/L); aspartate aminotransferase or alanine aminotransferase grade 1 or greater ( 1.25 x ULN); total bilirubin grade 1 or greater ( 1.1 x ULN); any other laboratory abnormality of grade 2 or above, including: proteinuria (spot urine) 2+ and microscopic hematuria (> 10 red blood cells/high power field). Treatment Treatment C Treatment D Treatment E Treatment F Dosage 100 mg TMC278 100 mg TMC278 150 mg TMC278 150 mg TMC278 Dosage Form [F No.] Phase III tablets Phase IIb tablet Phase III tablet Phase IIb tablets (25 mg [F006]) (100 mg [F002]) (150 mg [F007]) (50 mg [F003]) Usage 4 x 25 mg tablets 1 x 100 mg tablet 1 x 150 mg tablet 3 x 50 mg tablets on Day 1, single on Day 1, single on Day 1, single on Day 1, single oral dose oral dose oral dose oral dose Batch Number PD1975 PD1268 PD2024 PD1273 Panel 1: Treatments A and B – removed from the study design by protocol Dose Regimen amendment 1 before the start of dosing. Panel 2: Treatment C or D in Session I, 13-day washout, alternate treatment in Session II. Panel 3: Treatment E or F in Session I, 13-day washout, alternate treatment in Session II.
Clinical Research Report Synopsis Version: 1.0 Date: 10-May-2007
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Duration of Treatment Treatment C, D, E, and F: 1 day each. Duration of Trial Two treatment periods of 1 day with a washout period of at least 13 days in between (excluding screening and follow-up). Disallowed Medication During the entire trial, subjects were not to use any medication other than study medication and ibuprofen, of which limited use was allowed. All over-the-counter medication, except for ibuprofen, had to be discontinued at least 7 days before the first intake of study medication and all prescribed medication had to be discontinued at least 14 days before first intake of study medication. Subjects were not to use any herbal medications or dietary supplements including products containing Hypericum perforatum (e.g., St. John’s wort) from 14 days before the first intake of study medication and up to 14 days after the last intake of study medication. Ibuprofen could be used up to 3 days before intake of study medication. After that, the investigator could permit the use of ibuprofen from 3 days before intake of study medication until Day 8 of each session (at no more than 400 mg per day). In the event of cutaneous reaction/rash and/or an allergic reaction, the use of cetirizine, levocetirizine, topical corticosteroids, or antipruritic agents in the recommended dosing scheme was permitted. In case of nausea, the use of antiemetics was permitted. In case of diarrhea, the use of loperamide was allowed.
Clinical Research Report Synopsis Version: 1.0 Date: 10-May-2007
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Assessments Treatments C, D, E, and F (Session I or II) a Screening Follow-up h b Day 2 Day 3 Day 4 Day 6 Day 8 Day 7 Day 1 21 days days 21 and 30, and 30, d 31, or 32 31, or Pharmacokinetics Blood samplef X X X X X X Safety Adverse events + concomitant X X X X X X X X medsc Hemat & biochemd X Xe X X X Urinalysis X Xe X X X Cortisol and 17-OH-progesterone X Xg g T3, free-T4, and TSH X X ECG & vital signs X Xi X X Physical examinationj X X X X
meds = medication; Hemat & biochem = hematology & biochemistry; T3 = triidothyronine; T4 = thyroxine; TSH = thyroid stimulating hormone; ECG = electrocardiogram. a At screening, subject’s demographics, medical and surgical history, smoking habits, and concomitant diseases were recorded and an HIV-1 and -2 test, hepatitis A, B, and C test and urine drug screening were performed; a serum pregnancy test was also performed for females. b Subjects were admitted to the unit the afternoon before Day 1. c Adverse events and concomitant medications were monitored continuously from signing the ICF until the last trial-related activity. d Biochemistry samples were taken fasting for at least 10 hours, before breakfast. e Within 2 hours before drug intake. f For determination of TMC278 plasma concentrations. Immediately before drug intake plus 0.5, 1, 2, 3, 4, 5, 6, 9, 12, and 16 hours postdose on Day 1, 24 hours postdose on Day 2, 48 hours postdose on Day 3, 72 hours postdose on Day 4, 120 hours postdose on Day 6, and 168 hours postdose on Day 8. g On Day 8, tests were only conducted at the end of the last session for each subject. h Days were in relation to the date of last drug intake. On Day 7 of follow-up, overlapping assessments were only performed and captured once. i Within 2 hours before drug intake and 4 hours postdose. j Included skin examination. Statistical Methods Intent-to-treat analysis, descriptive statistics, frequency tabulations, linear mixed effects modeling, Wilcoxon matched pairs signed rank test.
Clinical Research Report Synopsis Version: 1.0 Date: 10-May-2007
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Main Features of the Subject Sample and Summary of the Results Baseline Characteristics - Subject Disposition Total N = 32 Number of Subjects Entered (M/F) 18/14 Age: median (range), yrs 45.0 (19-55) Race, n (%) Caucasian 32 (100) Drop-Outs 0
Treatment C Treatment D Pharmacokinetics of TMC278 100 mg TMC278 Phase III 100 mg TMC278 Phase IIb
(mean rSD, tmax: median [range]) (test) (reference) n 16 16
tmax, h 4.5 (3.0 – 9.0) 4.0 (2.0 – 12.0)
Cmax, ng/mL 339.2 ± 125.7 400.7 ± 149.6
AUClast, ng.h/mL 12270 ± 5123 12160 ± 3952
AUCf, ng.h/mL 14070 ± 6678 14010 ± 5539
t1/2term, h 52.82 ± 17.62 56.46 ± 27.17 LSmean ratio (90% CI), % Test vs reference - n 16 -
Cmax 85.36 (71.62 – 101.7) -
AUClast 99.07 (80.27 – 122.3) -
AUCf 98.21 (79.01 – 122.1) -
Treatment E Treatment F Pharmacokinetics of TMC278 150 mg TMC278 Phase III 150 mg TMC278 Phase IIb
(mean rSD, tmax: median [range]) (test) (reference) n 16a 16
tmax, h 4.0 (3.0 – 6.0) 4.0 (2.0 – 6.0)
Cmax, ng/mL 597.6 ±116.9 630.4 ± 165.5
AUClast, ng.h/mL 19640 ± 6467 19400 ± 6414
AUCf, ng.h/mL 20910 ± 8067 20740 ± 7389
t1/2term, h 40.02 ± 12.12 39.88 ± 11.80 LSmean ratio (90% CI), % Test vs reference - n 16a -
Cmax 96.29 (85.73 – 108.2) -
AUClast 98.40 (87.90 – 110.2) -
AUCf 100.4 (89.75 – 112.4) - a n=15 for AUClast
Clinical Research Report Synopsis Version: 1.0 Date: 10-May-2007
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Treatment E Treatment F Treatment C Treatment D 150 mg 150 mg Safety 100 mg TMC278 100 mg TMC278 TMC278 TMC278 (n = number of Phase III Phase IIb Phase III Phase IIb Totala subjects with data) N = 16 N = 16 N = 16 N = 16 N = 32 Adverse Events (AEs) Most frequently reported AEs (reported in > 2 subjects in the whole trial), n (%) Headache 6 (37.5) 3 (18.8) 5 (31.3) 3 (18.8) 14 (43.8) Nausea 1 (6.3) 2 (12.5) 3 (18.8) 1 (6.3) 6 (18.8) Erythema 1 (6.3) 0 1 (6.3) 1 (6.3) 3 (9.4) Nasopharyngitis 0 0 0 1 (6.3) 3 (9.4)b n (%) with 1 or 10 (62.5) 7 (43.8) 10 (62.5) 9 (56.3) 28 (87.5) more AEs n (%) of deaths 0 0 0 0 0 n (%) with 1 or 0 0 0 0 0 more other serious AEs n (%) of treatment 0 0 0 0 0 stopped due to AEs n (%) with 1 0 0 0 0 0 or more grade 3 or 4 AEs a Includes screening and follow-up. b Also reported for 1 subject during screening and for 1 subject during follow-up. Overall, 28 subjects (87.5%) reported at least 1 AE. The most common AEs were headache (14 subjects, 43.8%) and nausea (6 subjects, 18.8%). There were no deaths or other serious adverse events. All AEs were considered grade 1 or 2 in severity. No subjects prematurely discontinued the trial due to an AE. Eight AEs considered to be skin events of interest were reported during the trial for 7 subjects. All skin events of interest were grade 1 in severity. Four events of erythema were reported for 3 subjects (1 event with Treatment C, 2 events with Treatment E, and 1 event with Treatment F). Both events of erythema reported with Treatment E (erythema of eyelid and erythema of cheeks and lips) were reported for the same subject and were considered to be possibly related to TMC278. Two events of eczema were reported for 2 subjects (1 event with Treatment C and 1 event with Treatment F). The event of eczema reported with Treatment F was considered to be possibly related to TMC278. Vasculitis and rash erythematous were each reported for 1 subject with Treatment C and Treatment E, respectively. The rash erythematous was considered to be possibly related to TMC278. All other skin events of interest were considered not or doubtfully related to TMC278.
Clinical Research Report Synopsis Version: 1.0 Date: 10-May-2007
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Clinical Laboratory Tests Treatment C Treatment D Treatment E Treatment F 100 mg 100 mg 150 mg 150 mg TMC278 TMC278 TMC278 TMC278 Phase III Phase IIb Phase III Phase IIb Totala N = 16 N = 16 N = 16 N = 16 N = 32 n (%) with 1 or more treatment-emergent graded laboratory abnormalities: grade 1 2 (12.5) 2 (12.5) 1 (6.3) 0 7 (21.9)b grade 2 1 (6.3) 0 1 (6.3) 0 3 (9.4)c grade 3 0 0 0 0 1 (3.1)d grade 4 0 0 0 0 0 a Includes follow-up but not screening. b Includes 3 subjects during follow-up and 1 subject with a grade 1 treatment-emergent laboratory abnormality during more than one treatment period. c Includes 1 subject during follow-up. d One subject during follow-up. There were no consistent or clinically relevant treatment-emergent changes over time in laboratory parameters. Except for 1 grade 3 treatment-emergent laboratory abnormality (increased lipase) during follow-up (Day 8 of Treatment D), all laboratory abnormalities in this trial were grade 1 or 2. Two subjects had a laboratory abnormality that was reported as an AE (increased lipase); one of these AEs was the grade 3 laboratory abnormality of increased lipase. Both laboratory-related AEs were grade 2 in severity and were considered to be possibly related to TMC278. No clinically relevant urinalysis results were observed. Cardiovascular Safety Minor changes were reported for vital sign values and ECG. None of the changes was considered to be clinically relevant. Physical and Skin Examinations Physical examination revealed a treatment-emergent abnormal finding for 1 subject during the trial (eczema), which was reported as an AE. Conclusions In conclusion, the results of this trial demonstrate that the oral bioavailability of TMC278 using the Phase III tablet is comparable to the bioavailability using the Phase IIb tablet for both the 100 mg (Treatments C and D) as well as the 150 mg (Treatments E and F) dose. In these healthy subjects, the administration of a single dose of either 100 mg or 150 mg TMC278, as either the Phase III or Phase IIb tablet formulation, was generally safe and well tolerated.
Clinical Research Report Synopsis Version: 1.0 Date: 10-May-2007
0128661, Final, 10-May-2007 09:04 TMC278-TiDP38-C145 CONFIDENTIAL 1 Clinical Research Report Synopsis
SYNOPSIS Trial Identification and Protocol Summary
Company: Tibotec Pharmaceuticals Drug Substance: TMC278 Trade Name: - Trial no.: TMC278-TiDP38-C145 Indication: HIV-1 infection Clinical Phase: I Title: A Phase I, open-label, randomized, crossover trial in healthy adults to compare the oral bioavailability of 3 concept pediatric formulations of TMC278 (solution, suspension, granules) to that of the adult 25 mg Phase III tablet formulation, and to assess the food effect for each concept formulation. Investigator: Country: The Netherlands
The Netherlands. Trial Period: Start: 13-Jan-2009 No. of Investigators: 1 End: 02-May-2009 No. of Subjects: 36 Objectives: The primary objectives of this trial were: to compare the rate and extent of absorption of TMC278 when administered as a single 25 mg dose of the 3 concept pediatric formulations (solution [10 mg/mL], suspension [5 mg/mL], granules [2.5 mg/g]), under fed and fasted conditions, to that when administered as the 25 mg TMC278 Phase III tablet formulation, under fed conditions, in healthy adults; and to assess the effect of food on the bioavailability of TMC278 after a single 25 mg dose of the concept pediatric formulations in healthy adults. The secondary objectives were: to evaluate short-term safety and tolerability of TMC278 following administration of 3 single oral doses of 25 mg, formulated as one of the concept pediatric formulations (under fed and fasted conditions) and as the Phase III tablet (under fed conditions), in healthy adults; and to evaluate the palatability of each concept pediatric formulation in healthy adults under fasted conditions. Design: This was a Phase I, open-label, randomized, 3-way crossover trial to compare the oral bioavailability of TMC278 after administration as 1 of 3 concept pediatric formulations (a solution [10 mg/mL], a suspension [5 mg/mL], or granules [2.5 mg/g]) to that when administered as the adult 25 mg Phase III tablet formulation, and to assess the food effect for each concept formulation. The palatability of each concept formulation was assessed as well, under fasted conditions. TMC278 is being investigated for the treatment of HIV-1 infected subjects. The trial population consisted of 36 healthy adults, divided over 3 panels of 12 subjects each, 1 panel for each concept pediatric formulation. In each of the 3 panels, subjects received 3 different TMC278 treatments in a randomized fashion, in 3 subsequent sessions, separated by a washout period of at least 14 days. The different treatments were: Panel 1: single 25 mg TMC278 dose (2.5 mL) of oral solution (10 mg base/mL) in fed (Treatment A1) and fasted (Treatment B1) condition; Panel 2: single 25 mg TMC278 dose (5 mL) of oral suspension (5 mg base equivalents/mL) in fed (Treatment A2) and fasted (Treatment B2) condition; Panel 3: single 25 mg TMC278 dose (10 g) of granules (2.5 mg base equivalents/g) in fed (Treatment A3) and fasted (Treatment B3) condition; Panels 1, 2, and 3: single 25 mg TMC278 dose as a tablet (25 mg base equivalents/tablet) in fed condition
Clinical Research Report Synopsis TMC278-TiDP38-C145 CONFIDENTIAL 2 Clinical Research Report Synopsis
(Treatment C). In each treatment session, full pharmacokinetic profiles of TMC278 were measured up to 168 hours after intake. Safety and tolerability were monitored throughout the trial. Subject Selection Inclusion Criteria 1. Aged between 18 and 55 years, extremes included. 2. Non-smoking or smoking no more than 10 cigarettes, or 2 cigars, or 2 pipes per day for at least 3 months prior to selection. 3. A Body Mass Index (weight in kg divided by the square of height in meters) of 18.0 to 30.0 kg/m2, extremes included. 4. Informed Consent Form (ICF) signed voluntarily before the first trial-related activity. 5. Able to comply with protocol requirements. 6. Healthy on the basis of a medical evaluation that revealed the absence of any clinically relevant abnormality and included a physical examination, medical history, electrocardiogram (ECG), vital signs, and the results of blood biochemistry and hematology tests and a urinalysis carried out at screening. Exclusion Criteria 1. A positive human immunodeficiency virus (HIV)-1 or HIV-2 test at screening. 2. Female, except if postmenopausal since more than 2 years, or posthysterectomy, or postsurgical sterilization (without reversal operation). 3. History or evidence of current use of alcohol, barbiturate, amphetamine, recreational, or narcotic drug use, which in the investigator’s opinion would compromise subject’s safety and/or compliance with the trial procedures. 4. Hepatitis A, B, or C infection (confirmed by hepatitis A antibody IgM, hepatitis B surface antigen, or hepatitis C virus antibody, respectively) at screening. 5. A positive urine drug test at screening. Urine was tested to check the current use of methadone, barbiturates, amphetamines, benzodiazepines, cocaine, cannabinoids, and opioids. Note: a positive test could be repeated once to exclude a technical error. 6. Currently active or underlying gastrointestinal, cardiovascular, neurologic, psychiatric, metabolic, endocrinologic, genitourinary, renal, hepatic, respiratory, inflammatory, or infectious disease. 7. Currently significant diarrhea, gastric stasis, or constipation that in the investigator’s opinion could influence drug absorption or bioavailability. 8. Any history of significant skin disease such as, but not limited to, rash or eruptions, drug allergies, food allergy, dermatitis, eczema, psoriasis, or urticaria. 9. Previously demonstrated clinically significant allergy or hypersensitivity to any of the excipients of the investigational medication administered in this trial (i.e., TMC278). 10. Use of concomitant medication, including over-the-counter products, herbal medications, and dietary supplements. Over-the-counter medication had to be discontinued at least 7 days prior to the first administration of trial medication and prescribed medication had to be discontinued at least 14 days before the first intake of trial medication, except for ibuprofen and acetaminophen. 11. Participation in an investigational drug trial within 60 days prior to the first intake of trial medication. 12. Donation of blood or plasma or significant blood loss within the 60 days preceding the first intake of trial medication.
Clinical Research Report Synopsis TMC278-TiDP38-C145 CONFIDENTIAL 3 Clinical Research Report Synopsis
13. Subjects with the following laboratory abnormalities at screening, as defined by the Division of Acquired Immunodeficiency Syndrome Table for Grading the Severity of Adult and Pediatric Adverse Events and in accordance with the normal ranges of the clinical laboratory: serum lipase grade 1 or greater (≥ 1.1 x upper limit of laboratory range [ULN]); hemoglobin toxicity grade 1 or greater (≤ 10.9 g/dL); platelet count grade 1 or greater (≤ 124.999 x 109/L); absolute neutrophil count grade 1 or greater (≤ 1.3 x 109/L); aspartate aminotransferase or alanine aminotransferase grade 1 or greater (≥ 1.25 x ULN); total bilirubin grade 1 or greater (≥ 1.1 x ULN); any other laboratory abnormality of grade 2 or above, including proteinuria (spot urine) ≥ 2+, and microscopic hematuria (> 10 red blood cells/high power field), with the exception of grade 2 low density lipoprotein cholesterol or grade 2 total cholesterol values if < ULN of the local laboratory. 14. Having participated in more than 1 trial (single or multiple dose) with TMC125 (etravirine), TMC120 (dapivirine), and/or TMC278 (rilpivirine, formerly known as R278474), or having developed rash, erythema, or urticaria while participating in a trial with the aforementioned compounds. 15. History of clinically relevant heart rhythm disturbances or grade 2 or above electrolyte abnormalities (hypokalemia, hypocalcemia, hypomagnesemia) at screening. 16. Subjects with ageusia, hypogeusia, or dysgeusia.
