DATA SHEET OF CLINICAL TRIAL C.T. No 016-16 CLINICAL TRIAL REGISTRATION (EC) I. SPONSOR INFORMATION Foreign National 2. LEGAL PERSON 2.1 FOREIGN SPONSOR Institutos Nacionales de Salud (NIH, Institutos Nacionales de Salud (NIH, Registered Name: siglas en ingles) de los Estados Registered Tradename: siglas en ingles) de los Estados Unidos de America Unidos de America FOREIGN SPONSOR REPRESENTATIVE IN PERU SUBSIDIARY: BRANCH: CRO: OTHER: _________ Tradename: - TYPE OF INSTITUTION Instituto Nacional de Salud de otro país II. CLINICAL TRIAL GENERAL INFORMATION 1. CLINICAL TRIAL IDENTIFICATION Scientific Title: A TRIAL OF THE SAFETY, TOLERABILITY, AND PHARMACOKINETICS OF BEDAQUILINE AND DELAMANID, ALONE AND IN COMBINATION, AMONG PARTICIPANTS TAKING MULTIDRUG TREATMENT FOR DRUG-RESISTANT PULMONARY TUBERCULOSIS Public Title: BEDAQUILINE AND DELAMANID FOR MDR-TB TREATMENT Secundary ID(s): WHO UTN: PER-016-16 Protocol Code: A5343 Clinicaltrials.gov: NA EUDRACT N°: NA 1 1-2 2 2-3 Study clinical phase: 3 4 Clinical Trial Total Duration: 60 months No Aplica 0(exploratory trials) Enrolment start date in Peru (Initial) 01/07/2016 Worldwide enrolment start date (dd/ (dd/mm/aaaa): 01/06/2016 mm/aaaa): Enrolment start date in Peru (Posterior) (dd/mm/aaaa): Without starting enrollment In enrollment Peru enrolment status : Enrollment stopped Enrollment closed Other 2. CLINICAL TRIAL GOALS AND DESIGN Randomnized Simple Non randomnized Double Assignation method Type of blinding No aplica Triple Open Single arm Parallel Crossed Factorial Assignation Others: ____________________ Study Design This is a phase II, randomized, open-label, three-arm pharmacokinetic and safety trial of the anti-tuberculosis (TB) drugs bedaquiline and delamanid. Participants will be randomized to one of three arms. Participants in arms 1, 2, and 3 will receive bedaquiline, delamanid, or both drugs in combination, respectively, for 24 weeks together with multidrug background treatment. Purpose To estimate the mean changes from baseline (averaged over weeks 8-24) in QTcF when DLM and BDQ are co-administered (along with MBT; Arm 3), when BDQ is administered without DLM (along with MBT; Arm 1) and when DLM is administered without BDQ (along with MBT; Arm 2). 3. STUDY INTERVENTION Página 1 de 4 Indicate if the product is being developed as: Pharmaceutical product Medical device Herbal product Type of research product Galenic product Complementary product Dietary product and sweetener Other: ____________________ Research product identification N° Product name Generic name Product type ATC 1 Dolutegravir Dolutegravir Producto en investigación de origen J05 - Antivirales de uso sistémico químico 2 SIRTURO BEDAQUILINE Producto en investigación de origen J04 - Drogas antimicobacterinas químico 3 DELTYBA DELAMANID Producto en investigación de origen J04 - Drogas antimicobacterinas químico N° Comparator name Generic name Product type ATC Intervention(s) description: N° of Group Name Type of group Intervention(s) description participants Subjects' treatment time 24 weeks Subjects' follow up time 128 weeks 4. Study Population Inclusion Criteria: 1. • Men and women age  18 years of age. • Documented pulmonary infection due to strains of M. tuberculosis with resistance to isoniazid (INH) and rifampin (RIF) from a sputum sample collected within 60 days prior to entry. • Laboratory confirmation of infection with a Mycobacterium tuberculosis strain that is susceptible to fluoroquinolones and aminoglycosides within 60 days prior to entry. • HIV infection status must be documented as either absent or present • For HIV-positive candidates only: CD4+ count greater than or equal to 100 cells/mm3 within 60 days prior to entry. • For females of reproductive potential, negative serum pregnancy test within 48 hours prior to entry. • Female and male participants of reproductive potential who are participating in sexual activity that could lead to pregnancy must agree to use one of the following forms of birth control while receiving TB study medications and for 6 months after stopping TB study medications: • Chest x-ray performed within 60 days prior to entry to classify participant as having cavitary or non-cavitary disease. • Documentation of Karnofsky performance score  50 within 14 days prior to study entry. • Ability and willingness of participant or legally authorized representative to provide informed consent. • Willingness to be hospitalized for at least 2 months. • Taking MBT for a minimum of 7 days within the 10 days prior to entry Exclusion Criteria: 1. • History of clinically relevant, currently active or underlying gastrointestinal, hepatic, cardiovascular, nervous system, psychiatric, metabolic (eg, untreated