Article
Tolvaptan in Autosomal Dominant Polycystic Kidney Disease: Three Years’ Experience
Eiji Higashihara,*† Vicente E. Torres,*‡ Arlene B. Chapman,§ Jared J. Grantham, Kyongtae Bae,¶ Terry J. Watnick,** †† † ‡‡ ‡‡ ‡‡ 2 Shigeo Horie, Kikuo Nutahara, John Ouyang, Holly B. Krasa, Frank S. Czerwiec, for the TEMPO4 and 156-05-002 Study Investigators
Summary †Kyorin University Background and objectives Autosomal dominant polycystic kidney disease (ADPKD), a frequent cause of School of Medicine, end-stage renal disease, has no cure. V2-specific vasopressin receptor antagonists delay disease progression Mitaka, Tokyo, Japan; ‡ in animal models. Mayo Clinic College of Medicine, Rochester, Minnesota; §Emory Design, setting, participants, and measurements This is a prospectively designed analysis of annual total kid- University School of ney volume (TKV) and thrice annual estimated GFR (eGFR) measurements, from two 3-year studies of Medicine, Atlanta, ʈ tolvaptan in 63 ADPKD subjects randomly matched 1:2 to historical controls by gender, hypertension, age, Georgia; Kansas and baseline TKV or eGFR. Prespecified end points were group differences in log-TKV (primary) and eGFR University Medical Center, Kansas City, (secondary) slopes for month 36 completers, using linear mixed model (LMM) analysis. Sensitivity analyses Kansas; ¶University of of primary and secondary end points included LMM using all subject data and mixed model repeated mea- Pittsburgh School of sures (MMRM) of change from baseline at each year. Pearson correlation tested the association between Medicine, Pittsburgh, log-TKV and eGFR changes. Pennsylvania; **Johns Hopkins University, Baltimore, Maryland; Results Fifty-one subjects (81%) completed 3 years of tolvaptan therapy; all experienced adverse events ††Teikyo University (AEs), with AEs accounting for six of 12 withdrawals. Baseline TKV (controls 1422, tolvaptan 1635 ml) and School of Medicine, 2 Tokyo, Japan; eGFR (both 62 ml/min per 1.73 m ) were similar. Control TKV increased 5.8% versus 1.7%/yr for tolvaptan ‡‡ Ͻ and Otsuka (P 0.001, estimated ratio of geometric mean 0.96 [95% confidence interval 0.95 to 0.97]). Corresponding Pharmaceutical 2 annualized eGFR declined: Ϫ2.1 versus Ϫ0.71 ml/min per 1.73 m /yr (P ϭ 0.01, LMM group difference 1.1 Development and ml/min per 1.73 m2/yr [95% confidence interval 0.24 to 1.9]). Sensitivity analyses including withdrawn Commercialization, subjects were similar, whereas MMRM analyses were significant at each year for TKV and nonsignificant Inc., Rockville, for eGFR. Increasing TKV correlated with decreasing eGFR (r ϭϪ0.21, P Ͻ 0.01). Maryland
Correspondence: Dr. Conclusion ADPKD cyst growth progresses more slowly with tolvaptan than in historical controls, but AEs Vicente E. Torres, are common. Division of Nephrology Clin J Am Soc Nephrol 6: 2499–2507, 2011. doi: 10.2215/CJN.03530411 and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. Phone: Introduction ade consistently reduce cyst burden and protect 507-284-7572; Fax: Autosomal dominant polycystic kidney disease renal function (6). These compelling preclinical 507-266-9315; E-mail: torres.vicente@mayo. (ADPKD) is an inherited disorder which, over de- studies provided a rationale for vasopressin V2 re- edu cades, results in progressive development of mul- ceptor antagonism as a preventive therapy for hu- tiple renal cysts, urinary concentration defects, hy- man ADPKD. *E.H. and V.E.T. pertension, and ultimately ESRD (1–4). Kidney and Total kidney volume (TKV) is a practical, inter- contributed equally to back pain from cyst hemorrhage, stones, infection, mediate end point of later outcomes in ADPKD this report as the 156- 05-002 and 156-04-250 biomechanical stresses, stretching of the renal cap- including pain, hypertension, renal insufficiency, 2 (TEMPO4) leaders. All