17. Renal impairment: calculated creatinine clearance (CLCr) < 80 mL/min. Note: The site was to calculate CLCr using the Cockroft-Gault formula. Treatment Treatment A1, B1 Treatment A2, B2 Treatment A3, B3 Treatment C Concentration TMC278 TMC278 TMC278 TMC278 10 mg/mL 5 mg base 2.5 mg base 25 mg base equivalents/mL equivalents/g equivalents/tablet Dosage 25 mg TMC278 25 mg TMC278 25 mg TMC278 25 mg TMC278 (base) (HCl salt) (HCl salt) (HCl salt) Dosage Form (TF No.) Solution Suspension Granules Tablets (R278474-F008) (R314585-F014) (R314585-F015) (R314585-F006) Usage Treatment A1: Treatment A2: Treatment A3: 25 mg on Day 1 25 mg on Day 1 25 mg on Day 1 of session (fed) of session (fed) of session (fed) Treatment B1: Treatment B2: Treatment B3: 25 mg on Day 1 25 mg on Day 1 25 mg on Day 1 25 mg on Day 1 of session (fed) of session (fasted) of session (fasted) of session (fasted)
2.5 mL orally 5 mL orally 10 g orally 1 tablet orally single dose single dose single dose single dose Batch Number 08K13 08K17 08K17 8BL2H
Clinical Research Report Synopsis TMC278-TiDP38-C145 CONFIDENTIAL 4 Clinical Research Report Synopsis
Dose Regimen Panel 1: Group 1: treatment sequence A1/B1/C in 3 separate sessions. Group 2: treatment sequence B1/C/A1 in 3 separate sessions. Group 3: treatment sequence C/A1/B1 in 3 separate sessions. Group 4: treatment sequence C/B1/A1 in 3 separate sessions. Group 5: treatment sequence B1/A1/C in 3 separate sessions. Group 6: treatment sequence A1/C/B1 in 3 separate sessions. Panel 2: Groups 1 – 6: Same treatment sequences in 3 separate sessions as Panel 1, but with suspension formulation. Panel 3: Groups 1 – 6: Same treatment sequences in 3 separate sessions as Panel 1, but with granules formulation. Note: all sessions were separated by a 14-day washout period. Duration of Treatment Treatments A1, A2, A3, B1, B2, B3, and C: 1 day (single dose) each. Assessments were performed up to Day 8 (inclusive). Duration of Trial For each panel, 3 treatment periods of 1 day (single dose) each, with a washout period of 14 days in between each period (excluding screening and follow-up). Disallowed Medication All systemic over-the-counter medication had to be discontinued at least 7 days before the first administration of trial medication and all prescribed medication had to be discontinued at least 14 days before the first administration of trial medication, except for ibuprofen or acetaminophen. Subjects were not to use any medication other than the trial medication up to 14 days after the last intake of trial medication, except for ibuprofen or acetaminophen. Subjects were also not to use any systemic herbal medications or dietary supplements, including products containing Hypericum perforatum (e.g., St. John’s wort) from 14 days before the first trial medication intake up to 14 days after the last trial medication intake. Ibuprofen or acetaminophen could be used up to 3 days before the intake of trial medication in each treatment session. After that, the clinical investigator could permit the use of ibuprofen or acetaminophen from 3 days before the intake of trial medication until the last pharmacokinetic sample had been taken in each treatment session, at no more than 400 mg per day for ibuprofen, and at no more than 1000 mg per day for acetaminophen. Hormone replacement therapy was allowed in postmenopausal women. In case of cutaneous reaction/rash and/or an allergic reaction, the use of cetirizine (Zyrtec®), levocetirizine (Xyzal®), topical corticosteroids, or antipruritic agents in the recommended dosing scheme was permitted. In case of nausea, the use of antiemetics was permitted. In case of diarrhea, the use of loperamide was permitted.
Clinical Research Report Synopsis TMC278-TiDP38-C145 CONFIDENTIAL 5 Clinical Research Report Synopsis
Assessments Treatments
a A1 (Panel 1), A2 (Panel 2), A3 (Panel 3), and C (Panels 1, 2, and 3): fed conditions B1 (Panel 1), B2 (Panel 2), and Follow-up Screening B3 (Panel 3): fasted conditions (Session I, II, or III)b c f e d and 30, f Day 3 Day 4 Day 6 21 days Day 8 Day 2 Day 1 Day -1 31, or 32 ≤ Day 8 Pharmacokinetics Blood sampleg Xh XXXXX Safety AEs and concomitant medicationi XXXXXXXX X Hematology & biochemistryj XXk XXX Urinalysis X Xk XXX Urine drug screen X X Serum pregnancy test, females only X Xl Urine pregnancy test, females only X ECG X Xk Vital signsm XXk XXX Skin examination X X X X Physical examination X X X X Other Taste questionnaire Xn AE = adverse event; ECG = electrocardiogram. a Informed consent, smoking habits, inclusion/exclusion criteria, concomitant diseases, height, weight, subject characteristics and demographics, and medical and surgical history were recorded, and HIV-1 & -2 tests and hepatitis A, B, and C tests were performed before Day 1 of Session I. b Treatments were separated by a washout period of at least 14 days. c Subjects were admitted to the unit in the evening before Day 1. d Start of water restriction began 2 hours before intake of trial medication and stopped 2 hours postdose. e Subjects were discharged from the unit on this day. f In Session III for each subject, Day 8 coincided with the first follow-up visit; therefore these investigations were only performed once. g For determination of TMC278 plasma concentrations. h Pharmacokinetic samples were taken predose (within 2 hours before intake of trial medication), 0.5, 1, 2, 3, 4, 5, 6, 9, 12, and 16 hours postdose on Day 1. Further pharmacokinetic samples were taken at 24, 48, 72, 120, and 168 hours postdose. i Adverse events and concomitant medication were monitored continuously from signing the ICF until the last trial related activity. j Biochemistry samples were taken fasted for at least 10 hours, before breakfast. k Within 2 hours before intake of trial medication. l Performed on Day 30, 31, or 32. m Blood pressure and pulse rate: supine after 5 minutes, standing after 1 minute. n Taste questionnaire to be completed by the subject within 5 to 15 minutes after TMC278 intake in Treatments B1, B2, and B3 only.
Clinical Research Report Synopsis TMC278-TiDP38-C145 CONFIDENTIAL 6 Clinical Research Report Synopsis
Statistical Methods Descriptive statistics, graphical presentations, frequency tabulations including 90% confidence limits, intent-to-treat analysis, linear mixed effects modeling, Mann-Whitney U-Test.
Clinical Research Report Synopsis TMC278-TiDP38-C145 CONFIDENTIAL 7 Clinical Research Report Synopsis
Main Features of the Subject Sample and Summary of the Results Panel 1 Panel 2 Panel 3 Baseline Characteristics - Subject Disposition Solution Suspension Granules N = 12 N = 12 N = 12 Number of Subjects Entered (M/F) 8/4 10/2 11/1 Age: median (range), yrs 43.5 (22-54) 39.5 (21-54) 39.5 (20-54) Race, n (%) Caucasian 10 (83.3) 10 (83.3) 9 (75.0) Asian 1 (8.3) 1 (8.3) 1 (8.3) Black 1 (8.3) 1 (8.3) 2 (16.7) Drop-Outs – Reason Any reason 1 (8.3) 0 1 (8.3) AEs 1 (8.3) 0 0 Non-compliance 0 0 1 (8.3)
Panel 1: oral solution, single dose of 25 mg TMC278 Pharmacokinetics of TMC278 Tablet under Oral solution under fed Oral solution under (mean ! SD, tmax:median fed conditions conditions fasted conditions [range]) (reference) (test 1) (test 2) n 121211
Cmax, ng/mL 113.8 ± 30.00 137.9 ± 30.14 184.9 ± 28.82
tmax, h 4.0 (4.0-5.0) 4.0 (3.0-6.0) 1.0 (1.0-2.0)
AUClast, ng.h/mL 2910 ± 1150 3878 ± 890.9 3663 ± 561.4
AUC∀, ng.h/mL 3338 ± 1332 4204 ± 1072 3964 ± 730.7
t1/2term, h 46.59 ± 14.23 42.71 ± 12.87 44.46 ± 14.27 LS mean ratio (90% CI), % - Test 1 vs reference Test 2 vs reference n - 12 vs 12 11 vs 12
Cmax - 122.6 (102.8 - 146.3) 169.7 (153.3 - 187.8)
AUClast - 138.7 (118.9 - 161.7) 129.5 (114.7 - 146.3)
AUC∀ - 129.8 (111.5 - 151.1) 125.6 (110.9 - 142.1) - - Test 2 vs test 1 n - - 11 vs 12
Cmax - - 131.6 (119.2 - 145.3)
AUClast - - 92.94 (86.71 - 99.61)
AUC∀ - - 92.72 (85.74 - 100.3)
Clinical Research Report Synopsis TMC278-TiDP38-C145 CONFIDENTIAL 8 Clinical Research Report Synopsis
Panel 2: oral suspension, single dose of 25 mg TMC278 Pharmacokinetics of TMC278 Tablet under Oral suspension under Oral suspension under fed conditions fed conditions fasted conditions (mean ! SD, tmax:median [range]) (reference) (test 1) (test 2) n121212
Cmax, ng/mL 108.7 ± 34.92 115.5 ± 26.12 130.4 ± 32.82
tmax, h 4.5 (3.0-9.0) 4.0 (3.0-5.0) 2.0 (1.0-4.0)
AUClast, ng.h/mL 3127 ± 1129 3390 ± 1161 3263 ± 1291
AUC∀, ng.h/mL 3597 ± 1768 4005 ± 1897 3671 ± 1703
t1/2term, h 47.81 ± 21.87 54.17 ± 29.73 47.77 ± 18.01 LS mean ratio (90% CI), % - Test 1 vs reference Test 2 vs reference n - 12 vs 12 12 vs 12
Cmax - 108.4 (98.09 - 119.9) 121.6 (107.7 - 137.2)
AUClast - 108.4 (98.30 - 119.4) 103.4 (92.90 - 115.0)
AUC∀ - 111.4 (102.1 - 121.5) 102.4 (92.69 - 113.2) - - Test 2 vs test 1 n - - 12 vs 12
Cmax - - 112.1 (104.8 - 120.0)
AUClast - - 95.40 (91.09 - 99.91)
AUC∀ - - 91.92 (87.45 - 96.62)
Clinical Research Report Synopsis TMC278-TiDP38-C145 CONFIDENTIAL 9 Clinical Research Report Synopsis
Panel 3: oral granules, a single dose of 25 mg TMC278 Pharmacokinetics of TMC278 Tablet under Granules under fed Granules under fasted fed conditions (mean ! SD, t :median conditions (test 1) conditions (test 2) max (reference) [range]) n111111a
Cmax, ng/mL 102.9 ± 33.16 119.3 ± 26.81 85.95 ± 22.07
tmax, h 5.0 (2.0-5.0) 4.0 (3.0-5.0) 4.0 (2.0-5.0)
AUClast, ng.h/mL 2922 ± 1220 3665 ± 1273 2479 ± 1097
AUC∀, ng.h/mL 3263 ± 1467 3990 ± 1425 2740 ± 1192
t1/2term, h 43.34 ± 23.23 40.00 ± 16.89 45.90 ± 22.98 LS mean ratio (90% CI), % - Test 1 vs reference Test 2 vs reference n - 11 vs 11 11 vs 11
Cmax - 118.4 (100.0 - 140.3) 87.02 (78.55 - 96.41)
AUClast - 127.7 (110.6 - 147.6) 93.09 (84.94 - 102.0)
AUC∀ - 125.8 (108.6 - 145.8) 92.70 (85.96 - 99.98) - - Test 2 vs test 1 n - - 11 vs 11
Cmax - - 70.05 (58.94 - 83.24)
AUClast - - 71.08 (63.35 - 79.75)
AUC∀ - - 72.04 (64.34 - 80.67) a n=12 for t1/2term
Panel 1: oral solution, single dose of 25 mg TMC278 Safety TMC278 TMC278 (n = number of subjects with data) 25 mg solution 25 mg tablet Fed Fasted Fed N=12 N=11 N=12 Adverse Events (AEs) n (%) with 1 or more AEs 6 (50.0) 4 (36.4) 8 (66.7) n (%) of deaths 0 0 0 n (%) with 1 or more other serious AEs 0 0 0 n (%) of treatment stopped due to AEs 0 0 1 (8.3) n (%) with 1 or more grade 3 or 4 AEs 0 0 0 Most frequently reported treatment-emergent AEs (reported in ≥ 2 subjects with any treatment), n (%) Headache 2 (16.7) 2 (18.2) 4 (33.3) Myalgia 2 (16.7) 1 (9.1) 0 Fatigue 2 (16.7) 0 2 (16.7)
Clinical Research Report Synopsis TMC278-TiDP38-C145 CONFIDENTIAL 10 Clinical Research Report Synopsis
Panel 2: oral suspension, single dose of 25 mg TMC278 Safety TMC278 TMC278 (n = number of subjects with data) 25 mg suspension 25 mg tablet Fed Fasted Fed N=12 N=12 N=12 Adverse Events (AEs) n (%) with 1 or more AEs 6 (50.0) 5 (41.7) 6 (50.0) n (%) of deaths 0 0 0 n (%) with 1 or more other serious AEs 0 0 0 n (%) of treatment stopped due to AEs 0 0 0 n (%) with 1 or more grade 3 or 4 AEs 0 0 0 Most frequently reported treatment-emergent AEs (reported in ≥ 2 subjects with any treatment), n (%) Headache 4 (33.3) 2 (16.7) 2 (16.7) Nasopharyngitis 1 (8.3) 2 (16.7) 2 (16.7) Oropharyngeal Pain 0 0 2 (16.7)
Panel 3: oral granules, a single dose of 25 mg TMC278 Safety TMC278 TMC278 (n = number of subjects with data) 25 mg granules 25 mg tablet Fed Fasted Fed N=11 N=12 N=11 Adverse Events (AEs) n (%) with 1 or more AEs 7 (63.6) 5 (41.7) 3 (27.3) n (%) of deaths 0 0 0 n (%) with 1 or more other serious AEs 0 0 0 n (%) of treatment stopped due to AEs 0 0 0 n (%) with 1 or more grade 3 or 4 AEs 0 0 0 Most frequently reported treatment-emergent AEs (reported in ≥ 2 subjects with any treatment), n (%) Headache 3 (27.3) 1 (8.3) 1 (9.1) Nasopharyngitis 0 0 2 (18.2) There were no notable differences in the incidences of AEs across the panels. Within the solution, suspension, and granule treatment groups, a slightly higher incidence of AEs was observed under fed conditions, compared to fasted conditions. The most commonly reported AE during the trial was headache. One subject was reported with a grade 2 AE of rash maculo-papular during treatment with the TMC278 tablet (fed), which led to the withdrawal of the subject from the trial. No grade 3 (severe) or grade 4 (life-threatening) treatment-emergent AEs were reported. There were no deaths or SAEs reported in this trial. Skin events of interest were reported for 2 subjects during the trial: 1 (8.3%) subject during treatment with the TMC278 solution (fed) (rash papular) and 1 (8.3%) subject with a grade 2 AE of rash maculo-papular as mentioned above. Clinical Laboratory Tests No clinically meaningful changes over time were observed in the hematology, biochemistry, and urinalysis parameters in any treatment group. The majority of treatment-emergent abnormalities were DAIDS grade 1. The most common treatment-emergent grade 2 abnormalities were decreased phosphorus, hyperglycemia, increased lipase, and increased total bilirubin; reported in no more than 2 subjects in any session. No grade 3 or 4 treatment-emergent laboratory abnormalities were observed during the trial. No subjects were observed with treatment-emergent AEs related to laboratory parameters or discontinued the trial for this reason. Vital Signs There were no consistent or clinically relevant changes in vital signs parameters, and no clinically relevant individual abnormalities were observed. Physical Examination No clinically relevant new physical examination findings were reported. No new physical examination abnormalities were reported as AEs. Taste Questionnaire
Clinical Research Report Synopsis TMC278-TiDP38-C145 CONFIDENTIAL 11 Clinical Research Report Synopsis
A higher proportion of subjects rated the overall palatability of the TMC278 suspension and granule formulation as “acceptable” or “good” (83.3% and 8.3% [suspension], and 66.7% and 16.7% [granules], respectively), compared to the solution (25.0% and 16.7%, respectively). The results of the visual analogue scale revealed that a higher proportion (58.3%) of subjects in the TMC278 solution group expressed a dislike (very much or a little) to the solution compared to the suspension or granule groups (16.7% each).
Conclusions Pharmacokinetics The results of the present trial demonstrate that all 3 concept pediatric formulations of TMC278 have an acceptable oral bioavailability when administered as a single dose of 25 mg. Oral Solution Both in fed and fasted conditions, the TMC278 exposure (Cmax, AUC) for the oral solution was higher as compared to the tablet formulation in fed conditions, and this was especially apparent for Cmax of the solution in fasted conditions (70% higher). While the AUC for the solution was similar in fasted and fed conditions, the Cmax was 32% higher in the fasted as compared to the fed condition. Oral Suspension The exposure for the oral suspension, both under fed and fasted conditions, was comparable to that of the tablet formulation under fed conditions, except for a higher Cmax (22%) when the oral suspension was administered under fasted conditions. There was no food effect for the suspension formulation. Oral Granules When administered in fed conditions, the exposure (Cmax, AUC) for the granules was about 20-30% higher as compared to the tablet formulation in fed conditions. Under fasted conditions, the exposure (AUC) for the granules was similar, with a lower Cmax as compared to the tablet formulation in fed conditions. There was a food effect for the granules, with a 28-30% lower exposure (Cmax, AUC) when administered under fasted as compared to fed conditions. Safety No new safety signals for AEs, laboratory parameters, vital signs, or ECG were observed. Taste Questionnaire The proportion of subjects in each panel that rated the concept formulation as “acceptable” or “good” was 41.7%, 91.7%, and 83.3% for the TMC278 solution, suspension, and granule formulations, respectively.