hypothyroidism), renal, respiratory (other than due to TB), inflammatory, neoplastic, skin, immunological or infectious disease, which is not stable and controlled, that in the opinion of the investigator would preclude safe participation in the trial. • Clinically relevant extrapulmonary TB, in the opinion of the site investigator, including but not limited to CNS TB or TB osteoarthritis. • Previous treatment for MDR-TB, other than for the qualifying episode, at any time in the past. • Receipt of BDQ or DLM at any time in the past. • Breast-feeding. • QTcF interval > 450 ms within 72 hours prior to entry. • Clinically significant ECG abnormality in the opinion of the site investigator within 60 days prior to entry, including but not limited to second or third degree atrioventricular (AV) block, prolongation of the QRS complex over 120 ms (in both male and female participants), or clinically important arrhythmia. • Current clinically relevant cardiovascular disorder in the opinion of the site investigator, including but not limited to heart failure, coronary heart disease, arrhythmia, or tachyarrhythmia. • Known family history of Long QT Syndrome in a first-degree relative (ie, parent, offspring, or sibling). • Requirement or expected requirement for protease inhibitors (PIs), EFV, or any other medication that is a moderate to strong inhibitor or inducer of CYP3A and CYP3A4 over the 24 weeks of study treatment. • Requirement or expected requirement for a medication that significantly prolongs QTc, including but not limited to clofazimine and moxifloxacin (levofloxacin is acceptable), from 48 hours prior to study entry through 4 weeks after discontinuation of study treatment (week 28). • Known allergy/sensitivity or any hypersensitivity to components of study TB drugs or their formulation or to the nitroimidazole class of antibiotics. • Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements. • Any of the following laboratory abnormalities within 14 days prior to entry at any network-approved non-US laboratory that operates in accordance with Good Clinical Laboratory Practices (GCLP) and participates in appropriate external quality assurance programs. a. Serum creatinine >1.4 x ULN b. Lipase >1.6 x ULN c. ALT >2.5 x ULN d. Total bilirubin >1.6 x ULN e. Potassium <3.4 or >5.6 mmol/L; magnesium <0.59 mmol/L; calcium <1.75 mmol/L • Known current hepatitis B or C infection, current treatment for hepatitis B or hepatitis C infection, or positive for hepatitis B surface antigen or hepatitis C antibodies within 60 days prior to entry. • Among participants with HIV infection, in whom use of DTG is anticipated, any of the following: a. Unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, esophageal varices, or persistent jaundice), known biliary abnormalities (with the exception of Gilbert’s syndrome or asymptomatic gallstones) b. History or presence of allergy to DTG or its components c. Severe hepatic impairment (Class C) as determined by Child-Pugh classification d. Previous use of raltegravir • Documentation of any new and/or unstable AIDS-defining illness (other than TB) as defined by the CDC within 60 days prior to entry. • Acute or serious illness (other than TB) requiring systemic treatment and/or hospitalization within 60 days prior to entry Studied Condition: N/A A15Respiratory tuberculosis, Studied Condition bacteriologically and histologically Medical speciality : Pneumology classification(CIE-10): confirmed Countries where the enrolment is • Sud Africa • Peru conducted: Number of participants per gender 40 >Number of subjects to be included (Initial): 84 in all the countries: Number of participants per gender 0 (Posterior): Population to be included by gender Women Men Both Indicate if the study population Healthy volunteers Yes No includes: Subordinate Groups Yes No Indigenous or native people Yes No Minors Yes No Página 2 de 4 Subjects with disabilities to grant consent Yes No Women of childbearing age Yes No Pregnant women Yes No Women during labor, puerperium or lactation Yes No Fetus Yes No Adults(18-64 years) Yes No Elderly (>= 65 years) Yes No Under 18 years Yes No - In Utero Yes No Range of age of subjects to be - Preterm newborn infants (up to gestational age < 37 weeks) included: Yes No - Newborns (0-27 days) Yes No - Infants and toddlers (28 days-23months) Yes No - Children (2 - 11 years) Yes No - Adolescents (12 - 17 years) Yes No 5. EVALUATION CRITERIA Primary Evaluation Criteria N° Evaluation criteria name Method of measurement Time point for the measurement Secondary Evaluation Criteria N° Evaluation criteria name Method of measurement Time point for the measurement 6. DATA MONITORING Existence of the Data Monitoring