sule, or pressure on other organs can impact quality and ESRD. The Consortium of Radiologic Imaging investigators are listed of life (5). Less common extrarenal manifestations Studies of Polycystic Kidney Disease (CRISP) and in the Appendix. such as cerebral aneurysms may be life-threatening. other studies are establishing the relationship be- Studies in animal models have implicated argi- tween TKV growth and important clinical outcomes nine vasopressin and its second messenger cAMP (7–9). However, it will take years of study to prove as important promoters of cyst cell proliferation whether a treatment that slows TKV expansion will and fluid secretion into cysts (6). Suppression of positively affect estimated GFR (eGFR), ESRD, or vasopressin release by forced hydration, genetic death. The current study explores the potential use crosses between cyst-prone animals and those lack- of TKV as a surrogate for ADPKD therapies target-
ing vasopressin, and vasopressin V2 receptor block- ing vasopressin V2 signaling. www.cjasn.org Vol 6 October, 2011 Copyright © 2011 by the American Society of Nephrology 2499 2500 Clinical Journal of the American Society of Nephrology
Materials and Methods Consenting ADPKD subjects of prior trials were enrolled in two multicenter open-label tolvaptan-treatment studies, 2 in North America (156-04-250 TEMPO4, ClinicalTrials.gov; NCT00413777) and Japan (156-05-002, NCT00841568). Pro- tocols and informed consents for both studies were ap- proved by local ethics committees as outlined by the Dec- laration of Helsinki. De-identified data for matched controls were provided, after ethics committee approval, by the National Institutes of Health-sponsored Modifica- tion of Diet in Renal Disease (MDRD) and CRISP (NCT01039987) studies (10). 2 Eligibility for the TEMPO4 study required the following: men or women age Ͼ18 years fulfilling Ravine’s diagnostic criteria (11), prior participation in a phase 1 tolvaptan ADPKD trial, and willingness to adhere to contraceptive Figure 1. | Tolerability and efficacy during titration phase. In the precautions. Exclusion criteria included the following: in- 2 initial 2 months of the TEMPO4 study a split-dose regimen of oral ability to comply with study procedures, eGFR Ͻ30 ml/ tolvaptan (8 a.m./4 p.m.) was up titrated (15/15, 30/15, 45/15, 60/30, min per 1.73 m2, anticipation of renal replacement therapy 90/30 mg/d) until tolerability was reached. Tolerability was defined as self-reported tolerance of a specific dose regimen by responding within 1 year, and active treatment that would affect end yes to the question: “Could you tolerate taking this dose of tolvaptan point measures (e.g., diuretic administration). The 156-05- for the rest of your life?” Efficacy was defined by the capacity to 002 trial inclusions were similar except for age Ͼ20 years suppress the action of vasopressin on the kidney reflected by sus- without an upper limit. This study excluded subjects with tained urine hypotonicity (Uosm Ͻ300 mOsm/kg). serum creatinine Ն2.5 mg/dl, uncontrolled hypertension,
2 2 Figure 2. | Subject disposition in TEMPO4 and 156-05-002 trials. Of 48 eligible subjects for the TEMPO4 study, 47 entered screening and 46 participated; seven subjects withdrew early (including one of six in the high-dose group who permanently down-titrated), leaving 39 who completed 3 years’ therapy. Exposure verified by tolvaptan metabolite levels confirmed compliance in all but one subject in the 45/15-mg/d group. Of 18 eligible subjects for the 156-05-002 study, 17 participated, five withdrew, and 12 completed 3 years’ therapy. Subjects completing 36 months were used in the primary analysis; analyses including data from withdrawn subjects who received at least one dose of study drug and who had posttreatment data were also performed. Clin J Am Soc Nephrol 6: 2499–2507, October, 2011 Tolvaptan in ADPKD, Higashihara et al. 2501