Clinical Research Report Synopsis
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1. STUDY SYNOPSIS
Gilead Sciences, Inc. 333 Lakeside Drive Foster City, CA 94404
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Arithmetic Mean (SD) Tenofovir Pharmacokinetic Parameters (Treatments B and A)
Summary of the Pharmacokinetic Parameters of Serum and Urine Tenofovir for Treatments B and A
------Tenofovir ------Treatment B Treatment A ------Pharmacokinetic Arithmetic Arithmetic Parameters Mean SD Mean SD ------Cmax(ng/mL) 295.76 89.70 306.80 88.79 Tmax(hr) 0.993 0.384 1.01 0.595 AUC(0-24)(ng*hr/mL) 1541 405.6 1534 326.5 AUC(0-t)(ng*hr/mL) 1967 534.3 1958 442.5 AUC(0-inf)(ng*hr/mL) 2287 685.2 2266 549.5 t1/2λz (hr) 18.7 3.63 18.2 4.26 Kel(1/hr) 0.0382 0.00687 0.0399 0.00766 % dose recovered 16.7 4.8 16.9 4.6 CLr (mL/hr/kg) 167.3 43.8 172.5 67.0 CLCr (mL/hr/kg) 93.1 18.4 93.6 17.9 ------Treatment B = 1 x 300 mg TDF Tablet (Commercial Formulation), Fasted: test Treatment A = 4 x 75 mg TDF Tablets (Clinical Formulation), Fasted: reference
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STUDY SYNOPSIS (CONTINUED)
Arithmetic Mean (SD) Tenofovir Pharmacokinetic Parameters (Treatments C and B)
Summary of the Pharmacokinetic Parameters of Serum and Urine Tenofovir for Treatments C and B ------Tenofovir ------Treatment C Treatment B ------Pharmacokinetic Arithmetic Arithmetic Parameters Mean SD Mean SD ------Cmax(ng/mL) 334.87 80.22 295.76 89.70 Tmax(hr) 2.03 0.880 0.993 0.384 AUC(0-24)(ng*hr/mL) 2139 385.1 1541 405.6 AUC(0-t)(ng*hr/mL) 2710 499.5 1967 534.3 AUC(0-inf)(ng*hr/mL) 3100 597.8 2287 685.2 t1/2λz (hr) 17.4 3.47 18.7 3.63 Kel(1/hr) 0.0413 0.00789 0.0382 0.00687 % dose recovered 23.5 4.9 16.7 4.8 CLr (mL/hr/kg) 168.6 41.4 167.3 43.8 CLCr (mL/hr/kg) 92.3 14.6 93.1 18.4 ------Treatment C = 1 x 300 mg TDF Tablet (Commercial Formulation), Fed: test Treatment B = 1 x 300 mg TDF Tablet (Commercial Formulation), Fasted: reference
Statistical Comparisons of Serum Tenofovir Pharmacokinetic Parameters: Treatment B Versus Treatment A
Treatment Mean Confidence Intervals % Mean Parameter B A (90% Confidence) Ratio ------ln(Cmax) 5.649 5.687 87.8-105.6 96.3 ln[AUC(0-t)] 7.551 7.553 95.2-104.7 99.8 ln[AUC(0-inf)] 7.695 7.688 95.8-105.8 100.7 ------Treatment B = 1 x 300 mg TDF Tablet (Commercial Formulation), Fasted: test Treatment A = 4 x 75 mg TDF Tablets (Clinical Formulation), Fasted: reference
Values for Treatments B and A are the least - squares means (LSMEANS) from the ANOVA Parameters are ln-transformed parameters
Mean Ratio = 100*test/reference for untransformed parameters Mean Ratio = 100*exp(test-reference) for ln-transformed parameters
Statistical Comparisons of Serum Tenofovir Pharmacokinetic Parameters: Treatment C Versus Treatment B
Treatment Mean Confidence Intervals % Mean Parameter C B (90% Confidence) Ratio ------ln(Cmax) 5.784 5.649 104.4-125.4 114.4 ln[AUC(0-t)] 7.888 7.551 133.6-146.7 140.0 ln[AUC(0-inf)] 8.018 7.695 131.5-145.1 138.2 ------Treatment C = 1 x 300 mg TDF Tablet (Commercial Formulation), Fed: test Treatment B = 1 x 300 mg TDF Tablet (Commercial Formulation), Fasted: reference Values for Treatments C and B are the least - squares means (LSMEANS) from the ANOVA Parameters are ln-transformed parameters Mean Ratio = 100*test/reference for untransformed parameters Mean Ratio = 100*exp(test-reference) for ln-transformed parameters
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STUDY SYNOPSIS (CONTINUED)
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&21),'(17,$/ 3DJH -DQXDU\ Tenofovir Disoproxil Fumarate/Emtricitabine Tablet Final CSR GS-US-104-0172 Tenofovir Disoproxil Fumarate/Emtricitabine Fixed Dose Combination Product Protocol GS-US-104-0172 Clinical Study Report Final
2. STUDY SYNOPSIS
Gilead Sciences, Inc. 333 Lakeside Drive Foster City, CA 94404 USA
Name of Sponsor: Individual Study Table (For National Authority Use Gilead Sciences, Inc. Referring to Part Only) of the Dossier: Name of Finished Product: Volume: Tenofovir disoproxil fumarate/emtricitabine Page: fixed dose combination product
Name of Active Ingredients: Tenofovir disoproxil fumarate, emtricitabine
Title of Study: A Phase 1 Pharmacokinetic Study in Healthy Volunteers to Evaluate the Bioequivalence of the Combined Formulated Tablet of Tenofovir Disoproxil Fumarate and Emtricitabine Compared to Tenofovir Disoproxil Fumarate and Emtricitabine Administered Concurrently and the Effect of Food on Pharmacokinetics
Investigators:
Study Centers:
Publications: None
CONFIDENTIALCONFIDENTIAL Page Page 2 2 11FEB2004 11FEB2004 Tenofovir Disoproxil Fumarate/Emtricitabine Tablet Final CSR GS-US-104-0172 Tenofovir Disoproxil Fumarate/Emtricitabine Fixed Dose Combination Product Protocol GS-US-104-0172 Clinical Study Report Final
STUDY SYNOPSIS (CONTINUED)
Study Period: 20 (First study subject randomized) 20 (Last study subject observation) Phase of Development: Phase 1
Objectives: The primary objectives of this study were:
• To establish bioequivalence between the combination tablet (containing 300 mg tenofovir disoproxil fumarate/200 mg emtricitabine) and concurrent administration of the 300 mg tablet of tenofovir disoproxil fumarate and the 200 mg capsule of emtricitabine by evaluation of Cmax and AUC of tenofovir and emtricitabine.
• To investigate the effect of food (high-fat meal and light meal) on the pharmacokinetics (PK) of the combination tablet.
• To assess the safety of tenofovir disoproxil fumarate and emtricitabine when administered together either as a combination tablet or as separate formulations.
Methodology: Randomized, open-label, four-treatment, single center, four-way crossover study
Number of Subjects Planned: 36 evaluable subjects (Planned and Enrolled: 44 Analyzed): Completed: 39
Diagnosis and Main Healthy male and healthy, nonpregnant, nonlactating female Criteria for Inclusion: subjects between the ages of 18 and 60 years, inclusive
Duration of 28 days Treatment:
Test Product, Dose, Combination tablet of tenofovir disoproxil fumarate Mode of 300 mg/emtricitabine 200 mg, administered orally; Administration, and Lot No. V301B2 Lot No.:
CONFIDENTIALCONFIDENTIAL Page Page 3 3 11FEB2004 11FEB2004 Tenofovir Disoproxil Fumarate/Emtricitabine Tablet Final CSR GS-US-104-0172 Tenofovir Disoproxil Fumarate/Emtricitabine Fixed Dose Combination Product Protocol GS-US-104-0172 Clinical Study Report Final
STUDY SYNOPSIS (CONTINUED)
Reference Therapy, Single tablet of tenofovir disoproxil fumarate 300 mg, Dose, Mode of administered orally; Lot No. J110B1 Administration, and Lot No.: Single capsule of emtricitabine 200 mg, administered orally; Lot No. W303A1
Criteria for Evaluation:
Efficacy: Efficacy was not evaluated in this study.
Pharmacokinetics: The following parameters were assessed for each analyte in plasma: Cmax, Tmax, AUC0ít, AUC0í∞, % AUCexp, kel, T½λz,
CL/F, and Vz/F.
Safety: Safety was evaluated by assessment of clinical laboratory tests at baseline and at various time points during the study, periodic physical examinations including vital signs, and documentation of adverse events.
Statistical Methods:
Pharmacokinetics: For each analyte (tenofovir or emtricitabine), a parametric (normal theory) general linear model appropriate for a 4-treatment crossover design was fit to the natural logarithmic transformation of the Cmax and AUC parameters. The analysis of variance (ANOVA) model included the following factors: sequence, subjects within sequence, period, and treatment.
For the assessment of formulation bioequivalence, a 90% confidence interval was obtained for the geometric mean ratio using treatment A (separate tenofovir DF tablet and emtricitabine capsule fasted) as the reference treatment and treatment B (tenofovir DF/emtricitabine combination tablet, fasted) as the test treatment. Ninety-percent confidence intervals were constructed about the ratio of geometric means of Cmax and AUC. The two treatments were considered bioequivalent if the 90% confidence intervals were encompassed within the bounds of 80% to 125% for Cmax and AUC.
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STUDY SYNOPSIS (CONTINUED)
Statistical Methods:
Pharmacokinetics: From the same ANOVA, the assessment of food effect was (Continued) performed by obtaining 90% confidence intervals for the geometric mean ratios using treatment B (tenofovir DF/ emtricitabine combination tablet, fasted) as the reference, and treatment C (tenofovir DF/emtricitabine combination tablet, standard high-fat meal) and treatment D (tenofovir DF/ emtricitabine combination tablet, standard light meal) as test treatments. No food effect on PK was concluded if the 90% confidence intervals were within the bounds of 80% to 125% for Cmax and AUC.
Safety: The frequency of treatment-emergent adverse events, treatment-related adverse events, treatment-emergent serious adverse events, and adverse events leading to study drug discontinuation were summarized using the Medical Dictionary ® for Regulatory Activities (MedDRA , version 6.0). In addition, the change in value from pre-dose to post-dose in quantitative laboratory parameters (hematology, chemistry, and urinalysis) was summarized by parameter and treatment, as was the number of subjects with post-dosing laboratory toxicity by maximum toxicity grade.
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STUDY SYNOPSIS (CONTINUED)
SUMMARY – RESULTS:
Pharmacokinetics Results:
Bioequivalence: The mean (± SD) maximum concentrations (Cmax) of tenofovir after administration of the tenofovir DF tablet or the combination tablet were 267.59 ± 80.61 or 253.63 ± 83.46 ng/mL, respectively. Exposure (AUC0−∞) of tenofovir after administration of either tenofovir DF or the combination tablet was similar. The ratios for both the rate and extent (Cmax and AUC) of tenofovir bioavailability after its administration as tenofovir DF or as the combination tablet were contained within the bounds of 80% to 125%, demonstrating bioequivalence of tenofovir between the two treatments.
The mean emtricitabine Cmax values after administration of emtricitabine capsules or the combination tablet were 2.21 ± 0.59 and 2.13 ± 0.60 μg/mL, respectively. AUC0−∞ values were also similar between the two treatments (10.70 and 10.62 μg•hr/mL, respectively). The 90% confidence intervals for the geometric least squares means ratios of emtricitabine Cmax and AUC for treatment A (emtricitabine capsules) as reference and treatment B (combination tablet) as test were contained within the 80% to 125% interval, demonstrating bioequivalence for emtricitabine between the two study treatments.
Food Effect: Administration of the combination tablet with either a high-fat or light meal was associated with a delay in the time to maximum plasma tenofovir concentration (Tmax) relative to Tmax for the fasted state. The intake of a high-fat or light meal did increase the maximum plasma concentration (Cmax) of tenofovir by approximately 16% or 13.5%, respectively, compared with the fasted-state administration. Likewise, an increase of approximately 35% or 34% in tenofovir AUC0−∞ was observed after administration with a high-fat or light meal, respectively, compared with the fasted state.
Emtricitabine pharmacokinetic parameters after ingestion of food (high-fat or light meal) were essentially the same as those for the fasting state, indicating no food effect on the disposition of emtricitabine. The mean emtricitabine Cmax after fasting, high-fat meal, and light meal was 2.1, 2.0, and 2.0 μg/mL, and the mean total systemic exposure (AUC0−∞) was 10.6, 10.3, and 10.4 μg•hr/mL, respectively. These results indicate that food intake has no effect on emtricitabine pharmacokinetics.
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STUDY SYNOPSIS (CONTINUED)
Safety Results: Of the 44 subjects dosed with study drug, 8 subjects (18.2%) reported a total of 13 treatment-emergent adverse events. The only treatment-related adverse event reported in more than one subject of any treatment group was headache, which was reported in 2 (5%) of the 40 subjects receiving the combination tablet with a light meal. Twelve of the 13 adverse events were mild in severity (toxicity grade 1); 1 adverse event (hypertension, not related to study treatment) was considered to be of moderate severity (toxicity grade 2). The investigator considered 11 of the 13 adverse events to be related to the study treatment; the remaining (one grade 2 hypertension and one grade 1 headache) were considered to be unrelated to treatment. Two subjects were discontinued from the study because of adverse events, one because of moderate hypertension considered by the investigator to be not related to study treatment and the other because of mild rash considered to be related to study treatment. No serious adverse events were reported during this study.
CONCLUSION: The tenofovir DF/emtricitabine combination tablet is bioequivalent to coadministration of the tenofovir DF tablet and the emtricitabine capsule. Administration of the tenofovir DF/emtricitabine combination tablet with either a high-fat meal or a light meal increased the tenofovir exposure by approximately 30% compared with fasted-state administration. There is no effect of food on emtricitabine concentrations. Tenofovir DF and emtricitabine, either administered as the combination tablet (containing 300 mg tenofovir DF/200 mg emtricitabine) or coadministered as the 300 mg tablet of tenofovir DF and 200 mg capsule of emtricitabine, are well tolerated by the study subjects.
CONFIDENTIALCONFIDENTIAL Page Page 7 711FEB2004 11FEB2004 FINAL CLINICAL STUDY REPORT
Study Title: Bioequivalence Study of Two, Fixed-dose, Combination Tablet Formulations Containing Emtricitabine, Rilpivirine, and Tenofovir Disoproxil Fumarate Compared to the Concurrent Administration of the Individual Components Name of Test Drug: Emtricitabine (FTC), rilpivirine (RPV), and tenofovir disoproxil fumarate (TDF) Dose and Formulation: x Fixed-dose combination (FDC) tablet containing emtricitabine 200 mg, rilpivirine 25 mg, and tenofovir disoproxil fumarate 300 mg (FTC/RPV/TDF) x 200-mg strength capsule of emtricitabine, 25-mg strength tablet of rilpivirine, and 300-mg strength tablet of tenofovir disoproxil fumarate Indication: HIV-1 Infection Sponsor: Gilead Sciences, Inc. 333 Lakeside Drive Foster City, CA 94404 Study No.: GS-US-264-0101
Phase of Development: Phase 1 IND No.: 106,252 EudraCT No.: Not applicable Study Start Date: 20 (First Subject Screened) Study End Date: 20 (Last Subject Observation) Principal or Coordinating Name: Investigator: Affiliation: Gilead Responsible Name: Medical Monitor: Telephone: Fax: Report Date: 15 July 2010
CONFIDENTIAL AND PROPRIETARY INFORMATION This study was conducted in accordance with the guidelines of Good Clinical Practice, including archiving of essential documents. Emtricitabine/rilpivirine/tenofovir disoproxil fumarate Study GS-US-264-0101 Final Clinical Study Report Final
STUDY SYNOPSIS Study GS-US-264-0101: Gilead Sciences, Inc. 333 Lakeside Drive Foster City, CA 94404 United States of America
Title of Study: Study GS-US-264-0101: Bioequivalence Study of Two, Fixed-dose, Combination Tablet Formulations Containing Emtricitabine, Rilpivirine, and Tenofovir Disoproxil Fumarate Compared to the Concurrent Administration of the Individual Components
Investigator:
Study Centers: Single Phase 1 center in the US ( )
Publications: None
Study Period: 20 (First subject screened) 20 (Last subject observation)
Phase of Development: Phase 1
Objectives: The primary objective of this study was as follows: x To evaluate the bioequivalence of two fixed-dose combination tablets (each containing emtricitabine 200 mg, rilpivirine 25 mg, and tenofovir DF 300 mg) compared to a 200-mg capsule of emtricitabine, a 25-mg tablet of rilpivirine, and a 300-mg tablet of tenofovir DF taken concurrently under fed conditions The secondary objective of this study was as follows: x To evaluate the safety of emtricitabine, rilpivirine, and tenofovir DF when administered together either as fixed-dose combination tablets or individual dosage forms in healthy volunteers
CONFIDENTIAL Page 2 15JULY2010 Emtricitabine/rilpivirine/tenofovir disoproxil fumarate Study GS-US-264-0101 Final Clinical Study Report Final
Methodology: This was a Phase 1, randomized, open-label, single-center, single-dose, 3-way crossover study that evaluated the relative bioequivalence of 2 fixed-dose combination (FDC) tablets (each containing emtricitabine [FTC] 200 mg, rilpivirine [RPV] 25 mg, and tenofovir disoproxil fumarate [TDF] 300 mg) compared with a 200-mg strength capsule of emtricitabine, a 25-mg strength tablet of rilpivirine, and a 300-mg strength tablet of tenofovir disoproxil fumarate taken concurrently under fed conditions. Rilpivirine in each of the FDC products was 25 mg as 27.5 mg of the hydrochloride salt. Eligible subjects were randomized to 1 of 6 treatment sequences and received 1 dose of study drug during each of 3 dosing periods. Periods 1 and 2 were followed by a 14-day washout period. Following Period 3 dosing, subjects returned to the study center 14 days after the last dose for a follow-up visit. Number of Subjects (Planned and Analyzed): Planned: 48 subjects Analyzed: Safety analysis set: 48 subjects Pharmacokinetics (PK) analysis sets: FTC PK analysis set: 44 subjects; RPV PK analysis set: 44 subjects; TDF PK analysis set: 44 subjects Diagnosis and Main Criteria for Inclusion: Eligible subjects were males and nonpregnant, nonlactating females, with a body mass index (BMI) between 19 and 30 (inclusive), no significant medical history, normal renal function, and in good general health, as determined by the investigator at the screening evaluation performed no more than 28 days prior to the scheduled first dose.
Duration of Treatment: Three single doses over 29 days
Test Product, Dose, Mode of Administration, and Batch No.: FTC/RPV/TDF FDC Formulation 1: A single dose of FDC tablet (emtricitabine 200 mg, rilpivirine 25 mg [as 27.5 mg of the hydrochloride salt], and tenofovir disoproxil fumarate 300 mg) administered orally in the morning and within 5 minutes of consuming a standardized meal. Formulation identifier: FP-11131, Lot Number BY0902B1 FTC/RPV/TDF FDC Formulation 2: A single dose of FDC tablet (emtricitabine 200 mg, rilpivirine 25 mg [as 27.5 mg of the hydrochloride salt], and tenofovir disoproxil fumarate 300 mg) administered orally in the morning and within 5 minutes of consuming a standardized meal. Formulation identifier: FP-11132, Lot Number BY0901B1
Reference Therapy, Dose, Mode of Administration, and Batch No.: FTC+RPV+TDF (Reference): Single doses of emtricitabine 1 u 200-mg strength capsule, rilpivirine 1 u 25-mg strength tablet [as 27.5 mg of the hydrochloride salt], and tenofovir disoproxil fumarate 1 u 300-mg strength tablet administered together orally in the morning and within 5 minutes of consuming a standardized meal. FTC Lot Number: 67038AF21 RPV Lot Number: 9CL1F TDF Lot Number: J0604B1
CONFIDENTIAL Page 3 15JULY2010 Emtricitabine/rilpivirine/tenofovir disoproxil fumarate Study GS-US-264-0101 Final Clinical Study Report Final
Criteria for Evaluation: Efficacy: Not applicable.
Pharmacokinetics: The following plasma PK parameters were calculated: Cmax, Tmax, Clast, Tlast, Ȝz, AUClast, AUCinf, AUCexp, and T1/2. Safety: Safety was evaluated by assessment of clinical laboratory tests, electrocardiograms (ECGs), periodic physical examinations, vital signs, and adverse events (AEs).
Statistical Methods: Efficacy: Not applicable. Pharmacokinetics: PK parameters were estimated by application of a nonlinear model using standard noncompartmental methods (WinNonlin, Version 5.2) and summarized by analyte (emtricitabine, rilpivirine, and tenofovir [TFV]) using descriptive statistics. For each analyte, a parametric analysis of variance (ANOVA) model appropriate for this crossover design was fitted to the natural logarithmic transformation of PK parameters AUCinf, AUClast, and Cmax for evaluable subjects. The mixed-effects model included treatment, sequence, and period as fixed effects, and subject-within-sequence as a random effect. For the assessment of bioequivalence, the 90% confidence intervals (CIs) were constructed for the ratio of geometric least-squares (GLS) means (test treatment/reference treatment) of AUCinf, AUClast, and Cmax for each of the 3 analytes. Formulation bioequivalence was concluded if the 90% CIs for the ratio of the GLS means were within the range of 80% to 125% for each of the 3 PK parameters. Safety: All safety data collected during the course of the study (after administration of the first dose of study drug until the date of the last dose of study drug plus 30 days) were listed by subject. Safety data were summarized by treatment group at baseline and at all post-dose visits. All AEs and clinical laboratory abnormalities in summaries were treatment emergent.
SUMMARY – RESULTS: Subject Disposition and Demographics: Forty-eight subjects were enrolled and received study drug, 8 in each of the 6 treatment sequences. Six subjects (12.5%) did not complete the study, 2 for protocol deviations and 4 withdrew consent. Five subjects (10.4%) did not complete all 3 study treatments. One subject completed all 3 treatments, but was withdrawn after the third treatment for protocol deviations. Of the 48 treated subjects, 45 (93.8%) received the reference treatment (FTC+RPV+TDF), 46 (95.8%) received FTC/RPV/TDF FDC Formulation 1, and 46 (95.8%) received FTC/RPV/TDF FDC Formulation 2. In the safety analysis set, 62.5% of the subjects were male, and the mean age was 28 years (range, 19 to 44 years). The majority of subjects (68.8%) were white, 22.9% were black, and 8.3% were American Indian or Alaska Native.
Efficacy Results: Not applicable
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Pharmacokinetic Results: Bioequivalence testing results showed that while emtricitabine and tenofovir exposures met the bioequivalence criterion in each FDC test formulation versus the reference product, rilpivirine exposures did not. As shown in the table below, the 90% CIs for the geometric means ratio (GMR) of test:reference for the 3 primary PK parameters fell within the 80% to 125% range for emtricitabine and tenofovir, but not for rilpivirine.
GLS Mean GMR (%) FTC Test Formulation 1a Referenceb Test/Reference 90% CI
AUCinf (ngh/mL) 9659.28 9563.29 101.00 (99.27, 102.77)
AUClast (ngh/mL) 9432.01 9337.61 101.01 (99.31, 102.75)
Cmax (ng/mL) 1796.99 1656.68 108.47 (104.15, 112.97) Test Formulation 2b Referenceb Test/Reference
AUCinf (ngh/mL) 9577.65 9563.29 100.15 (98.45, 101.88)
AUClast (ngh/mL) 9348.45 9337.61 100.12 (98.44, 101.82)
Cmax (ng/mL) 1681.62 1656.68 101.51 (97.50, 105.68)
GLS Mean GMR (%) TFV Test Formulation 1a Referenceb Test/Reference 90% CI
AUCinf (ngh/mL) 3115.44 3042.89 102.38 (99.74, 105.10)
AUClast (ngh/mL) 2862.12 2794.61 102.42 (99.38, 105.55)
Cmax (ng/mL) 289.34 270.57 106.94 (100.70, 113.57) Test Formulation 2b Referenceb Test/Reference
AUCinf (ngh/mL) 3177.35 3042.89 104.42 (101.75, 107.16)
AUClast (ngh/mL) 2924.22 2794.61 104.64 (101.56, 107.81)
Cmax (ng/mL) 282.18 270.57 104.29 (98.25, 110.70)
GLS Mean GMR (%) RPV Test Formulation 1a Referenceb Test/Reference 90% CI
AUCinf (ngh/mL) 3859.25 2864.10 134.75 (128.62, 141.17)
AUClast (ngh/mL) 3582.32 2639.35 135.73 (129.91, 141.80)
Cmax (ng/mL) 162.37 105.99 153.19 (146.26, 160.45) Test Formulation 2b Referenceb Test/Reference
AUCinf (ngh/mL) 3818.38 2864.10 133.32 (127.31, 139.62)
AUClast (ngh/mL) 3522.72 2639.35 133.47 (127.80, 139.39)
Cmax (ng/mL) 158.94 105.99 149.95 (143.23, 157.00) GLS = geometric least squares; GMR = geometric means ratio; CI = confidence interval Reference = FTC+RPV+TDF: single doses of FTC 200-mg strength capsule, RPV 25-mg strength tablet, and TDF 300-mg strength tablet Test Formulation 1: FTC/RPV/TDF, a single dose of FDC tablet (FTC 200 mg, RPV 25 mg, and TDF 300 mg) Test Formulation 2: FTC/RPV/TDF, a single dose of FDC tablet (FTC 200 mg, RPV 25 mg, and TDF 300 mg) a N = 43 b N = 44
CONFIDENTIAL Page 5 15JULY2010 Emtricitabine/rilpivirine/tenofovir disoproxil fumarate Study GS-US-264-0101 Final Clinical Study Report Final
Safety Results: Safety results demonstrate that the 3 treatments (FTC+RPV+TDF reference, FTC/RPV/TDF FDC Formulation 1, and FTC/RPV/TDF FDC Formulation 2) were well tolerated in this study. Higher percentages of subjects had AEs following FTC/RPV/TDF FDC Formulation 2 than the other 2 treatments. Treatment-emergent AEs were seen in 24.4% of those taking FTC+RPV+TDF reference, in 15.2% of those taking FTC/RPV/TDF FDC Formulation 1, and in 30.4% of those taking FTC/RPV/TDF FDC Formulation 2. Treatment-emergent AEs considered to be study drug related were reported in 8.9%, 6.5%, and 21.7% of subjects following administration of FTC+RPV+TDF reference, FTC/RPV/TDF FDC Formulation 1, and FTC/RPV/TDF FDC Formulation 2, respectively. Nausea and headache were the most common AEs, and were seen in more subjects with FTC/RPV/TDF FDC Formulation 2. Nausea was reported in 2 subjects with FTC+RPV+TDF reference, 2 subjects with FTC/RPV/TDF FDC Formulation 1, and 6 subjects with FTC/RPV/TDF FDC Formulation 2. Headache was experienced by 1 subject with FTC+RPV+TDF reference, 1 subject with FTC/RPV/TDF FDC Formulation 1, and 6 subjects with FTC/RPV/TDF FDC Formulation 2. All AEs were mild or moderate. Moderate AEs were reported in 6.7%, 4.3%, and 13.0% of subjects with FTC+RPV+TDF reference, FTC/RPV/TDF FDC Formulation 1, and FTC/RPV/TDF FDC Formulation 2, respectively. There were no Grade 3 or 4 AEs or serious AEs reported in this study, nor were there any early study discontinuations because of AEs. No Grade 4 treatment-emergent laboratory abnormalities were reported in this study, and no AEs related to graded laboratory abnormalities were reported. Two female subjects experienced Grade 3 hematuria on Day 14 following FTC/RPV/TDF FDC Formulation 1. No clinically relevant changes in vital signs, safety ECGs, or other observations related to safety occurred during the study.
CONCLUSIONS: While emtricitabine and tenofovir exposures met the bioequivalence criterion in each FDC test formulation (FTC/RPV/TDF FDC Formulation 1 and FTC/RPV/TDF FDC Formulation 2) versus the reference product, rilpivirine exposures did not. Since the bioequivalence criterion could not be achieved for all 3 components of the FDC formulations, the study concludes that FTC/RPV/TDF FDC Formulation 1 and FTC/RPV/TDF FDC Formulation 2 are not bioequivalent to the reference treatment (individual components FTC+RPV+TDF administered concurrently). Safety results demonstrate that the 3 treatments (FTC+RPV+TDF reference, FTC/RPV/TDF FDC Formulation 1, and FTC/RPV/TDF FDC Formulation 2) were well tolerated in this study.
CONFIDENTIAL Page 6 15JULY2010 TMC278 (rilpivirine) Clinical Study Report TMC278IFD4005
SYNOPSIS Name of Sponsor/Company Janssen Pharmaceutical K.K. Name of Finished Product EDURANT tablets Name of Active Ingredient TMC278 (rilpivirine)
Status: Final Date: 21 AUG 2013 Prepared by: Janssen Pharmaceutical K.K.
Protocol No.: TMC278IFD4005 Title of Study: An Open-label, Single-dose Study to Investigate the Pharmacokinetics and Safety of TMC278 After Oral Administration of TMC278 25 mg Tablet Under Fed Condition in Healthy Japanese Adult Male Subjects NCT No.: NCT01804244 Principal Investigator: Study Center: Publication (Reference): Not applicable Study Period: 19 February 2013 (date of first subject enrolled [informed consent]) to 22 March 2013 (date of last observation for last subject); 20 (database lock) Phase of Development: Phase 4
Objectives:
Primary objective To evaluate the pharmacokinetics (PK) of TMC278 after a single oral dose of TMC278 25 mg tablet (27.5 mg as the hydrochloride salt) under fed condition in healthy Japanese adult male subjects.
Secondary objective To evaluate safety after a single oral dose of TMC278 25 mg tablet under fed condition in healthy Japanese adult male subjects.
Hypothesis: No formal statistical hypothesis testing was planned for this study. This study was designed only to collect plasma TMC278 PK profiles in healthy Japanese adult male subjects, not to explore or generate any hypotheses.
Methodology: This was a single center, open-label, single oral dose study in healthy Japanese adult male subjects. The study consisted of 3 phases: a screening phase up to 26 days (Day -28 to Day -3), an inpatient phase from Day -2 to Day 8, and a follow-up assessment phase on Day 15 (±2 days) or at the time of early withdrawal. Subjects who met the selection criteria were admitted to the investigational institute 2 days before receiving the study drug (Day -2). All enrolled subjects received a single oral dose of one TMC278 25 mg
7 Final, Date: 27 AUG 2013 TMC278 (rilpivirine) Clinical Study Report TMC278IFD4005 tablet on Day 1 within 10 minutes after completion of a standardized breakfast. Enrolled subjects remained in the investigational institute for the entire duration of the inpatient phase. Subjects were discharged on Day 8 after the completion of all required assessments. Serial blood samples for determination of plasma concentrations of TMC278 were collected over a period of 168 hours (7 days).
Standardized Breakfast Japanese breakfast. Total energy was approximately 450 kcal, with percentages of energy from carbohydrates, protein, and fat of about 60%, 15%, and 25%, respectively.
Number of Subjects (planned and analyzed): Eight subjects were enrolled to ensure that at least 6 subjects completed the planned collection of PK samples. All of the 8 subjects completed the study and were included in the safety and PK analysis population (Table 1).
Table 1: Subject Disposition and Number of Subjects Per Analysis Set; Safety Number of subjects Total number of subjects who were administered the study drug 8 Completed 8 Discontinued after administration 0 Evaluable subjects PK analysis set 8 Safety analysis set 8 Subjects excluded from analysis set PK analysis set 0 Safety analysis set 0 Cross-reference: Attachment TSIDISP
Diagnosis and Main Criteria for Inclusion: Healthy Japanese men aged 20 to 40 years, inclusive; BMI between 18.5 and 25.0 kg/m2, inclusive; body weight of at least 50 kg.
Test Product, Dose and Mode of Administration, Batch No.: TMC278 25 mg tablet containing 25 mg of TMC278 as the hydrochloride salt (27.5 mg). The batch number of the TMC278 25 mg tablet was 0002A. The TMC278 25 mg tablet was taken between approximately 9:00 AM and 10:00 AM within 10 minutes after completion of a standardized breakfast as an oral dose with 150 mL of noncarbonated water and was swallowed whole, not chewed, divided, dissolved, or crushed.
Reference Therapy, Dose and Mode of Administration, Batch No.: Not applicable
Duration of Treatment: The maximum study duration for each subject was 45 days, including the screening phase, inpatient period, and follow-up visit. If it was considered necessary, the study duration could be prolonged for additional follow-up.
8 Final, Date: 27 AUG 2013 TMC278 (rilpivirine) Clinical Study Report TMC278IFD4005 Criteria for Evaluation:
Pharmacokinetics Venous blood samples (4 mL each) were collected for the measurement of plasma TMC278 concentrations at the following time points: Predose, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 16, 24, 48, 72, 120, and 168 hours postdose. The PK parameters determined for each subject included (but were not limited to) the following: maximum plasma concentration (Cmax), time to reach the maximum plasma concentration (tmax), area under the plasma concentration-time curve from time 0 to the last quantifiable time, calculated by linear trapezoidal summation (AUClast), area under the plasma concentration-time curve from time 0 to infinity (AUC), elimination rate constant associated with the terminal phase (Ȝz), elimination half-life (t1/2), apparent total body clearance of drug at the terminal phase after extravascular administration (CL/F), and apparent volume of distribution at the terminal phase after extravascular administration (Vdz/F), estimated by non-compartmental analysis using WinNonlin® (Version 6.2.1).
Safety Safety was evaluated throughout the study by examining incidence, severity, type of adverse events (AEs), changes in clinical laboratory results (hematology, biochemistry, and urinalysis), vital signs, physical examinations, and 12-lead ECGs.
Statistical Methods:
Sample Size Determination Eight subjects were enrolled in the study to ensure that at least 6 subjects completed the study assessments up to Day 8. Based on a previous study (TMC278-TiDP38-C145), the intersubject coefficients of variation (CVs) for AUClast and Cmax of a single dose of TMC278 were estimated to be less than or equal to 42% in healthy non-Japanese adult subjects. Using an estimate of approximately 42% for intersubject CVs and a sample size of 6 subjects, the true mean AUClast and Cmax of TMC278 were estimated to be within 72% to 139% of the observed geometric means with 95% confidence.
Subject Information For all subjects who had received at least one dose of study drug, descriptive statistics were provided. All demographic (age, height, weight, and BMI) and other initial subject characteristics (eg, medical history, physical examination) were tabulated and analyzed descriptively.
Pharmacokinetics For all subjects with at least one available plasma TMC278 concentration, plasma TMC278 concentration data were tabulated. Individual plasma TMC278 concentration-time profiles were visually presented. All subjects who completed the treatment with sufficient TMC278 plasma concentration data for the estimation of the PK parameters were included in the PK analysis population. Descriptive statistics (eg, number of collected data, mean, standard deviation, median, minimum, maximum, CV) of plasma TMC278 concentration data at each time point were reported. Mean plasma TMC278 concentration-time profile data was visually presented on a linear scale. PK parameters of plasma TMC278 were estimated using a non-compartmental analysis method with WinNonlin® (Version 6.2.1). Individual and descriptive statistics of plasma PK parameters of TMC278 were tabulated.
9 Final, Date: 27 AUG 2013 TMC278 (rilpivirine) Clinical Study Report TMC278IFD4005 Safety All subjects who received at least one dose of the study drug were included in the safety analysis. Baseline laboratory evaluations, vital signs, and ECG measurements were defined as the last evaluation done before the study drug administration. Safety data were summarized using descriptive statistics and frequency tables.
RESULTS:
Study Population: Eight healthy Japanese male subjects aged 20 to 37 years, inclusive, were enrolled in the study. All of the 8 subjects received a single dose of the study drug, and all subjects completed the study.
Pharmacokinetic Results: The estimated PK parameters are shown in Table 2.
Table 2: Summary of Plasma Pharmacokinetic Parameters After a Single Oral Dose of TMC278 25 mg Under Fed Condition (Number of Subjects=8)
Parameters Cmax tmax AUClast AUC t1/2 Ȝz Vdz/F CL/F (unit) (ng/mL) (h) (ng·h/mL) (ng·h/mL) (h) (1/h) (L) (L/h) Mean 144.3 4.50 4,246 4,542 43.0 0.01695 397.4 6.389 SD 49.660 1.20 1,911.8 2,001.2 10.9 0.0038610 183.32 2.3964 Minimum 91.3 2.00 2,513 2,574 31.7 0.0109 178 3.27 Median 129.0 5.00 3,565 3,840 39.2 0.01770 361.6 6.559 Maximum 244 6.00 7,287 7,653 63.4 0.0219 665 9.71 %CV 34.4 45.0 44.1 25.4 22.8 46.1 37.5 Geo Mean 137.8 3,917 4,199 41.9 0.01654 360.1 5.954 h = hour(s), Geo Mean = geometric mean. Cross-reference: Attachment TPKPARAM
Safety Results: No death, serious adverse event (SAE), or withdrawal from the study due to an AE occurred in this study (Table 3).
Table 3: Subjects With Adverse Events/Reactions TMC278 25 mg (N=8) N(%) One or more AEs 0 (0) One or more SAEs 0 (0) Deaths 0 (0) Treatment stopped due to AEs 0 (0) N = Number of subjects. Cross-reference: Attachment TSFAE01
No consistent changes in mean laboratory values over time were observed. All laboratory values outside the reference range were considered clinically insignificant by the investigator. One subject experienced a change in QT corrected according to Bazett’s formula (QTcB) from baseline of >30 ms at 24 hours postdose. The finding was considered not clinically relevant. No other abnormal findings were reported in 12-lead ECGs, physical examination, and vital signs.
10 Final, Date: 27 AUG 2013 TMC278 (rilpivirine) Clinical Study Report TMC278IFD4005 Study Limitations: No notable study limitations were identified by the sponsor.
CONCLUSIONS:
Plasma TMC278 concentrations attained Cmax at 5.00 h postdose (median) and then declined with a mean t1/2 of 43.0 h after a single oral administration of TMC278 25 mg under fed condition in healthy Japanese adult male subjects. TMC278 25 mg (single oral dose) was generally well tolerated in the Japanese subjects. There were no deaths or SAEs during this study, and no subject discontinued the study due to an AE. No clinically significant findings were observed for laboratory results (hematology, biochemistry and urinalysis), vital signs, physical examination, and 12-lead ECGs.
11 Final, Date: 27 AUG 2013 R278474: Clinical Study Report 278474-CDE-101
SYNOPSIS
NAME OF SPONSOR/COMPANY: INDIVIDUAL STUDY (FOR NATIONAL Johnson & Johnson Pharmaceutical Research TABLE REFERRING TO AUTHORITY USE ONLY) & Development, Division of Janssen-Cilag PART OF THE DOSSIER Ltd. NAME OF FINISHED PRODUCT: Volume: Not applicable NAME OF ACTIVE INGREDIENT(S): Page: R278474 Protocol No.: R278474-CDE-101 Title of Study: Double-blind, randomized, placebo-controlled study to evaluate the safety, tolerability, pharmacokinetics and ex vivo pharmacodynamics of single oral doses of R278474 in healthy male subjects. Principal Investigator: Belgium. Publication (Reference): Not applicable Study Period: 20 – 20 Phase of development: 1 Objectives: To evaluate the safety, tolerability, pharmacokinetics and ex vivo pharmacodynamics of single ascending oral doses of R278474 (NNRTI [Non-nucleoside Reverse Transcriptase Inhibitor]) in healthy male subjects. The pharmacokinetic profile of R278474 was to be compared with historical data for 3 other structurally related NNRTI compounds, R147681, R165335, and R152929. Methodology: This was a randomized, double-blind, placebo-controlled study, with 6 planned groups each of 9 healthy male subjects. Planned doses were 12.5, 25, 50, 100, 200, and 400 mg R278474. In each study group, 6 subjects were to receive R278474 and 3 subjects were to receive placebo. Progression to the next dose level was dependent on a satisfactory review of the safety and plasma PK data. Adrenal function was assessed during the screening phase (at Day –5) and postdose by measuring the diurnal changes in cortisol and adrenocorticotrophic hormone (ACTH) levels over a 24-hour period. Subjects were then stimulated with corticotrophin releasing hormone (CRH) and adrenal function measured for a further 2 hours. Dosing was not escalated beyond 50 mg due to safety concerns raised by blunted responses to CRH in the 50-mg dosing group, therefore doses of 12.5 to 50 mg R278474 were studied. Number of Subjects (planned and analyzed): 54 planned; 27 randomized and dosed; 27 analyzed. Diagnosis and Main Criteria for Inclusion: Healthy caucasian males aged between 18 and 55 years (inclusive) with a body mass index range between 18.0 and 28.0 kg/m2. All subjects were to have a baseline morning cortisol (between 08:00 and 09:00 am) of at least 100 nmol/L and normal cortisol response to the CRH test at screening of a >20% increase in peak cortisol over baseline. Test Product, Dose and Mode of Administration, Batch No.: 100% PEG 400 solution of R278474, 25 mg/mL. Subjects were given a single oral dose of 12.5, 25, and 50 mg as an oral solution. Batch no: 02130/F002 Reference Therapy, Dose and Mode of Administration, Batch No.: 100% PEG 400 solution, equal-volume dose, oral administration. Batch no: 02130/F001 Duration of Treatment: Single oral dose
Criteria for Evaluation: Pharmacokinetics: Blood and urine samples were collected for pharmacokinetic analysis before and up to 144 hours and 72 hours, respectively, after administration of R278474 or placebo. Pharmacodynamics (Ex Vivo Antiviral Activity): Serum and urine samples were collected for ex vivo antiviral activity assessment immediately before and up to 48 hours after administration of R278474 or placebo. Safety: Adverse events, physical examination, clinical laboratory data, adrenal function testing, vital signs, and 12-lead ECG.