Table 1. Very common (>10%) adverse events reported with Table 1. (Continued) tolvaptan in North American and Japanese subjects Number of Subjects Number of Subjects Reporting AEsa; a b 2c Reporting AEs ; 156-05-002 or TEMPO4 b 2c 156-05-002 or TEMPO4 MedDRA Adverse 15/15 45/15 90/30 15/15 45/15 90/30 Event Term mg/d mg/d mg/d MedDRA Adverse Event mg/d mg/d mg/d (n ϭ 17) (n ϭ 22) (n ϭ 24) Term (n ϭ 17) (n ϭ 22) (n ϭ 24) Pain in extremity 2 (12) 2 (9) 0 (0) Nasopharyngitis 13 (76) 2 (9) 1 (4) Blood triglyceride 2 (12) 0 (0) 2 (8) Thirst 9 (53) 8 (36) 16 (67) increase Pollakiuria 2 (12) 10 (46) 14 (58) Hyperuricemia 2 (12) 0 (0) 2 (8) Renal pain 0 (0) 10 (46) 9 (38) Arthropod sting 2 (12) 1 (5) 1 (4) Nocturia 2 (12) 9 (41) 3 (13) Tinea pedis 2 (12) 1 (5) 0 (0) Upper respiratory tract 0 (0) 1 (5) 9 (38) Musculoskeletal pain 2 (12) 0 (0) 1 (4) infection Neck pain 2 (12) 0 (0) 1 (4) Polyuria 1 (6) 8 (36) 6 (25) Keratitis 2 (12) 0 (0) 0 (0) Dizziness 2 (12) 8 (36) 4 (17) Gastric polyps 2 (12) 0 (0) 0 (0) Contusion 6 (35) 1 (5) 0 (0) Malaise 2 (12) 0 (0) 0 (0) Fatigue 1 (6) 6 (27) 8 (33) Muscle injury 2 (12) 0 (0) 0 (0) Hypertension 5 (29) 4 (18) 4 (17) Alanine 2 (12) 0 (0) 0 (0) Abdominal pain 1 (6) 3 (14) 7 (29) aminotransferase Diarrhea 2 (12) 2 (9) 7 (29) increased d d Blood antidiuretic 5 (29) N/A N/A Blood cholesterol 2 (12) 0 (0) 0 (0) hormone increase increase Urinary tract infection 1 (6) 3 (14) 6 (25) Blood glucose increase 2 (12) 0 (0) 0 (0) Sinusitis 2 (12) 3 (14) 6 (25) Hemoglobin decrease 2 (12) 0 (0) 0 (0) Headache 4 (24) 3 (14) 6 (25) Blood phosphorus 2 (12) 0 (0) 0 (0) Blood uric acid 4 (24) 0 (0) 0 (0) increase increased Spinal; osteoarthritis 2 (12) 0 (0) 0 (0) Anemia 1 (6) 5 (23) 1 (4) Intervertebral disc 2 (12) 0 (0) 0 (0) Back pain 3 (18) 5 (23) 3 (13) protrusion Dry skin 2 (12) 5 (23) 2 (8) Intracranial aneurysm 2 (12) 0 (0) 0 (0) Dyspnea 0 (0) 1 (5) 5 (21) Eczema 2 (12) 0 (0) 0 (0) Constipation 1 (6) 0 (0) 5 (21) Pruritus 2 (12) 0 (0) 0 (0) Dehydration 3 (18) 0 (0) 2 (8) Upper respiratory tract 2 (12) 0 (0) 0 (0) Gastritis 3 (18) 0 (0) 0 (0) inflammation Palpitations 3 (18) 3 (14) 1 (4) Gastritis erosive 3 (18) 0 (0) 0 (0) Vertigo 3 (18) 0 (0) 0 (0) An adverse event (AE) is a new or worsening untoward Dental caries 3 (18) 0 (0) 0 (0) symptom or sign occurring after receiving at least one dose of Bronchitis 1 (6) 4 (18) 2 (8) tolvaptan. Medical Dictionary for Regulatory Activities. a Values in parentheses are percentage. Abdominal distension 1 (6) 3 (14) 4 (17) b Nausea 1 (6) 1 (5) 4 (17) Subjects receiving at least one dose from Japanese 156-05-002 (n ϭ 17) studies. Cough 0 (0) 0 (0) 4 (17) c Edema, peripheral 1 (6) 3 (14) 3 (13) Subjects receiving at least one dose from U.S. 156-04-250 2 ϭ Hypotension 0 (0) 3 (14) 3 (13) TEMPO4 (n 46) studies who were randomized to separate dose groups. Arthralgia 1 (6) 3 (14) 3 (13) d Chest pain 1 (6) 3 (14) 2 (8) Not applicable (n/A) because antidiuretic hormone Dry eye 0 (0) 3 (14) 2 (8) (vasopressin) was not assessed in TEMPO. Polydipsia 0 (0) 3 (14) 1 (4) Erythema 0 (0) 3 (14) 0 (0) Ͻ Weight increase 0 (0) 3 (14) 0 (0) systolic BP 90 mmHg, serious cardiac or hepatic disease, Blood creatinine increase 2 (12) 1 (5) 3 (13) or a history of significant bleeding or bleeding tendency. 2 Viral upper respiratory 0 (0) 1 (5) 3 (13) The primary objective of TEMPO4 and 156-05-002 stud- tract infection ies was to confirm the long-term safety and tolerability of Dyspepsia 0 (0) 1 (5) 3 (13) tolvaptan. Subject safety was assessed by regular monitor- Dry mouth 0 (0) 0 (0) 3 (13) ing of adverse events (AEs), directed physical examina- Vomiting 0 (0) 1 (5) 3 (13) tions, vital signs, laboratory, and electrocardiogram mea- Insomnia 1 (6) 1 (5) 3 (13) surements. The secondary objective of these trials was to Rash 0 (0) 0 (0) 3 (13) acquire pilot efficacy data. Efficacy was assessed by Muscle spasms 0 (0) 0 (0) 3 (13) changes in urine osmolality (Uosm), TKV, eGFR, and Anxiety 0 (0) 0 (0) 3 (13) hypertension status. Pharmacokinetic/pharmacodynamic analyses were also performed. This report focuses on com- parisons of tolvaptan to historical matched-control trajec- 2502 Clinical Journal of the American Society of Nephrology