Clinical Research Report Synopsis 1 R278474: Clinical Study Report 278474-CDE-10122
NAME OF SPONSOR/COMPANY: INDIVIDUAL STUDY (FOR NATIONAL Johnson & Johnson Pharmaceutical Research TABLE REFERRING TO AUTHORITY USE ONLY) & Development, Division of Janssen-Cilag PART OF THE DOSSIER Ltd. NAME OF FINISHED PRODUCT: Volume: Not applicable NAME OF ACTIVE INGREDIENT(S): Page: R278474 Statistical Methods: Pharmacokinetics: Descriptive statistics were conducted on plasma and urine drug concentration data and pharmacokinetic parameters. Comparisons of the PK profile of R278474 to historical data for 3 structurally related NNRTI compounds (R147681, R165335, and R152929), as well as dose normalized Cmax, AUC, tmax and t1/2term, were performed. No formal statistical analysis was carried out. Pharmacodynamics: Descriptive statistics were conducted on ex vivo antiviral activity data. Safety: Safety data were summarized and listed only; no formal statistical analysis was carried out. All subjects receiving treatment were included in the analysis. SUMMARY – CONCLUSIONS PHARMACOKINETIC RESULTS: R278474 Parameter 12.5 mg (N=6) 25 mg (N=6) 50 mg (N=6) a Cmax (ng/mL) 73.1 r 14.1 149 r 32.3 267 r 27.4 b tmax (h) 4 (4-4) 4 (2-6) 4 (4-4) a AUC0-144h (ng·h/mL) 2097 r 360 4496 r 1240 7879 r 973 a AUCf (ng·h/mL) 2467 r 526 5210 r 2001 8872 r 1342 a t1/2 (h) 50.5 r 21.6 47.7 r 18.6 44.7 r 8.7 aMean r SD; bMedian (min-max) Following a single oral dose of R278474, a gradual absorption phase was observed with the peak drug concentration attained at 4 hours postdose. Cmax and AUCt increased proportionally from 12.5 to 50 mg R278474 and the mean terminal elimination half-life was close to 48 hours at all doses. Less than 1% of the dose was excreted as unchanged drug in the urine. R278474 showed higher systemic exposure when compared with the historical data for 3 structurally related NNRTI compounds (R147681, R152929, and R165335). R278474 was stable in plasma and blood. No Z-isomer was detected in these matrices. Small amounts of the Z- isomer were found in urine samples. PHARMACODYNAMIC RESULTS: (Ex Vivo Antiviral Activity) R278474 Parameter 12.5 mg (N=6) 25 mg (N=6) 50 mg (N=6) a tmax (h) 3.6 r 0.9 3.3 r 1.0 3.7 r 0.8 Median (min-max) 4 (2-4) 4 (2-4) 4 (2-4) a Emax (ng/mL) 26.6 r 6.0 103 r 80.0 205 (43.6) Median (min-max) 27.3 (18.9-33.2) 86.3 (29.2-234) 205 (160-261) a AUEC12h (ngh/mL) 578 r 145 1745 r 1357 4279 r 1225 Median (min-max) 604 (377-730) 1567 (438-4028) 4328 (2120-5737) a Mean r SD The antiviral activity of serum samples from subjects dosed with R278474 appeared to increase in a concentration-dependent manner. No circulating active metabolites in the serum and urine were detected. Urine samples were not suitable for testing.
Clinical Research Report Synopsis 2 R278474: Clinical Study Report 278474-CDE-101
NAME OF SPONSOR/COMPANY: INDIVIDUAL STUDY (FOR NATIONAL Johnson & Johnson Pharmaceutical Research TABLE REFERRING TO AUTHORITY USE ONLY) & Development, Division of Janssen-Cilag PART OF THE DOSSIER Ltd. NAME OF FINISHED PRODUCT: Volume: Not applicable NAME OF ACTIVE INGREDIENT(S): Page: R278474 SAFETY AND TOLERABILITY RESULTS: Single oral doses of R278474 were well tolerated when administered at dose levels of 12.5 to 50 mg. There were no serious adverse events and no subjects were withdrawn due to adverse events. Adverse events were reported by all 9 subjects (100%) receiving placebo and by 14 (78%) of 18 subjects receiving R278474. There were no apparent dose-related trends in the incidence of adverse events. The majority of adverse events were mild in severity. One severe adverse event was reported during the study but was considered of doubtful relationship to the study drug. The most common adverse events were mild or moderate hot flushes and palpitations, which were noted in subjects receiving R278474 and placebo. These adverse events were associated with CRH stimulation and are documented in the product literature. There was no evidence of any drug-specific adverse events. There were no clinically significant treatment-related changes in clinical laboratory analyses and no indication of any effect of treatment on vital signs and ECG parameters. R278474 had no treatment effects on diurnal variation of plasma cortisol and ACTH. Blunted responses to CRH stimulation were seen after the 50-mg dose. The study was stopped to allow investigation of these changes. The lack of data for this test in healthy subjects made interpretation difficult. However, it appears that the effect on response to CRH stimulation at the 50-mg dose can be explained by the variability of the test and a high cortisol baseline in the placebo-treated subject group. CONCLUSION: Systemic exposure to R278474 increased in a dose-proportional manner at doses between 12.5 and 50 mg. AUC and Cmax values for R278474 were higher than for structurally related NNRTIs. The ex vivo antiviral activity of R278474 in serum increased in a dose-dependent manner. R278474 single dose administration up to 50 mg/kg was safe and generally well tolerated. Given that the blunted reponses to CRH stimulation seen after the 50-mg dose can be explained by the variability of the test and high baseline cortisol levels, further investigation of higher doses was considered appropriate. Date of the report: 15 September 2004
Clinical Research Report Synopsis 3 R278474: Clinical Study Report 278474-CDE-102
SYNOPSIS
NAME OF SPONSOR/COMPANY: INDIVIDUAL STUDY (FOR NATIONAL Johnson & Johnson Pharmaceutical Research TABLE REFERRING TO AUTHORITY USE ONLY) & Development, Division of Janssen-Cilag PART OF THE DOSSIER Ltd. NAME OF FINISHED PRODUCT: Volume: Not applicable NAME OF ACTIVE INGREDIENT(S): Page: R278474 Protocol No.: R278474-CDE-102 Title of Study: A double-blind, randomized, placebo-controlled study to evaluate the safety and tolerability, pharmacokinetics and ex vivo pharmacodynamics of multiple oral doses of R278474 in healthy male volunteers Principal Investigator: The Netherlands. Publication (Reference): Not applicable Study Period (years): 20 - 20 Phase of development: 1 Objectives: To assess the safety and tolerability, pharmacokinetics, and ex vivo antiviral activity following multiple oral doses of R278474 (NNRTI [Non-nucleoside Reverse Transcriptase Inhibitor]) in healthy male subjects. Methodology: This was a double-blind, randomized, placebo-controlled study. Twenty-seven subjects were randomized to 3 groups of 9, with 6 subjects receiving R278474 and 3 subjects receiving placebo in each group. Three doses (25, 75, and, 150 mg) of R278474 in PEG 400 solution were given once daily for 14 days in ascending order. Progression to the next dose level was dependent on a satisfactory review of the safety, tolerability and plasma PK data. Adrenal function was assessed during the screening phase and postdose on Days 1, 7, and 14 by measuring the diurnal changes in cortisol and adrenocorticotrophic hormone (ACTH) levels over a 24-hour period. Subjects were then stimulated with low-dose ACTH and adrenal function measured for a further 2 hours. Supine and standing renin and aldosterone levels, and precursors of cortisol were also measured. Number of Subjects (planned and analyzed): 27 planned; 27 randomized and dosed; 27 analyzed. Diagnosis and Main Criteria for Inclusion: Healthy, caucasian males, aged between 18 and 55 years with a body mass index range between 18.0 and 28.0 kg/m2. A baseline morning cortisol of at least 100 nmol/L and a normal 24 hour diurnal variation in cortisol and ACTH levels, and an increase of >20% from baseline in cortisol in response to low-dose ACTH stimulation. Test Product, Dose and Mode of Administration: R278474 was supplied as a 25-mg/mL solution in 100% PEG 400. Subjects were given daily oral doses of 25, 75, and 150 mg R278474 as an oral solution. Batch No.: 03E13/F002 (25 mg), 03E15/F002 (75 and 150 mg), 03E19/F002 (150 mg), 03E22/F002 (150 mg) Reference Therapy, Dose and Mode of Administration: 100% PEG 400 solution (1.12 g/mL), equal-volume dose, oral administration. Batch No.: 03E26/F001 Duration of Treatment: Once daily doses for 14 days. Criteria for Evaluation: Pharmacokinetics: Plasma concentration-time profiles (0-24 hours) on Day 1 and Day 14 were determined. Peak and trough concentrations were measured from Day 2 to Day 13. Terminal elimination half-life of R278474 was estimated after the last dose. A predose urine sample and complete urinary output during a 24-hour dosing interval were collected on Day 1 and Day 14 for the assessment of urinary clearance of unchanged R278474. Pharmacodynamics (Ex Vivo Antiviral Activity): Blood samples were taken at predose and up to 24 hours postdose on Day 1 and Day 14, respectively, after administration of R278474 or placebo. Safety: Adverse events, physical examination, clinical laboratory data, adrenal function testing, vital signs, and 12-lead ECG.
Clinical Research Report Synopsis 1 R278474: Clinical Study Report 278474-CDE-102
NAME OF SPONSOR/COMPANY: INDIVIDUAL STUDY (FOR NATIONAL Johnson & Johnson Pharmaceutical Research TABLE REFERRING TO AUTHORITY USE ONLY) & Development, Division of Janssen-Cilag PART OF THE DOSSIER Ltd. NAME OF FINISHED PRODUCT: Volume: Not applicable NAME OF ACTIVE INGREDIENT(S): Page: R278474
Statistical Methods: Pharmacokinetics: Descriptive statistics were conducted for the plasma concentrations of R278474 at each sampling
time and for the pharmacokinetic parameters. Mean (SD) Cmax and AUCW on Day 1 and Day 14 were plotted as a function of dose in order to explore dose linearity. Statistical analysis of dose proportionality on log-transformed (dose
normalized) Cmax and AUCW on Day 1 and Day 14 was performed. Pharmacodynamics: Descriptive statistics were conducted on ex vivo antiviral data. Safety: Safety data were summarized and listed only; no formal statistical analysis was carried out. All subjects receiving treatment were included in the analysis. SUMMARY – CONCLUSIONS PHARMACOKINETIC RESULTS: Day 1 Day 14 Parameter 25 mg (N=6) 75 mg (N=6) 150 mg (N=6) 25 mg (N=6) 75 mg (N=6) 150 mg (N=6) a Cmax (ng/mL) 100 ± 42 328 ± 76 463 ± 133 222 ± 21 664 ± 109 1069 ± 269 b tmax (h) 4 (2-6) 4 (2-6) 4 (2-6) 4 (4-6) 4 (2-4) 4 (4-6) a Ctrough (ng/mL) 44 ± 9 126 ± 28 155 ± 14 109 ± 14 375 ± 89 547 ± 95 a AUCW (ngh/mL) 1345 ± 398 4397 ± 1058 5663 ± 981 3626 ± 368 11215 ± 2125 17703 ± 2908 a t1/2 (h) N/A N/A N/A 48.9 ± 18.0 41.9 ± 9.9 41.0 ± 5.0 a Mean rSD; b Median (min-max); N/A = Not available
R278474 was well absorbed when dosed orally as a PEG 400 solution. Following the first dose, the median tmax was attained at 4 hours postdose following all doses. The mean Cmax increased dose proportionally from 25 to 75 mg, but the increase in Cmax was less than dose proportional from 75 to 150 mg R278474. AUCW (W = 24 hour) and Ctrough levels showed similar dose proportional increases between 25 and 75 mg and a less than dose proportional increase between 75 and 150 mg R278474. Plasma concentrations of R278474 accumulated during once daily dosing and
reached steady-state after 8 to 10 doses. The median accumulation index was 2.0 fold for Cmax, 2.6 fold for AUCW, and 3.0 fold for Ctrough. The drug exposure increased with dose on both Day 1 and Day 14. Very little R278474 was excreted unchanged in urine. The estimated mean renal clearance was low, ranging from 0.0020 to 0.0027 L/h. Renal clearance of R278474 appeared not to be a significant route of elimination. Small amounts of the Z-isomer were found in the urine samples. PHARMACODYNAMIC RESULTS: (Ex Vivo Antiviral Activity) Day 1 Day 14 Parameter 25 mg (N=6) 75 mg (N=6) 150 mg (N=6) 25 mg (N=6) 75 mg (N=6) 150 mg (N=6) a Emax (ng/mL) 43 ± 27 186 ± 38 288 ± 166 83 ± 32 502 ± 87 549 ± 51 b tmax E (h) 5 (4-24) 5 (4-12) 4 (4-6) 6 (4-6) 5 (4-12) 4 (4-24) a AUECW (ngh/mL) 469 ± 195 2641 ± 727 3418 ± 1318 1268 ± 523 7555 ± 1188 9770 ± 3132 a b Mean r SD; Median (min-max); Emax = maximum antiviral effect; tmax E = time to reach Emax AUECW = area under the effect-time curve over a dosing interval The maximum antiviral activity assessed by the ex vivo assay was attained between 4 and 6 hours postdose (median
times). Emax and AUECW increased by 2 to 3-fold over the 14-day dosing schedule. The magnitude of increase was similar to that of Cmax and AUCW.
Clinical Research Report Synopsis 2 R278474: Clinical Study Report 278474-CDE-102
NAME OF SPONSOR/COMPANY: INDIVIDUAL STUDY (FOR NATIONAL Johnson & Johnson Pharmaceutical Research TABLE REFERRING TO AUTHORITY USE ONLY) & Development, Division of Janssen-Cilag PART OF THE DOSSIER Ltd. NAME OF FINISHED PRODUCT: Volume: Not applicable NAME OF ACTIVE INGREDIENT(S): Page: R278474 SAFETY AND TOLERABILITY RESULTS: Multiple oral doses of R278474 were well tolerated at dose levels of 25 to 150 mg. There were no serious adverse events. Adverse events were reported by all 9 subjects (100%) receiving placebo and by 16 (89%) of 18 subjects receiving R278474. The majority of adverse events were mild in severity and no adverse events were severe. The only safety concern was the higher incidence of headaches observed in subjects receiving R278474 compared with placebo, however all these adverse events were mild in severity, all resolved, and there were no apparent dose-related trends. Subject 1004, who received 25 mg R278474 daily for 9 days, did not receive study drug from Day 10 onwards because of increased liver transaminases that were possibly related to the study drug. However, liver transaminase values returned to predose levels 19 days after receiving the last dose of R278474 on Day 9. There were no other clinically significant treatment-emergent changes in clinical laboratory analyses and no indication of any effect of treatment on vital signs and ECG parameters. Adrenal function was assessed by measuring the 24-hour diurnal variation in cortisol and ACTH levels before and after dosing with R278474. The response to low-dose ACTH stimulation was also assessed for 2 hours at the end of the 24-hour period. Diurnal changes in cortisol and ACTH levels were normal for the 0 to 24 hour postdose period for all doses of R278474. Similarly, low-dose ACTH stimulation produced the expected response. CONCLUSIONS: The results in this study suggest that daily dosing with R278474 for 14 days is well tolerated in healthy male volunteers with no major adverse events. There were no adverse effects on adrenal function. There was good drug exposure and pharmacokinetics were linear over time. The ex vivo antiviral activity showed a linear correlation with the plasma drug concentration. Date of the report: 15 September 2004
Clinical Research Report Synopsis 3 R278474: Clinical Study Report 278474-CDE-103
SYNOPSIS
NAME OF SPONSOR/COMPANY: INDIVIDUAL STUDY (FOR NATIONAL Johnson & Johnson Pharmaceutical Research TABLE REFERRING TO AUTHORITY USE & Development, Division of Janssen-Cilag PART OF THE DOSSIER ONLY) Ltd. NAME OF FINISHED PRODUCT: Volume: Not applicable NAME OF ACTIVE INGREDIENT(S): Page: R278474 Protocol No.: R278474-CDE-103 Title of Study: Double-blind, randomized, placebo-controlled study to evaluate the safety, tolerability, pharmacokinetics and ex vivo pharmacodynamics of single oral doses of R278474 in healthy male subjects. Principal Investigator: The Netherlands. Publication (Reference): Not applicable Study Period (years): 20 - 20 Phase of development: 1 Objectives: To assess the safety, tolerability, pharmacokinetics and ex vivo pharmacodynamics after single oral doses of 50 to maximally 300 mg of R278474 (NNRTI [Non-nucleoside Reverse Transcriptase Inhibitor]) in PEG 400 solution in healthy male subjects. Methodology: This was a double-blind, randomized, placebo-controlled study in 4 groups of 9 healthy male subjects at doses of 50, 100, 200 and 300 mg R278474 in PEG 400 solution. In each group, 6 subjects were to receive R278474 and 3 subjects were to receive placebo. Progression to the next dose level was dependent on a satisfactory review of the safety and plasma PK data. Adrenal function was assessed during the screening phase (at Day –5) and postdose by measuring the diurnal changes in cortisol and adrenocorticotrophic hormone (ACTH) levels over a 24-hour period. Subjects were then stimulated with low-dose ACTH and adrenal function measured for a further 2 hours. Number of Subjects (planned and analyzed): 36 planned; 36 randomized and dosed; 36 analyzed. Diagnosis and Main Criteria for Inclusion: Healthy, caucasian, male subjects, aged between 18 and 55 years with a body mass index range between 18.0 and 28.0 kg/m2. A baseline morning cortisol of at least 100 nmol/L and a normal 24 hour diurnal variation in cortisol and ACTH levels, and an increase of >20% from baseline in cortisol in response to low-dose ACTH stimulation. Test Product, Dose and Mode of Administration: R278474 supplied as a 25 mg/mL solution in 100% PEG 400. Subjects were given a single oral dose of 50, 100, 200 and 300 mg R278474 as an oral solution. Batch No.: 03E06/F002. Reference Therapy, Dose and Mode of Administration: 100% PEG 400 solution (1.12 g/mL), equal-volume dose, oral administration. Batch No.: 03C20/F001. Duration of Treatment: Single oral dose Criteria for Evaluation: Pharmacokinetics: Blood and urine samples were collected from each subject before and up to 144 hours and 72 hours, respectively, after the administration of R278474 or placebo. Pharmacodynamics (Ex Vivo Antiviral Activity): Blood samples were taken from each subject before and up to 12 hours postdose after the administration of R278474 or placebo. Safety: Adverse events, physical examination, clinical laboratory data, adrenal function testing, vital signs, and 12-lead ECG.