and baseline value of the parameter of interest (TKV di- Table 2. Baseline demographic profile of North American and vided by height or eGFR using ethnicity-adjusted CKD-EPI Japanese completing subjects and their matched controls equation) from their potential matches (14,15). Once iden- TKV eGFR tified, each control subject was used only once. Matching Tolvaptan Parameter ϭ a Control Control proceeded in a randomly selected order for tolvaptan- (n 51) ϭ b ϭ c (n 102) (n 102) treated subjects. The first control subject was matched to Maled 17 (33.3) 34 (33.3) 34 (33.3) the first tolvaptan-treated subject, and then the second Femaled 34 (66.7) 68 (66.7) 68 (66.7) control was matched to the second tolvaptan-treated sub- Age (years)e 42 (8.8) 37 (6.5) 42 (9.4) ject, and so on until all had one match. The process then Raced proceeded in reverse, selecting a second control subject for Caucasian 38 (74.5) 89 (87.3) 90 (88.2) the tolvaptan-treated subject who was last matched, pro- Black 1 (2.0) 9 (8.8) 6 (5.9) gressing to the first tolvaptan-treated subject in this order Asian 12 (23.5) 1 (1.0) 1 (1.0) until all had two matches. Other 0 (0) 3 (2.9) 5 (4.9) In the initial 2 months of the TEMPO2 study, a split-dose Hypertensiond 43 (84.3) 86 (84.3) 86 (84.3) 4 Height (cm)e 170 (9.8) 172 (11) 171 (10.1) regimen of oral tolvaptan (8 a.m./4 p.m.) was up-titrated Weight (kg)e 77 (21.1) 78 (18.2) 78 (16.3) (15/15, 30/15, 45/15, 60/30, 90/30 mg/d) until tolerability TKV (ml)e 1635 (978) 1422 (725) — was reached. Subjects were then randomized to one of two eGFR (ml/min 62 (20.1) 77 (18.4) 62 (19.1) doses (45/15 and 60/30 mg) chosen after analysis of effi- per 1.73 m2)f cacy (Uosm Ͻ300 mOsm/Kg in 70% and 77% of patients, respectively) and self-reported tolerability (tolerable for TKV, total kidney volume; eGFR, estimated GFR; MDRD, the rest of life in 96% and 61% of patients, respectively; Modification of Diet in Renal Disease Study; CRISP, Figure 1). After the titration period, those on the higher Consortium of Radiologic Imaging Studies of Polycystic dose were allowed to down-titrate as needed. A 15/15- Kidney Disease; —, not available. mg/d split dose regimen was used in study 156-05-002. a Tolvaptan subjects for TKV and eGFR derived from those 2 Tolvaptan subjects were evaluated at predose baseline, completing 3 years’ treatment in the U.S. 156-04-250 TEMPO4 ϭ ϭ weekly during titration, at 2, 6, 9, and 12 months, and (n 39) and 156-05-002 (n 12) studies. 2 b Control subjects for TKV derived from CRISP cohort. every 4 months thereafter for 36 months in TEMPO4 and at c Control subjects for eGFR derived from CRISP (n ϭ 66) and predose baseline, 1, 2, and 4 weeks, and every 4 weeks MDRD (n ϭ 36) cohorts. thereafter for 36 months in study 156-05-002. Serum creat- d Values are number of subjects with percentage in parentheses. inine data for CRISP and/or MDRD were available at e Values are mean with SD in parentheses. screening, baseline, at 2, 4, 8, and 12 months, and every 4 f eGFR by MDRD ϭ 186 ϫ (SCr) Ϫ 1.154 ϫ (age) Ϫ 0.203 ϫ (0.742 if months thereafter and were available annually for CRISP. ϫ female) (1.21 if African American or 0.808 if Japanese). Additional values were available between 36 and 42 2 months for some subjects. TEMPO4 and 156-05-002 study tories of TKV and eGFR. These slope comparisons were measurements of serum creatinine tests were performed analyzed as a linear mixed model of annualized change in centrally at Quest Laboratories and SRL Inc., respectively. log-transformed TKV or eGFR over 3 years. Assessing Serum creatinine measurements in 156-05-002 used an en- 2 slope reduces the variability associated with eGFR and zymatic assay, whereas TEMPO4, CRISP, and MDRD used facilitates projection over time (12). kinetic alkaline picrate assays. 2 Control data were gathered from participants in the TKV in CRISP, TEMPO4, and 156-05-002 studies was CRISP and MDRD studies (7,10,13). CRISP included 241 determined by magnetic resonance imaging at baseline ADPKD subjects, 15 to 46 years old with eGFR Ͼ70 ml/ and at months 12, 24, and 36 using comparable methods. min by Cockcroft-Gault at entry. MDRD included 200 Computed tomography was used in one 156-05-002 sub- 2 ADPKD subjects, 18 to 70 years old, segregated by iothal- ject. TKV was also measured at month 2 for TEMPO4 and 2 amate GFR (study A 25 to 55 or study B 13 to 24 ml/min at month 6 for 156-05-002. The TEMPO4 magnetic reso- per 1.73 m2) and randomized to low or usual BP targets nance imaging acquisition protocol included T2-weighted and a usual or low-protein diet. All matched controls for single-shot fast spin-echo images with fat saturation and eGFR were from study A, an observational cohort equiv- three-dimensional spoiled gradient interpolated T1- alent because interventions did not influence the rate of weighted images without fat saturation. T2- and T1- renal function decline. weighted images were similar for the 156-05-002 study. Longitudinal TKV were available only in the CRISP Gadolinium enhancement used at baseline and some 2 study. MDRD subjects were needed to match the lower 1-year visits in TEMPO4 were abandoned due to safety GFR values in some subjects in the tolvaptan group. There- concerns. Gadolinium-enhanced images were not used for 2 fore for matched control pairing, the pool of matches was measuring TKV. Coronal 3- to 5-mm (TEMPO4) and 5- to restricted to CRISP subjects for TKV, but included both 7-mm (156-05-002)-thick slices covering the entire kidneys CRISP and MDRD subjects for eGFR. Sets of potential were acquired during a breath-hold and sent to central controls were first identified by matching gender and hy- reading facilities (Perceptive Informatics, Inc., Billerica, pertensive status for each tolvaptan-treated subject. Then MA, or Biovisiq Japan, Inc., Osaka, Japan) for quality con- tolvaptan-treated subjects were ordered randomly, and in trol and TKV measurement using Alic software (Perceptive this order they were matched to subjects in their set who Informatics, Inc.) or Virtual Place Advance version 2.01 had the smallest sum of percent absolute differences in age (AZE Ltd., Tokyo, Japan). Serial kidney outlines were ver- Clin J Am Soc Nephrol 6: 2499–2507, October, 2011 Tolvaptan in ADPKD, Higashihara et al. 2503
Table 3. Annualized progression rate of TKV and eGFR in completing subjects projected over 3 years
Annualized TKV Growth Ratea
Group N Annual Change (%/yr)b RGMc P-Value TKV control 102 5.8 (4.3) 0.96 (0.95 to 0.97) Ͻ0.01 Tolvaptan 51 1.7 (3.5)
Annualized eGFR Sloped
Annual Change LS Mean Difference Group N 2 b 2 c P-Value (ml/min per 1.73 m per year) (ml/min per 1.73 m per year) eGFR control 102 Ϫ2.1 (3.1) 1.1 (0.24 to 1.92) ϭ0.01 Tolvaptan 51 Ϫ0.7 (2.2)