Clinical Research Report Synopsis 1 R278474: Clinical Study Report 278474-CDE-103
NAME OF SPONSOR/COMPANY: INDIVIDUAL STUDY (FOR NATIONAL Johnson & Johnson Pharmaceutical Research TABLE REFERRING TO AUTHORITY USE & Development, Division of Janssen-Cilag PART OF THE DOSSIER ONLY) Ltd. NAME OF FINISHED PRODUCT: Volume: Not applicable NAME OF ACTIVE INGREDIENT(S): Page: R278474 Statistical Methods: Pharmacokinetics: Descriptive statistics were conducted for plasma concentrations and pharmacokinetic parameters of R278474. Mixed effect ANOVA modeling, with dose as the primary predictor, was fitted to
evaluate the dose proportionality on log-transformed (dose normalized), AUCf, AUC0-144 and Cmax values. For the urine analysis, the total amount of unchanged R278474 excreted over each collection period and the cumulative amount were calculated. Urinary recovery was expressed as percentage of dose excreted as unchanged R278474 over 72 hours (Ae72h). Pharmacodynamics: Descriptive statistics were conducted on ex vivo antiviral data. Safety: Safety data were summarized and listed only; no formal statistical analysis was carried out. All subjects receiving treatment were included in the analysis. SUMMARY – CONCLUSIONS PHARMACOKINETIC RESULTS: R278474 Parameter 50 mg (N=6) 100 mg (N=6) 200 mg (N=6) 300 mg (N=6) a Cmax (ng/mL) 226 ± 15 482 ± 121 807 ± 207 944 ± 172 b tmax (h) 4 (4.2-6) 4 (4-6) 4 (4-6) 4 (4-4) a AUC0-144h (ng·h/mL) 6,118 ± 1,558 13,013 ± 4,039 25,600 ± 5,621 27,910 ± 7,298 a AUCf (ng·h/mL) 6,584 ± 1,881 15,820 ± 4,568 28,669 ± 6,876 32,794 ± 10,352 a t1/2term (h) 34.2 ± 12.0 54.6 ± 17.9 43.1 ± 13.1 52.0 ± 17.2 a Mean r SD; b Median (min-max)
Following a single oral dose of R278474, the drug was well absorbed and median tmax was achieved at 4 hours postdose in all dosing groups. After tmax, the drug concentration declined bi-exponentially with time, with slow elimination of the drug. The pharmacokinetics of R278474 were linear up to 200 mg, as Cmax, AUCt and AUCf increased proportionally with the dose. From 200 to 300 mg, the Cmax and AUCt increased less than proportionally. The average urinary recovery of unchanged R278474 was d0.03% of the administered dose, suggesting that renal excretion was a minor route of drug elimination. No Z-isomer was detected in the plasma samples. Small amounts of the Z-isomer were found in the urine samples. PHARMACODYNAMIC RESULTS: (Ex Vivo Antiviral Activity): R278474 Parameter 50 mg (N=6) 100 mg (N=6) 200 mg (N=6) 300 mg (N=6) a tmax (h) 5 r 3 5 r 1 4 r 2 5 r 4 Median (min-max) 4 (4-12) 4 (4-6) 4 (2-6) 4 (2-12) a Emax (ng/mL) 249 r 191 207 r 110 463 r 121 557 r 140 Median (min-max) 180 (92-613) 183 (91-417) 460 (268-589) 569 (326-697)
a AUEC12h (ngh/mL) 1,230 r 310 1,279 r 632 3,176 r 538 3918 r 1586 Median (min-max) 1,210 (772-1,733) 1,128 (678-2,514) 3,292 (2,224-3,665) 3,280 (2,142-6,253) a Mean r SD The ex vivo activity increased in a concentration-dependent manner. The median time for the maximum antiviral effect was observed at 4 hours postdose for all doses.
Clinical Research Report Synopsis 2 R278474: Clinical Study Report 278474-CDE-103
NAME OF SPONSOR/COMPANY: INDIVIDUAL STUDY (FOR NATIONAL Johnson & Johnson Pharmaceutical Research TABLE REFERRING TO AUTHORITY USE & Development, Division of Janssen-Cilag PART OF THE DOSSIER ONLY) Ltd. NAME OF FINISHED PRODUCT: Volume: Not applicable NAME OF ACTIVE INGREDIENT(S): Page: R278474 SAFETY AND TOLERABILITY RESULTS: Single oral doses of R278474 were well tolerated when administered at dose levels of 50 to 300 mg. There were no serious adverse events and no subjects were withdrawn due to adverse events. Adverse events were reported by 7 (58%) of 12 subjects receiving placebo and by 14 (58%) of 24 subjects receiving R278474. There were no apparent dose-related trends in the incidence of adverse events. The majority of adverse events were mild in severity. There was no evidence of any drug-specific adverse events. There were no consistent clinically significant treatment-emergent changes in clinical laboratory analyses and no indication of any effect of treatment on vital signs and ECG parameters. Adrenal function was assessed by measuring the 24-hour diurnal variation in cortisol and ACTH levels before and after dosing with R278474. The response to low-dose ACTH stimulation was also assessed for 2 hours at the end of the 24-hour period. There was no indication of any consistent treatment effects on diurnal changes in cortisol and ACTH levels and the response to low-dose ACTH stimulation. CONCLUSIONS: The results in this study suggest that R278474 is a well-tolerated NNRTI with no major adverse events in healthy male subjects. There were no adverse effects on adrenal function. Good drug exposure, slow drug elimination and low inter-subject variability in PK parameters were observed. The ex vivo antiviral activity showed linear correlation with the plasma drug concentration. Date of the report: 16 September 2004
Clinical Research Report Synopsis 3 TMC278-C103 1
SYNOPSIS Trial Identification and Protocol Summary Company: Tibotec Pharmaceuticals Ltd. Drug Substance: TMC278 Trade Name: Not applicable Trial no.: TMC278-C103 Indication: HIV-1 infection Clinical Phase: I Title: A Phase I, open label, randomized, multiple dose ranging trial in four parallel panels of 12 healthy subjects each, to determine the pharmacokinetics, safety and tolerability of once daily dosing of TMC278 formulated as a solid formulation Investigator: Country: Belgium Belgium Trial Period: Start: - -20 No. of Investigators: 1 End: - -20 No. of Subjects: 48 Objectives: The objectives of the trial were to determine single dose and steady-state pharmacokinetics and dose-proportionality of TMC278 after multiple once daily dosing of a solid oral formulation and to determine the short-term safety and tolerability of TMC278 after once daily dosing over a period of 14 days. Design: This was a Phase I, open label, multiple dose ranging trial in which 48 healthy subjects were randomized over 4 parallel panels of 12 subjects each. To each panel, TMC278 was administered orally as a once daily (q.d.) dose from Day 1 until 14. Panels 1, 2, 3, and 4 received 25 mg (Treatment A), 50 mg (Treatment B), 100 mg (Treatment C), and 150 mg (Treatment D) TMC278 q.d., respectively. Full pharmacokinetic profiles of TMC278 were determined on Day 1 up to 24 hours and on Day 14 up to 216 hours. Furthermore, tolerability and safety were assessed on an ongoing basis. The aim of this trial was to explore the single dose and steady-state pharmacokinetics and dose-proportionality of TMC278 after multiple oral q.d. dosing of this solid formulation. Subject Selection Inclusion Criteria 1. Aged between 18 and 55 years, extremes included. 2. Smoking no more than 10 cigarettes, or 2 cigars, or 2 pipes per day (or non-smoking) for at least 3 months prior to selection. 3. Normal weight as defined by a Quetelet Index (Body Mass Index: weight in kg divided by square of height in meters) of 18.0 to 30.0 kg/m2, extremes included. 4. Informed Consent Form signed voluntarily before the first trial-related activity. 5. Cortisol of at least 550 nmol/L (19.9 Pg/dl) at any time point at screening (i.e., morning cortisol, 30 or 60 minutes after 250 Pg adrenocorticotropic hormone [ACTH] stimulation). 6. Able to comply with protocol requirements. 7. Healthy on the basis of a pre-trial physical examination, medical history, electrocardiogram, vital signs, and the results of blood biochemistry, hematology and coagulation tests, and a urinalysis at screening.
Exclusion Criteria 1. A positive HIV-1 or HIV-2 test at study screening. 2. Female, except if postmenopausal for more than 2 years, or posthysterectomy or post tubal ligation (without reversal operation). 3. History or suspicion of alcohol, barbiturate, amphetamine, recreational, or narcotic drug use that, in the investigator’s opinion, could compromise the subject’s safety and/or ability to comply with trial procedures. 4. Hepatitis A infection (confirmed by Hepatitis A antibody IgM), or Hepatitis B infection (confirmed by Hepatitis B surface antigen), or Hepatitis C infection (confirmed by Hepatitis C virus antibody) at study screening. 5. A positive urine drug test at study screening. Urine was tested for the presence of amphetamines, benzodiazepines, cocaine, cannabinoids, and opioids. 6. Currently active or underlying gastrointestinal, cardiovascular, neurological, psychiatric, metabolic, renal, hepatic, respiratory, inflammatory, or infectious disease. 7. Any previous or current adrenal illness. 8. Currently significant diarrhea, gastric statis, or constipation that in the investigator’s opinion could influence drug absorption or bioavailability.
Clinical Research Report Synopsis Version: 2.0 Date: 02-Jun-2005 TMC278-C103 2
9. Any history of significant skin disease such as but not limited to drug rash or eruptions, drug allergies, food allergy, dermatitis, eczema, psoriasis, or urticaria. 10. Previously demonstrated clinically significant allergy or hypersensitivity to any of the excipients of the investigational medication administered in this trial. 11. Use of concomitant medication, including over the counter products and dietary supplements, except for ibuprofen up to 3 days before the first dose of trial medication. All other medication must have been discontinued at least 14 days before the first dose of trial medication. 12. Participation in an investigational drug trial within 30 days prior to the screening visit. 13. Donation of blood or plasma in the 60 days preceding the first intake of trial medication. 14. Having previously participated in a trial with TMC125, TMC120, or TMC278. 15. Subjects with the following laboratory abnormalities at screening as defined by the enhanced toxicity grading severity list: serum creatinine grade 1 or greater; pancreatic amylase or lipase grade 1 or greater; hemoglobin toxicity grade 1 or greater; platelet count grade 1 or greater; absolute neutrophil count grade 1 or greater; aspartate aminotransferase or alanine aminotransferase grade 1 or greater; total bilirubin grade 1 or greater; any other toxicity grade 2 or above, including: proteinuria (spot urine) > 1+ and gross hematuria. Treatment Treatment A Treatment B Treatment C Treatment D Dose 25 mg q.d. 50 mg q.d. TMC278 100 mg q.d. TMC278 150 mg q.d TMC278 TMC278
Dosage Form Tablet Tablet Tablet Tablet (TF No.) (F001) (F001) (F002) (F001) and (F002)
Usage 1 tablet p.o. 2 tablets p.o. 1 tablet p.o. 2 x 25 mg tablets p.o. Day 1-14 Day 1-14 Day 1-14 and 1 x 100 mg tablet p.o. Day 1-14 Batch Number PD1216 PD1216 PD1211 PD1216, PD1211 Dose Regimen Panel 1: Treatment A, Panel 2: Treatment B, Panel 3: Treatment C, Panel 4: Treatment D Duration of Treatment 14 days Duration of Trial 24 days (excluding screening and follow-up) Disallowed Medication During the entire trial, subjects were not allowed to use any medication other than the trial medication. All medication had to be discontinued at least 14 days before first drug administration, except for ibuprofen. Ibuprofen was allowed up to 3 days before drug administration. After that, the investigator could permit the use of ibuprofen (no more than 1 x 400 mg per day) until 9 days (216 hours) after the last trial medication intake. Subjects were not to use any herbal medications or dietary supplements including products containing Hypericum perforatum (e.g., St. John’s wort) from 14 days before the first drug administration up to 9 days after the last drug administration. In case of cutaneous event/rash and/or an allergic reaction, the use of cetirizine, topical corticosteroids, or antipruritic agents in the recommended dosing scheme was permitted. In case of nausea, the use of antiemetics was permitted. In case of diarrhea the use of loperamide was allowed.
Clinical Research Report Synopsis Version: 2.0 Date: 02-Jun-2005 TMC278-C103 3
Assessments Screen- Panels 1, 2, 3, and 4 Follow- inga upb
+ 11 Day 1 Day 2 Day 7 21 days days 21 Day –1 Day 10 Day 14 Day 15 Day 23 32, or, 33 d Day 16-21 Day 16-21 Day 30, 31, Day 30, Day 12 + 13 Day 12 + Day 3-6, 8-9 8-9 Day 3-6, Drug X X X X X X X administration Drug screening X Pregnancy test, if X applicable Pharmacokinetics Blood sample Xc Xd Xd Xd Xd Xe Xf Xg Xg Safety Adverse eventsh X X X X X X X X X X X X Concomitant meds X X X X X X X X X X X X Hemat & biochemi X Xk Xj X Xk X X X Urinalysis X Xj Xj Xj X X X ECG & vital signs X Xj, k Xj Xj, k X X X Morning cortisol X X ACTH stimulation X X test Skin exam X X X X Xl X X X Physical exam X X X Xm X meds = medication; Hemat & biochem = hematology & biochemistry; ACTH = adrenocorticotropic hormone; ECG = electrocardiogram; exam = examination. a At screening, subject’s demographics and characteristics, medical and surgical history, concomitant diseases, HIV-1 and -2 test, Hepatitis A, B, and C test, and smoking habits were recorded. b In case of dropout for reasons other than withdrawal of consent: additional blood and urine samples for safety were taken; additional ECG and vital signs were recorded; and a physical examination (including skin examination) was performed at the time of dropout or the following morning, 7, 8, or 9 days after dropout, and 30, 31, 32, or 33 days after last drug intake. A morning cortisol and ACTH stimulation test was performed 7, 8, or 9 days after dropout (preferably 7 days after dropout). Additional blood samples for pharmacokinetics were also taken at the time of dropout (or the following morning). A skin examination was performed 10 days after the first intake of TMC278 (only applicable in case of dropout for a non-cutaneous event/rash and if this time point had not yet been reached at the time of dropout). c Within 2 hours before TMC278 intake, before breakfast, and at 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours postdose. d Within 15 minutes before TMC278 intake. e Within 15 minutes before TMC278 intake and at 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours postdose. f At 24 and 32 hours postdose. g Time window of 48 ± 1 hour on Day 16, 72 ± 1 hour on Day 17, 96 ± 1 hour on Day 18, 120 ± 1 hour on Day 19, 144 ± 1 hour on Day 20, 168 ± 1 hour on Day 21, and 216 ± 1 hour on Day 23. h Adverse events were monitored continuously from signing of the informed consent to final trial-related visit. i Biochemistry samples were taken fasting for at least 10 hours except at 4 hour postdose timepoint. j Within 2 hours before TMC278 intake and before breakfast. k Measured predose and at 4 hours postdose. l On Day 13 only. m Physical examination could be done on Day 21, in case Day 23 was a weekend. Statistical Methods Descriptive statistics, frequency tabulations, graphical presentations, Intent-to-Treat analysis, Wilcoxon matched-pairs signed-ranks test, linear mixed effects modeling.
Clinical Research Report Synopsis Version: 2.0 Date: 02-Jun-2005 TMC278-C103 4
Main Features of the Subject Sample and Summary of the Results Baseline Characteristics - Subject 25 mg q.d. 50 mg q.d. 100 mg q.d. 150 mg q.d. Disposition TMC278 TMC278 TMC278 TMC278 Total Number of Subjects Entered (M/F) 11/1 10/2 10/2 11/1 42/6 Age: median (range), yrs 39.0 (21-54) 39.0 (26-52) 43.0 (22-52) 38.0 (21-53) 39.5 (21-54) Drop-Outs - Reason 0 0 1 1 2 Adverse Event 0 0 1 0 1 Subject Withdrew Consent 0 0 0 1 1
Pharmacokinetics of TMC278
(meanrSD; tmax: 25 mg q.d. TMC278 50 mg q.d. TMC278 100 mg q.d. TMC278 150 mg q.d. TMC278 median (range)) n 12 12 12a 12b Day 1
Cmax, ng/mL 90.08 ± 44.28 138.2 ± 63.10 397.6 ± 147.3 523.8 ± 136.9 tmax, h 4.0 ( 2.0 - 6.0 ) 4.0 ( 3.0 - 4.0 ) 4.0 ( 2.0 - 6.65 ) 4.0 ( 3.0 - 6.0 )
AUC24h, ng.h/mL 1072 ± 585.6 1551 ± 596.0 4464 ± 1520 5608 ± 1902 Day 7
C0h, ng/mL 79.13 ± 30.22 169.7 ± 61.44 353.6 ± 111.4 431.4 ± 133.7 Day 10
C0h, ng/mL 90.43 ± 39.36 161.8 ± 85.20 312.3 ± 105.3 482.4 ± 178.0 Day 12
C0h, ng/mL 91.72 ± 38.43 149.7 ± 52.83 336.5 ± 116.4 449.4 ± 198.0 Day 13
C0h, ng/mL 83.64 ± 38.23 168.6 ± 74.71 326.8 ± 129.3 459.5 ± 178.6 Day 14
C0h, ng/mL 89.85 ± 38.07 157.9 ± 52.23 347.8 ± 148.7 504.9 ± 174.6
Cmin, ng/mL 66.85 ± 29.53 115.7 ± 49.30 249.5 ± 90.51 362.0 ± 130.9
Cmax, ng/mL 203.8 ± 75.81 298.6 ± 98.05 685.5 ± 202.4 1019 ± 222.0 tmax, h 4.0 ( 2.0 - 4.0 ) 4.0 ( 2.0 - 6.0 ) 4.0 ( 2.0 - 6.0 ) 4.0 ( 3.0 - 6.0 )
AUC24h, ng.h/mL 2589 ± 868.8 4139 ± 1236 9278 ± 2846 13581 ± 3195 t1/2term, h 50.92 ± 19.56 48.75 ± 16.34 46.07 ± 15.44 44.83 ± 12.31
Css,av, ng/mL 107.8 ± 36.20 172.5 ± 51.48 386.6 ± 118.6 565.9 ± 133.1 FI, % 128.5 ± 41.71 107.8 ± 45.20 113.7 ± 35.59 121.7 ± 46.55 Acc. Ratio 3.020 ± 1.966 2.880 ± 0.7982 2.071 ± 0.7491 2.503 ± 0.7211 a for the parameters of Day 10 until Day 14: n=11 b for the parameters of Day 7 until Day 14: n=11
Clinical Research Report Synopsis Version: 2.0 Date: 02-Jun-2005 TMC278-C103 5
Safety 25 mg q.d. 50 mg q.d. 100 mg q.d. 150 mg q.d. (n = number of subjects with data during TMC278 TMC278 TMC278 TMC278 TMC278 treatment phase) (n=12) (n=12) (n=12) (n=12) Adverse Events (AEs) Most frequently reported AEs (reported in > 1 subject), n (%) Headache 2 (16.7%) 4 (33.3%) 2 (16.7%) 2 (16.7%) Hyperbilirubinaemia 2 (16.7%) 2 (16.7%) 2 (16.7%) 1 (8.3%) Lipase Increased 1 (8.3%) 1 (8.3%) 2 (16.7%) 1 (8.3%) Bowel Sounds Abnormal 2 (16.7%) 1 (8.3%) 1 (8.3%) 0 Dizziness 2 (16.7%) 1 (8.3%) 0 1 (8.3%) n (%) with 1 or more AEs 8 (66.7%) 8 (66.7%) 7 (58.3%) 5 (41.7%) n (%) of deaths 0 0 0 0 n (%) with 1 or more other serious AEs 0 0 0 0 n (%) of treatment stopped due to AEs 0 0 1 (8.3%) 0 n (%) with 1 or more grade 3 or 4 AEs 0 0 2 (16.7%) 2 (16.7%) Clinical Laboratory Tests n (%) with 1 or more grade 3 or 4 0 0 2 (16.7%) 1 (8.3%) laboratory abnormalities Laboratory Tests There were no consistent or clinically relevant treatment-emergent changes over time in laboratory parameters. No grade 4 events were reported. Four grade 3 abnormalites were reported during the trial: 2 during treatment with 100 mg q.d. TMC278 (elevated amylase and lipase) and 1 posttreatment (elevated lipase), and 1 during treatment with 150 mg q.d. TMC278 (elevated lipase). All grade 3 events had associated AEs reported. Urinalysis indicated occasional abnormalities in each panel however, no urinalysis results were considered to constitute an AE. Adrenal Function Testing Normal adrenal function was recorded for all subjects at screening and on Day 15.