TKV, total kidney volume; eGFR, estimated GFR; N, number of subjects; RGM, ratio of geometric means; LS, least significant, MDRD, Modification of Diet in Renal Disease. a Summary statistics were derived by regressing logarithm-transformed TKV against time, and then exponential the regression slopes and P-value of ratio of geometric means were derived from testing the time-treatment interaction using linear mixed model in which both intercept and slope are fixed and random effects. The ratio of geometric means is an estimate of the ratio of the geometric mean of annualized growth rate of tolvaptan and control. b Values are mean with SD in parentheses. c Values in parentheses are 95% confidence interval. d Summary statistics were derived by slope of change by regressing eGFR data against time by subject. LS means difference derived from testing the time-treatment interaction using a linear mixed model in which both intercept and slope are fixed and random effects. eGFR by MDRD ϭ 186 ϫ (SCr) Ϫ 1.154 ϫ (age) Ϫ 0.203 ϫ (0.742 if female) ϫ (1.21 if African American or 0.808 if Japanese). ified by independent radiologists familiar with ADPKD, squares mean differences of the two treatment groups at each blinded to patient name and acquisition sequence. yearly visit under the MMRM were used to estimate group The statistical analysis plan prespecified a primary end differences at years 1, 2, and 3. The MMRM included group, point of percent rate of change in TKV over 3 years in visit, and group visit interaction as class variables and base- tolvaptan-treated subjects and matched controls (1:2) re- line TKV or eGFR as covariates. MMRM analysis used all ceiving standard care. Secondary end points included rate available data at baseline and years 1, 2, and 3. of change in eGFR, by the four-variable MDRD equations. Correlation of annualized percent change in TKV with The formula was adjusted for Japanese ethnicity for the annualized change in eGFR was assessed using available 156-05-002 subjects using a coefficient of 0.808 (15). Sum- data for the tolvaptan completers and TKV-matched CRISP mary statistics of baseline characteristics were evaluated to control subjects. This comparison was a prospective objec- ensure adequate balance between cohorts. tive of the protocol; however, specific use of Pearson cor- For the primary end point, comparison of tolvaptan- relation was decided upon post hoc. Data analysis was treated month 36 completers with their TKV control performed by one of the authors (J.O.) according to proto- matches was performed using a linear mixed model on the col-specified statistical analysis plan prepared in collabo- log-transformed TKV slope analysis procedure with group ration with the authors. The sponsor holds the data, which and group time interaction as fixed effect, baseline as fixed are freely available. covariate, intercept and time as both fixed and random effect, and unknown variance-covariance structure for the Results random effects. Time is a continuous variable. Sandwich Subject disposition is described in Figure 2. Overall com- estimate of the variance-covariance matrix was used to test pliance was good for those completing 36 months’ treat- 2 the group time interaction. This analysis was based on all ment. For the TEMPO4 study the average dose reported available data. For the secondary analysis, all available after 36 months as taken in the 18 subjects assigned 45/15 data for tolvaptan-treated completers were compared with (i.e., 60 mg/d) group was 59.2 mg/d; for the 21 subjects in eGFR control matches using a linear mixed model on the 60/30 (i.e., 90 mg/d) group, including five subjects eGFR, using a similar slope analysis procedure to the pri- who had down-titrated (thus an expected exposure of 82.9 mary analysis, except that eGFR was not log-transformed. mg/d after adjustment after down-titration to 45/15), was A sensitivity analysis of primary and secondary end points 80.7 mg/d. Compliance in all but one subject in the 45/15 2 included all available TKV and eGFR data from TEMPO4 mg/d group was confirmed by measurements of tolvaptan and 156-05-002 noncompleters to assess impact of with- metabolite levels. Eighty percent of completers for the drawn subjects. 156-05-002 study were more than 90% compliant by pill In addition to the primary and sensitivity analyses de- count, whereas the remaining two maintained more than scribed above, mixed model repeated measures (MMRM) 50% compliance. sensitivity analyses were applied to change from baseline for The observed AEs were consistent with the mechanism eGFR and percent changes from baseline in TKV. Least- of action of tolvaptan and the natural history of ADPKD. 2504 Clinical Journal of the American Society of Nephrology