Clinical Research Report Synopsis Version: 2.0 Date: 02-Jun-2005 TMC278-C103 6
Cardiovascular Safety Minor changes were reported for vital signs, with statistically significant changes mainly being decreases in diastolic blood pressure and mostly with the high doses (Panels 3 and 4). None of the statistically significant changes were considered to be clinically relevant. Minor changes were reported for ECG parameters, very few of which were statistically significant. No trends or relationship to treatment were apparent and no clinically relevant changes in ECG parameters were reported. Physical Examination Physical examination revealed abnormal, new findings in each panel of subjects during the treatment phase. In the 25 mg q.d. TMC278 dose group, 1 subject had painful muscles (flu-like syndrome) on Day 15 and 2 subjects had red pharynx on Day 23. In the 50 mg q.d. TMC278 dose group, 1 subject had stuffed nose on Day 23. In the 100 mg q.d. TMC278 dose group, 1 subject had superficial phlebitis, left arm on Day 23. In the 150 mg q.d. TMC278 dose group, 1 subject had red pharynx (common cold) on Day 23 and 1 subject had pain lumbar region at follow-up. Skin examination also revealed abnormal, new findings during the treatment phase in the 50 mg q.d. TMC278 dose group (some scratch marks on left arm on Day 10, and dry skin disappeared on Day 13). No abnormal, new findings were reported in the 25, 100, or 150 mg q.d. TMC278 dose groups during the treatment phase.
Conclusions The results of this study demonstrate that single dose and steady-state pharmacokinetic characteristics of TMC278 are independent of the dose within the investigated dose range of 25 mg to 150 mg once daily. Steady-state was reached before Day 7 for all dose levels. In these healthy subjects, the administration of TMC278 as multiple oral once daily doses (25, 50, 100, or 150 mg q.d.) for 14 days was generally well tolerated and safe. The safety and tolerability profile of TMC278 was similar for all dose groups.
Clinical Research Report Synopsis Version: 2.0 Date: 02-Jun-2005 TMC278-C119 1
SYNOPSIS Trial Identification and Protocol Summary Company: Tibotec Pharmaceuticals Ltd. Drug Substance: TMC278 Trade Name: - Trial no.: TMC278-C119 Indication: HIV-1 infection Clinical Phase: I Title: A Phase I, open label, single dose, mass-balance trial with 14C-labeled TMC278 Investigator: Country: Belgium
Belgium Trial Period: Start: - -20 No. of Investigators: 1 End: - -20 No. of Subjects: 6 Objectives: The objective of this study was to characterize the excretion and the overall metabolic profile after a single dose of 14C-labeled TMC278 in humans. Design: This was a Phase I, open label, single dose, mass-balance trial in 6 healthy male subjects. TMC278 (14C-labeled and unlabeled) was administered at a dose of 150 mg as an oral solution. Plasma and urine samples were collected at least until Day 8 and thereafter until the respective discharge criteria had been met. After discharge, feces continued to be collected at home on a daily basis until Day 14. Unchanged TMC278 was determined in plasma. Total radioactivity was determined in whole blood, plasma, urine, and feces. Metabolic profiles were determined in selected plasma, urine, and feces samples, and structures of major metabolites were characterized, whenever possible. The mass-balance was calculated. Safety and tolerability after a single dose of TMC278 were assessed. There was a safety follow-up visit at least 30 days after TMC278 intake. Subject Selection Inclusion Criteria 1. Male. 2. Aged between 40 and 60 years, extremes included. 3. Smoking no more than 10 cigarettes, or 2 cigars, or 2 pipes per day (or nonsmoking) for at least 3 months prior to selection. 4. Normal weight as defined by a Quetelet Index (Body Mass Index: weight in kg divided by length in meters squared) of 18.0 to 30.0 kg/m2, extremes included. 5. Informed Consent Form signed voluntarily before the first trial-related activity. 6. Cortisol of at least 550 nmol/L (19.9 Pg/dL) at any time point at screening (i.e., morning cortisol, 30 or 60 minutes after 250 Pg adrenocorticotropic hormone [ACTH] stimulation). 7. Able to comply with protocol requirements. 8. Healthy on the basis of a physical examination, medical history, electrocardiogram (ECG), vitals signs, and the results of blood biochemistry, and hematology tests, and a urinalysis at screening. Exclusion Criteria 1. A positive human immunodeficiency virus type 1 (HIV-1) or HIV-2 test at screening. 2. History or suspicion of alcohol, barbiturate, amphetamine, recreational, or narcotic drug use which in the investigator’s opinion would compromise subject’s safety and/or compliance with the trial procedures. 3. Hepatitis A, B, or C infection (confirmed by hepatitis A IgM antibody, hepatitis B surface antigen, or hepatitis C antibody, respectively) at screening. 4. A positive urine drug test at screening. Urine will be tested for the presence of amphetamines, benzodiazepines, cocaine, cannabinoids, and opioids. 5. Currently active or underlying gastrointestinal, cardiovascular, nervous system, psychiatric, metabolic, renal, hepatic, respiratory, inflammatory, or infectious disease. 6. Any previous or current adrenal illness. 7. Currently significant diarrhea, gastric statis, or constipation that in the investigator’s opinion could influence drug absorption or bioavailability. 8. Any history of significant skin disease such as, but not limited to, rash or eruptions, drug allergies, food allergy, dermatitis, eczema, psoriasis, or urticaria. 9. History of renal insufficiency (calculated creatinine clearance < 60 mL/min).
Clinical Research Report Version: 1.0 Date: 14-Jun-2006 TMC278-C119 2
10. Previously demonstrated clinically significant allergy or hypersensitivity to any of the excipients of the investigational medication administered in this trial. 11. Use of concomitant medication, including over the counter products and dietary supplements, except for ibuprofen up to 3 days before the administration of study medication. All other medication must have been discontinued at least 14 days before the administration of study medication. 12. Participation in an investigational drug trial within 30 days preceding the administration of study medication. 13. Donation of blood or plasma in the 60 days preceding the administration of study medication. 14. Having received TMC125, TMC120, or TMC278 (formerly known as R278474) in a previous trial. 15. Exposure to noncosmic sources of radiation in the past year, such as X-ray photographs (except dental X-rays), intake of radionuclides for medical diagnostic purposes, and professional exposure to radionuclides). 16. Irregular defecation pattern (less than 1 defecation per 2 days). 17. Subjects with the following laboratory abnormalities at screening as defined by the enhanced toxicity grading severity list: serum creatinine grade 1 or greater (> 1.0 x upper limit of normal [ULN]); lipase grade 1 or greater (> 1.0 x ULN); hemoglobin grade 1 or greater (< 9.4 g/dL); platelet count grade 1 or greater (< 99000/mm3); aspartate aminotransferase or alanine aminotransferase grade 1 or greater (> 1.25 x ULN); total bilirubin grade 1 or greater (> 1.0 x ULN); any other toxicity grade 2 or above, including: proteinuria (spot urine) > 1+ and gross hematuria. Treatment All Subjects Concentration 25 mg/mL 14C-labeled and unlabeled TMC278 in Dosage Form (F no.) polyethylene glycol 400 Usage Solution (F002) Single dose on Day 1 Batch Number FK5343 Dose Regimen All subjects received a single 150 mg (6 mL) oral dose of TMC278 Duration of Treatment 1 day Duration of Trial 14 days (excluding screening and follow-up) Disallowed Medication Until the last urine or feces collection, subjects were not to use any medication other than the study medication and ibuprofen. All other mediation had to be discontinued at least 14 days before drug administration. Subjects were not to use any herbal medications or dietary supplements including products containing Hypericum perforatum (e.g., St. John’s wort) from at least 14 days before the start of the trial until the last urine or feces collection. Ibuprofen could be used up to 3 days before administration of study medication. From 3 days before the drug intake until the last urine or feces collection, the investigator could permit the use of ibuprofen at no more than 1 x 400 mg per day.
Clinical Research Report Version: 1.0 Date: 14-Jun-2006 TMC278-C119 3
Assessments Screen- All subjects inga
p Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 21 days days 21 Day –1 Day 11 d Day 30-35 Day 30-35 Leaving site Drug administration X Pharmacokinetics Blood sample Xc,d Xd,l Xd Xm Xm Xm Xm Xm X Safety Adverse eventsg X X X X X X X X X X X X X Concomitant meds X X X X X X X X X X X X X Hemat & biochemh X Xb Xe X X X X X Urinalysis X Xe,f Xi Xn X X ECG & vital signs X Xe X X X X Morning cortisol X X 17-OH-progesterone X X ACTH stimulation test X X T3, free T4, and TSH X X X D1-acid glycoprotein X X Feces collectionj X Xf X X X X X X Urine collectionk X X X X X X Skin exam X X X X X X Physical exam X X Xo X X meds = medication; Hemat & biochem = hematology & biochemistry; ACTH = adrenocorticotropic hormone; ECG = electrocardiogram; exam = examination; TSH = thyroid stimulating hormone, T3 = triiodothyronine, T4 = thyroxine. a At screening, subject’s demographics, medical and surgical history, concomitant diseases, HIV-1 and -2 test, hepatitis A, B, and C test, and smoking habits were recorded, and drug screening was performed. b Only for testing of coagulation parameters. c Within 2 hours before TMC278 intake, before breakfast, and at 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours postdose. d At 1, 2, 4, 8, and 12 hours postdose on Day 1, 24 hours postdose on Day 2, and 48 hours postdose on Day 3, in addition to the regular blood sample, an additional amount of blood was collected for determination of radioactivity in whole blood and in plasma, as well as for metabolite quantification and structural characterization in plasma. e Within 2 hours before TMC278 intake and before breakfast. f For safety and pharmacokinetic assessments. Feces collection on Day 1 includes urine collection from 0-4, 4-8 and 8-24 hours. g Adverse events were monitored continuously from signing of the informed consent to final trial-related visit. h Biochemistry samples were taken fasting for at least 10 hours. On Day 1, water intake was allowed until 2 hours before drug intake. On all other days, water intake was allowed. Coagulation parameters were only determined on Days –1 and 7, and at the last trial-related visit. i 10 mL was taken from urine sample for safety analysis, remainder of urine sample was to be added to urine collection. j After discharge, feces continued to be collected at home on a daily basis until Day 14. k From 24-48 hours postdose on Day 2, 48-72 hours postdose on Day 3, 72-96 hours postdose on Day 4, 96-120 hours postdose on Day 5, 120-144 hours postdose on Day 6, and 144-168 hours postdose on Day 7. l Taken 24 and 32 hours postdose. m Time window of r 1 h. n Only when leaving the site on Day 8. Subjects left the site on Day 8 if at least 7 stools had been delivered and if the radioactivity in the latest 2 urine collections (120-144 hours and 144-168 hours) accounted for d 2% of the dose/24 hours. After discharge, feces continued to be collected at home on a daily basis until Day 14.
Clinical Research Report Version: 1.0 Date: 14-Jun-2006 TMC278-C119 4
o Only if the discharge criteria on Day 8 were not met, collection of plasma continued with 24-h intervals until the radioactivity level fell d 2% of the dose/24 hours in urine and at least 7 stools were delivered, but until Day 14 at the latest. Collection of urine continued with 24-h intervals until the radioactivity level fell d 2% of the dose/24 h in urine and collection of feces continued per stool until at least 7 stools were available, but until Day 14 at the latest. p Only applicable for subjects who left the site on another day than Day 8. After Day 8, subjects left the site when the radioactivity level fell d 2% of the dose/24 h in urine and at least 7 stools had been delivered, but on Day 14 at the latest. Stools were collected for 14 days. Statistical Methods Descriptive statistics, frequency tabulations, graphical presentations, Wilcoxon matched-pairs signed-ranks test.
Main Features of the Subject Sample and Summary of the Results Baseline Characteristics - Subject TMC278 Disposition (N = 6) Number of Subjects Entered (M/F) 6/0 Age: median (range), yrs 47.5 (45-51) Drop-Outs 0
Pharmacokinetics of TMC278 TMC278 14C Total Radioactivity (mean r SD, tmax: median [range]) (N = 6) (N = 6) tmax, h 3.5 (3.0-4.0) 4.0 (3.0-4.0) Cmax, ng(eq.)/mL 602.8 r 126.1 794.7 r 170.7 AUClast, ng(eq.)h/mL 16240 r 4186 33040 r 11160 AUCf, ng(eq.)h/mL 18520 r 4709 56620a r 14090a a a Oz, l/h 0.01283 r 0.003019 0.006796 r 0.001735 a a t1/2term, h 56.56 r 12.98 107.7 r 27.45 a Accurate determination was not possible. Mass balance At 336 hours (14 days) after the administration of a single oral dose of TMC278, on average 85.1% r 4.0% of the administered radioactivity had been excreted via the feces. The average recovery in urine was 6.1% r 2.1%. The total radioactivity recovered after 14 days was about 91.2 r 5.1% of the administered dose (range 82.5-96.3%). Unchanged drug was excreted in feces and accounted for 25.5% of the dose on average (range 12.1-33.4%). Metabolite profiling and identification TMC278 was extensively metabolized and more than 15 metabolites were detected. The major fecal metabolites originated from oxidative pathways. The most abundant metabolite, metabolite 42, originated from oxidation at the 5-position of the pyrimidinyl moiety and accounted for 16.1% of the dose on average (10.2-20.5%). Three other metabolites each accounted for 2.2-3.0% of the dose on average. In urine, apart from one carboxylic acid metabolite (metabolite 30), all metabolites were phase-2 metabolites (glucuronides or glutathione-derived conjugates). Overall, glutathione-derived metabolites accounted for 1.2% of the dose on average. In plasma, unchanged drug accounted for the major part of the total radioactivity (76% based on Cmax and 51% based on AUClast). Blood/plasma ratios were time-independent and mean values ranged from 65-75%. These results indicate that TMC278 and its metabolites are not bound to blood cells to a significant extent.
Clinical Research Report Version: 1.0 Date: 14-Jun-2006 TMC278-C119 5
Safety TMC278 (n = number of subjects with data) (N = 6) Adverse Event (AE): Ear congestion 1 (16.7%) Diarrhea 1 (16.7%) Wound 1 (16.7%) Gastric pH decreased 1 (16.7%) Headache 1 (16.7%) n (%) with 1 or more AEs 4 (66.7%) n (%) of deaths 0 n (%) with 1 or more other serious AEs 0 n (%) of treatment stopped due to AEs 0 n (%) with 1 or more grade 3 or 4 AEs 0 No AE was reported by more than 1 subject. No grade 3 or 4 AEs or serious adverse events (SAEs) occurred during the trial. Clinical Laboratory Tests n (%) with 1 or more treatment-emergent 2 (33.3%) grade 3 or 4 laboratory abnormalities There was no overall pattern of change in the clinical laboratory tests. No grade 4 abnormalities were reported. Grade 3 abnormalities were reported for 2 subjects: 1 subject reported increased alanine aminotransferase (ALT), which resolved by the follow-up visit, and 1 subject reported increased lipase, which reduced to grade 1 toxicity by the follow-up visit. No associated AEs were reported. Adrenal Function Testing No effects of treatment were apparent on median values or median changes from reference (screening visit) for the adrenal function assessments of cortisol or 17-OH progesterone. All but one subject achieved a cortisol value t 550 nmol/L at T60 post ACTH stimulation on Day 7. The cortisol value at T0 for this subject was within the normal laboratory ranges (82.77-689.75 nmol/L). In addition, the 17- OH progesterone value for this subject was not increased at T0 (within the normal laboratory ranges of 1.8-7.5 nmol/L), indicating that there was no accumulation of this precursor of cortisol. No AEs related to adrenal function test results were reported. Cardiovascular Safety Minor changes were reported for vital signs. None of the changes was considered to be clinically significant. No trends or relationships to trial medication were apparent, and no clinically relevant changes in ECG parameters were reported. Physical Examination Physical examination revealed 1 skin abnormality during the trial: 1 subject reported an AE (wound), which was not related to treatment with TMC278.
Conclusions The results of this study demonstrate that after a single dose of 150 mg TMC278 (14C-labeled and unlabeled), the radioactivity recovered from feces after 14 days was on average, 85.1% r 4.0% of the administered dose and the radioactivity recovered from urine after 7 days was on average, 6.1% r 2.1% of the administered dose. The total radioactivity recovered from feces and urine after 14 days was on average, 91.2% r 5.1% of the administered dose.
Clinical Research Report Version: 1.0 Date: 14-Jun-2006 TMC278-C119 6
A mean Cmax of unchanged TMC278 of 602.8 ng/mL was achieved at a median of 3.5 hours postdose. The mean 14 ratio for Cmax of unchanged TMC278 versus total C-radioactivity was 76%. In the elimination phase, plasma concentrations for total radioactivity declined slower than those of unchanged TMC278. TMC278 was extensively metabolized and more than 15 metabolites were detected. The major fecal metabolites originated from oxidative pathways. The most abundant metabolite, metabolite 42, originated from oxidation at the 5-position of the pyrimidinyl moiety and accounted for 16.1% of the dose on average (10.2-20.5%). In urine, apart from the carboxylic acid metabolite (metabolite 30), all metabolites were phase-2 metabolites (glucuronides or glutathione-derived conjugates). In plasma, unchanged drug accounted for the major part of the total radioactivity in plasma. In these healthy subjects, the single dose administration of 150 mg TMC278 was generally safe and well tolerated.
Clinical Research Report Version: 1.0 Date: 14-Jun-2006
4 5 iv v vi vii viii ix x 4
TMC278-TiDP6-C130 CONFIDENTIAL 1 Clinical Research Report
SYNOPSIS Trial Identification and Protocol Summary
Company: Tibotec Pharmaceuticals Drug Substance: TMC278 Trade Name: - Trial no.: TMC278-TiDP6-C130 Indication: Human immunodeficiency virus type 1 (HIV-1) Clinical Phase: I Title: Pharmacokinetics, safety and tolerability of TMC278 in subjects with mildly or moderately impaired hepatic function. Coordinating Investigator: Country: Germany
Germany Trial Period: Start: 18-Jun-2008 No. of Investigators:2 End: 16-Nov-2009 No. of Subjects:32 Objectives: The primary objective of this study was to assess the single-dose and steady-state pharmacokinetics of TMC278 in subjects with mild or moderate hepatic impairment compared to matched healthy control subjects. Secondary objective was to assess the short-term safety and tolerability of TMC278 in subjects with mild or moderate hepatic impairment compared to matched healthy control subjects. Design: This was a Phase I, open-label, parallel, controlled, sequential study to investigate the single-dose and steady-state pharmacokinetics, and short-term safety and tolerability of TMC278 in subjects with mild or moderate hepatic impairment compared to subjects with normal hepatic function. The study population consisted of a total of 32 male and female subjects between 18 and 65 years. Panel A consisted of 8 subjects with mild hepatic impairment (Child-Pugh A, Panel A1) and 8 healthy subjects (Panel A2) matched for gender, age (± 5 yrs), and body mass index (BMI) (± 15%). Panel B consisted of 8 subjects with moderate hepatic impairment (Child-Pugh B, Panel B1) and 8 healthy subjects (Panel B2) matched for gender, age (± 5 yrs), and BMI (± 15%). Treatment in Panel A and Panel B was conducted sequentially. Subjects in Panel A received TMC278 25 mg once daily (q.d.) for a total of 11 days. Full pharmacokinetic profiles of TMC278 were determined on Day 1 up to 24 hours postdose, and on Day 11 up to 168 hours postdose. Safety and tolerability were assessed at regular intervals throughout the trial. The anticipated dose of TMC278 to be administered to subjects in Panel B was the same dose as for Panel A (25 mg q.d.). Subject Selection Inclusion Criteria 1. Male or female, aged between 18 and 65 years, extremes included. 2. Non-smoking or smoking no more than 10 cigarettes, or 2 cigars, or 2 pipes per day for at least 3 months prior to selection. 3. Body mass index (weight in kg divided by the square of height in meters) of 18.0 to 32.0 kg/m2, extremes included. 4. Informed Consent Form (ICF) signed voluntarily before the first trial-related activity. 5. Able to comply with protocol requirements. Only for subjects with hepatic impairment (Panels A1 and B1): 6. History of hepatic disease, such as alcoholic liver disease, chronic infection with hepatitis B and C viruses, primary biliary cirrhosis and primary sclerosing cholangitis or non-alcoholic steatohepatitis. 7. Documented liver cirrhosis.
Clinical Research Report Synopsis Issued Date: 14-Apr-2010 TMC278-TiDP6-C130 CONFIDENTIAL 2 Clinical Research Report
8. Mild or moderate liver function impairment defined by the Child-Pugh classification: - Mild (Panel A1): Child-Pugh score of 5 to 6. - Moderate (Panel B1): Child-Pugh score of 7 to 9. 9. General medical condition, in the Investigator’s opinion, did not interfere with the assessments and the completion of the trial. Only for healthy control subjects (Panels A2 and B2): 10. Healthy on the basis of a physical examination, medical history, electrocardiogram (ECG), vital signs and the results of blood biochemistry and hematology tests and a urinalysis carried out at screening. 11. Matched to a subject with hepatic impairment with regards to gender, age (! 5 yrs), and BMI (! 15%). Exclusion Criteria 1. A positive HIV-1 or HIV-2 test at trial screening. 2. Female, except if post-menopausal for more than 2 years, or post-hysterectomy, or post-tubal ligation (without reversal operation). 3. Current barbiturate, amphetamine, recreational or narcotic drug use. 4. Current use of more than 1 unit of alcoholic beverages per day (1 unit of alcohol equals 1 pint [285 mL] of beer, 1 glass [125 mL] of wine, 25 mL shot of 40% spirit). 5. A positive urine drug test at trial screening. Urine was tested for the presence of amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, methadone, and opioids. 6. Currently active gastrointestinal disease (with the exception of liver cirrhosis in the hepatically impaired subjects), cardiovascular, neurologic, psychiatric, metabolic, renal, respiratory, inflammatory, or infectious disease. 7. Currently significant diarrhea, gastric stasis, or constipation that in the Investigator’s opinion could influence drug absorption or bioavailability. 8. History of any significant skin disease. 9. Previously demonstrated clinically significant allergy or hypersensitivity to any of the excipients of the investigational medication administered in this trial (i.e. TMC278). 10. Use of disallowed concomitant medication as specified in the protocol. 11. Having previously participated in more than 1 trial (single or multiple dose) with TMC125, TMC120 and/or TMC278 (formerly known as R278474) or having developed a rash, erythema or urticaria while participating in a trial with the aforementioned compounds. 12. Participation in an investigational drug trial within 60 days prior to the first administration of study medication. 13. Donation of blood or plasma or significant blood loss within the 60 days preceding the first administration of study medication. 14. Unlikely to comply with the protocol requirements, instructions and study-related restrictions; e.g. uncooperative attitude, inability to return for follow-up visits, and improbability of completing the study. 15. Subject was the Investigator or any Sub-Investigator, Research Assistant, Pharmacist, Study Coordinator, other staff or relative thereof directly involved in the conduct of the study. 16. Vulnerable subjects (e.g. persons kept in detention). 17. Subjects who were not able to read or write. Only for subjects with hepatic impairment (Panels A1 and B1): 18. Acute or active hepatitis (i.e. infection for less than 6 months). 19. Evidence of hepatic decompensation. 20. Grade 3 or 4 encephalopathy (Child-Pugh classification). 21. Hepatic carcinoma. 22. Hepatorenal syndrome. 23. Severe liver insufficiency defined as class C according to Child–Pugh classification.
Clinical Research Report Synopsis Issued Date: 14-Apr-2010 TMC278-TiDP6-C130 CONFIDENTIAL 3 Clinical Research Report
24. Active candidate for liver transplantation. 25. Any grade 3 laboratory abnormalities with the exception of laboratory abnormalities related to hepatic impairment. Only for healthy control subjects (Panels A2 and B2): 26. Hepatitis A infection (confirmed by hepatitis A antibody immunoglobulin M), or hepatitis B infection (confirmed by hepatitis B surface antigen), or hepatitis C infection (confirmed by hepatitis C virus antibody) at trial screening. 27. Any current hepatic disease. 28. Subjects with the following laboratory abnormalities at screening as defined by the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (“DAIDS grading table”) and in accordance with the normal ranges of the clinical laboratory: - Serum creatinine grade 1 or greater (≥ 1.1 x upper limit of normal, ULN), - Serum lipase grade 1 or greater (≥ 1.1 x ULN), - Hemoglobin toxicity grade 1 or greater (≤ 10.9 g/dL), - Platelet count grade 1 or greater (≤ 124,999/mm3), - Absolute neutrophil count grade 1 or greater (≤ 1300/mm3), - Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) grade 1 or greater (≥ 1.25 x ULN), - Total bilirubin grade 1 or greater (∀ 1.1 x ULN), - Any other toxicity grade 2 or above, including on urinalysis. Treatment Dosage TMC278 25 mg for Panels A and B Dosage Form (F No.) TMC278 25 mg tablet (F006) Usage 1 tablet orally q.d. for 11 days Batch Number 8BL2H Dose Regimen TMC278 25 mg for 11 days Duration of Treatment 11 days per panel Duration of Trial 18 days per panel, excluding screening and follow-up
Clinical Research Report Synopsis Issued Date: 14-Apr-2010 TMC278-TiDP6-C130 CONFIDENTIAL 4 Clinical Research Report
Disallowed Medication Only for subjects with hepatic impairment (Panels A1 and B1): The subjects with hepatic impairment were allowed to continue to use their regular medications for the management of their hepatic insufficiency e.g. albumin, diuretics, lactulose, beta-blockers and vitamins. Proton-pump inhibitors were prohibited. If necessary, proton-pump inhibitors could have been replaced by H2-antagonsist during treatment with TMC278 and were to be administered either 4 hours after or 12 hours before intake of TMC278. Any other medication the subject was using was to be discussed prior to inclusion with Tibotec Pharmaceuticals on a case-by-case basis, except for ibuprofen or paracetamol (acetaminophen). Concomitant therapy that was allowed was not to be changed (started, stopped, or change in regimen) from screening until the last pharmacokinetic sample had been obtained, except for ibuprofen or paracetamol. However, if there was a need to change (start, stop, or change in regimen) concomitant therapies during the trial, dosage and regimen had to be discussed in advance with Tibotec Pharmaceuticals. Only for healthy control subjects (Panels A2 and B2): The matched healthy control subjects must have discontinued all over-the-counter medication at least 7 days before the first intake of study medication and all prescribed medication must have been discontinued at least 14 days before first intake of study medication, except for ibuprofen and paracetamol. Subjects were not permitted to use any medication other than the study medication up to 14 days after the last intake of study medication, except for ibuprofen or paracetamol and the comedication specified below for the treatment of specific adverse events (AEs). For all subjects (Panels A1, A2, B1 and B2): Subjects were not to use any herbal medications or dietary supplements (except vitamins) including products containing Hypericum perforatum (e.g. St. John’s wort) from 14 days before the first intake of study medication and up to 14 days after the last intake of study medication. Ibuprofen and paracetamol were permitted up to 3 days before the first intake of study medication. After that, the Investigator could permit the use of ibuprofen (at no more than 400 mg per day) or paracetamol (at no more than 1000 mg per day). Other comedication was allowed in the following cases: - In case of cutaneous reaction/rash and/or an allergic reaction, the use of cetirizine (Zyrtec#), levocetirizine (Xyzal#), topical corticosteroids, or antipruritic agents in the recommended dosing scheme was permitted. - In case of nausea, the use of antiemetics was permitted. - In case of diarrhea, the use of loperamide was permitted. In case any medication was used, the dose and dose regimen had to be recorded in the Concomitant Therapy section of the Case Report Form (CRF). For any concomitant therapy given as a treatment for a new condition or a worsening of an existing condition, the condition had to be documented on the AE section of the CRF.
Clinical Research Report Synopsis Issued Date: 14-Apr-2010 TMC278-TiDP6-C130 CONFIDENTIAL 5 Clinical Research Report
Assessments a Panels A and B Follow-up Screening Day -1b 1 2 3-4 5 6-8 9 10b 11 12- 18c 16 d intake 21 days last drug ≤ 32 days after 7, and 30, 31 or Pharmacokinetics Blood samplee Xf Xg Xh Xg,h Xg,h Xf Xf Xf Xi Safety Hematology & X Xk Xk Xk XX biochemistryj Urinalysis X X Xk Xk XX ECG, pulse & XXk Xl Xl Xl Xk XX BP Physical XXm Xm XX examination (including skin examination) AEs and XX X X X X X X X X X X X concomitant medicationsn a Informed consent, smoking habits, inclusion/exclusion criteria, concomitant diseases, subject demographics, medical and surgical history, HIV-1 & -2 test, hepatitis A/B/C test, urine drug screening, serum pregnancy test (females only), plus Child-Pugh classification, documentation of clinical diagnosis of hepatic impairment and coagulation tests (only for subjects with hepatic impairment). b Urine drug screening and also, on Day -1 only, urine pregnancy test (females only). c Day 18 corresponded to the first Follow-up visit (i.e. 7 days after last drug intake). d Coagulation test for subjects with hepatic impairment and serum pregnancy test (females only) 30, 31 or 32 days after last drug intake. e For determination of TMC278. f Days 1 and 11: pre-dose (after breakfast, immediately before TMC278 intake), postdose at 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 14 (Panel B only), 16, 18 (Panel B only), 20 (Panel B only) and 22 hours. The predose sample on Day 2 corresponds with the 24 hour postdose sample on Day 1. Samples on Days 12, 13, 14, 16 and 18 were taken at 24, 48, 72, 120 and 168 hours postdose, respectively. g Predose sample, after breakfast, immediately before TMC278 intake. h Sample at 4 hours post dose for Panel B only. i 7 days after last drug intake only. j All biochemistry samples must be taken fasted for at least 10 hours. k Within 2 hours before TMC278 intake, and, on Days 1 and 11, ECG, pulse and blood pressure (BP) were additionally assessed at 4 hours post dose. l Panel B only. m Within 2 hours before drug intake. n Adverse events and concomitant medication monitored continuously from signing of the ICF until the last trial-related visit.
Clinical Research Report Synopsis Issued Date: 14-Apr-2010 TMC278-TiDP6-C130 CONFIDENTIAL 6 Clinical Research Report
Statistical Methods Descriptive statistics and frequency tabulations were produced for safety parameters, and additional exploratory graphical analyses were done. Descriptive statistics, linear mixed effects modeling and a non-parametric statistical test were done for TMC278 plasma concentrations and pharmacokinetic parameters.
Clinical Research Report Synopsis Issued Date: 14-Apr-2010 TMC278-TiDP6-C130 CONFIDENTIAL 7 Clinical Research Report
Main Features of the Subject Sample and Summary of the Results Panel A Panel B Mild Moderate Hepatic Hepatic Healthy Impairment Healthy Impairment Baseline Characteristics - Subject Disposition N=8 N=8 N=8 N=8 Number of Subjects Enrolled (male/female) 4/4 4/4 6/2 6/2 Age: median (range), years 48.0 (36-61) 47.5 (41-57) 52.0 (45-65) 53.0 (47-64) Dropouts 0 0 0 0
Panel A Panel B Pharmacokinetics of TMC278
(mean ! SD, tmax: median Healthy Mild Hepatic Healthy Moderate Hepatic [range]) (reference) Impairment (test) (reference) Impairment (test) n88b 88d Day 1 Cmax, ng/mL 81.73 ± 20.01 90.29 ± 31.96 62.99 ± 22.31 44.43 ± 17.69 tmax, h 4.0 (3.0 - 9.0) 4.5 (2.0 - 5.0) 5.0 (3.0 - 5.0) 5.0 (2.0 - 22.0) AUC24h, ng.h/mL 890.2 ± 169.0 1071 ± 266.3 726.9 ± 214.0 569.6 ± 227.5 Day 9
C0h, ng/mL 64.04 ± 18.79 126.8 ± 46.17 79.68 ± 24.35 98.31 ± 24.73 Day 10 C0h, ng/mL 69.08 ± 25.75 126.3 ± 49.95 86.26 ± 16.08 118.9 ± 53.73 Day 11 C0h, ng/mL 77.56 ± 22.12 137.8 ± 62.25 81.83 ± 17.81 122.2 ± 51.53 Cmin, ng/mL 65.65 ± 18.58 84.13 ± 20.72 67.31 ± 14.88 76.55 ± 26.24 C24h, ng/mL 82.09 ± 20.87 147.1 ± 50.20 88.75 ± 23.56 121.7 ± 62.22 Cmax, ng/mL 144.3 ± 35.70 187.0 ± 66.31 146.8 ± 30.21 143.5 ± 49.69 tmax, h 5.0 (3.0 - 12.0) 5.0 (2.0 - 24.0) 5.0 (3.0 - 5.0) 20.0 (2.0 - 24.0) AUC24h, ng.h/mL 2152 ± 538.1 3206 ± 1080 2318 ± 385.9 2525 ± 851.2 c c c c t1/2term, h 60.59 ± 20.03 80.82 ± 33.17 56.01 ± 21.31 90.56 ± 37.04
Css,av, ng/mL 89.68 ± 22.42 133.6 ± 45.00 96.58 ± 16.08 105.2 ± 35.47 FI, % 89.91 ± 29.74 74.40 ± 22.04 83.63 ± 30.34 65.26 ± 13.20
AUC24h = area under the plasma concentration-time curve over 24 hours, C0h = predose plasma concentration, C24h = plasma concentration after 24 hours, Cmax = maximum plasma concentration, Cmin = minimum plasma concentration, Css,av = average steady-state plasma concentration over 24 hours, FI = fluctuation index, SD = standard deviation, tmax = time to maximum plasma concentration, t1/2term = terminal elimination half-life. a Ratio of mean pharmacokinetic parameter values b n = 7 for t1/2term c Accurate determination not possible d n = 6 for Day 1 and n = 5 for t1/2term
Clinical Research Report Synopsis Issued Date: 14-Apr-2010 TMC278-TiDP6-C130 CONFIDENTIAL 8 Clinical Research Report
Panel A Panel B Pharmacokinetics of Healthy Mild Hepatic Healthy Moderate Hepatic TMC278 (reference) Impairment (test) (reference) Impairment (test) Least squares mean ratio (90% confidence interval) - Test versus reference - Test versus reference n - 8 versus 8 - 8a versus 8 Day 1 -- Cmax - 1.060 ( 0.7834 - 1.435 ) - 0.7062 ( 0.4835 - 1.031 )
AUC24h - 1.177 ( 0.9315 - 1.487 ) - 0.7635 ( 0.5426 - 1.074 ) Day 11 -- Cmin - 1.307 (1.004 - 1.702) - 1.111 ( 0.8671 - 1.423 )
C24h - 1.758 ( 1.343 - 2.301 ) - 1.276 ( 0.9079 - 1.792 )
Cmax - 1.268 ( 0.9804 - 1.641 ) - 0.9496 ( 0.7514 - 1.200 )
AUC24h - 1.467 ( 1.144 - 1.881 ) - 1.052 ( 0.8379 - 1.320 ) a n = 6 for Day 1 of test
Clinical Research Report Synopsis Issued Date: 14-Apr-2010 TMC278-TiDP6-C130 CONFIDENTIAL 9 Clinical Research Report
Panel A Panel B Moderate Mild Hepatic Hepatic Safety Healthy Impairment Healthy Impairment (n = number of subjects with data) N=8 N=8 N=8 N=8 2 (25.0) 4 (50.0) 3 (37.5) 3 (37.5) n (%) with 1 or more AEs during treatment with TMC278 n (%) most frequently reported AEs in ≥ 2 subjects across all panels during treatment with TMC278 Dizziness 0 1 (12.5) 0 1 (12.5) Headache 0 1 (12.5) 1 (12.5) 0 Back pain 0 1 (12.5) 0 1 (12.5) Conjunctivitis 0 0 1 (12.5) 1 (12.5) Nasopharyngitis 0 1 (12.5) 0 1 (12.5) Pruritus 0 0 1 (12.5) 1 (12.5) n (%) deaths during the trial 0000 n (%) with 1 or more serious adverse event (SAE) during the trial 0 0 0 1 (12.5) n (%) treatment stopped due to AE during the trial 0 0 0 0 n (%) with 1 or more grade 3 or 4 AEs during the trial 0 0 0 2 (25.0) n (%) skin events of interest during the trial 0 0 0 0 There were no deaths, AEs leading to discontinuation, or skin events of interest reported during the trial. One SAE (grade 3, inguinal hernia leading to hospitalization, considered not related to TMC278) and 1 grade 4 AE (blood bilirubin increased, considered doubtfully related to TMC278) were reported during the trial, both during follow-up, in subjects with moderate hepatic impairment. Over the course of the trial, AEs were most frequently reported in subjects with hepatic impairment. The majority of AEs were grade 1 or 2 in severity and no AEs were considered probably or very likely related to TMC278. The only AE considered possibly related to TMC278 that was experienced by > 1 subject across all panels was headache. No single type of AE was reported by more than 1 subject in the same panel and no single type of AE was reported by > 2 subjects across all panels during treatment with TMC278. Nervous system disorders were the most frequently experienced AEs during treatment with TMC278, which were reported for a total of 5 subjects.
Clinical Research Report Synopsis Issued Date: 14-Apr-2010 TMC278-TiDP6-C130 CONFIDENTIAL 10 Clinical Research Report
Clinical Laboratory Tests No consistent or clinically relevant changes in mean laboratory parameters were observed. Graded treatment-emergent laboratory abnormalities were reported for more subjects with hepatic impairment (mild or moderate) than healthy subjects; most frequently in subjects with moderate hepatic impairment. The majority of graded laboratory abnormalities were grade 1 or 2 in severity. Two subjects experienced grade 4 laboratory abnormalities during the trial; both subjects had moderate hepatic impairment and experienced grade 4 increased total bilirubin during follow-up. One of these subjects also experienced a grade 4 decreased platelet count. A grade 4 AE corresponding to the grade 4 laboratory abnormality for total bilirubin was reported for 1 of the subjects. This subject also experienced grade 2 AEs for ALT and AST with corresponding grade 2 increased ALT and AST values at the same time as the grade 4 bilirubin AE. These were the only AEs relating to laboratory abnormalities reported during the trial. No subjects had treatment-emergent abnormalities for urinalysis. Cardiovascular Safety There were no notable variations in vital signs parameters over the course of the trial and no grade 3 abnormalities or AEs relating to vital signs parameters were reported. There were no notable variations in ECG parameters over time and no AEs relating to ECGs were reported. Treatment-emergent abnormalities for QTcF and QTcB were reported more frequently in subjects with hepatic impairment than healthy subjects, and more frequently in subjects with mild hepatic impairment than moderate hepatic impairment. No subjects had increases > 60 ms or actual values > 500 ms for QTcB or QTcF intervals. Physical Examination Two treatment-emergent abnormalities were reported for the physical examination. Both were abnormalities for the ears, nose and throat body system and were reported for 1 subject with moderate hepatic impairment and 1 healthy subject at follow up, 30 to 32 days after last study medication intake. The abnormality for the subject with moderate hepatic impairment was submandibular pain, which was linked to the subject’s AEs of nasopharyngeal pain and influenza. The abnormality for the healthy subject was mild rhinitis.
Conclusions
After a single dose, TMC278 Cmax and AUC24h were 6% and 18% higher, respectively, in subjects with mild hepatic impairment, compared to healthy subjects. At steady-state (Day 11) Cmax, AUC24h, Cmin and C24h were 27%, 47%, 31% and 76% higher, respectively. After a single dose in subjects with moderate hepatic impairment, Cmax and AUC24h were 29% and 24% lower, respectively, compared to healthy subjects. At steady-state, Cmax was 5% lower and AUC24h was 5% higher. Mean Cmin and C24h were increased by 11% and 28%, respectively, in subjects with moderate hepatic impairment as compared to healthy subjects. The results of the trial also demonstrate that administration of TMC278 25 mg q.d. was generally safe and well tolerated and that no dose adjustment of TMC278 is needed in subjects with mild or moderate hepatic impairment.
Clinical Research Report Synopsis Issued Date: 14-Apr-2010
3. STUDY SYNOPSIS
Gilead Sciences, Inc. 333 Lakeside Drive Foster City, CA 94404 USA
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