Most were mild or moderate in severity. Table 1 lists very common AEs (reported in Ͼ10% of patients; Supplemental Table 1 lists all AEs). Small mean increases from baseline were seen for serum creatinine and uric acid, starting at the earliest time points. No clinically meaningful trends were seen for any hematology, urinalysis, or ECG parameter. Twelve (19%) patients withdrew from the study. Rea- sons for withdrawal are shown in Supplemental Table 2. AEs accounted for six (50%) of the withdrawals, including renal impairment, acute renal failure, benign pituitary tu- mor, transient ischemic attack, eye swelling, and subarach- noid hemorrhage with a fatal outcome. ⅐ Urine osmolality below 300 mOsm/kg H2O was used in 2 the TEMPO4 and 156-05-002 study as a target for tolvaptan 2 inhibition of vasopressin activity. The TEMPO4 and 156- 05-002 mean (median) Uosm premorning dose was 264
(228) and 343 (310) mOsm/kg per H2O. This was below mean (median) baseline levels of 472 (409) and 478 (461) mOsm/kg per H2O. Tolvaptan subject cohorts were closely matched to con- trols for gender and hypertension status, age, height, race, and baseline parameter of interest. Mean TKV was 13% lower, and age was 5 years younger in the TKV controls (Table 2). Forty-five percent and 37% of tolvaptan-treated patients and 47% and 23% of CRISP matches were treated with angiotensin-converting enzyme inhibitors or angioten- sin II receptor blockers. Forty-two percent of subjects in the MDRD study were treated with angiotensin-converting en- zyme inhibitors (16). TKV growth in tolvaptan-treated subjects was 1.7%/yr compared with 5.8%/yr for control CRISP subjects (P Ͻ 0.001, ratio of geometric mean [RGM] 0.96, 95% confidence interval 0.95 to 0.97) (Table 3, Figure 3a). This represents a 70% slower growth rate per year in tolvaptan-treated pa- tients. A similar result was obtained when all completers and withdrawn subjects were included in the analysis: 1.7%/yr and 5.8%/yr, respectively (P Ͻ 0.001, RGM 0.96, 95% confidence interval 0.95 to 0.97) (Supplemental Table 3). The corresponding slopes of eGFR were Ϫ0.71 in tolvaptan-treated patients and Ϫ2.1 ml/min per 1.73 m2/yr in CRISP (n ϭ 66) and MDRD (n ϭ 36) control subjects (P ϭ 0.01, linear mixed model [LMM] group dif- ference 1.1, 95% confidence interval 0.24 to 1.9) for a group Figure 3. | Change in total kidney volume and renal function over 3 difference of approximately 65% (Table 3, Figure 3b). Re- years of tolvaptan compared with matched control and their cor- relation for individual subjects. The primary analysis for slope of total sults were similar, but less marked (15% effect size), for the Ϫ kidney volume (TKV) and estimated GFR (eGFR) use each parameter’s all completers and withdrawn group comparison; 1.7 annualized change and a linear mixed model to test for group differ- Ϫ 2 ϭ versus 2.0 ml/min per 1.73 m /yr (P 0.02, LMM group ences. Because these data are not easily displayed, subjects completing difference 0.95, 95% confidence interval 0.13 to 1.8) (Sup- 3 years of tolvaptan (black circles) and their controls (red triangles) are plemental Table 3). displayed for TKV (a) and eGFR (b). Control subjects were matched 1:2 The effect of tolvaptan on kidney growth was confirmed by gender, presence of hypertension, age, and either baseline TKV (a) or by the MMRM sensitivity analysis. At each visit, average baseline eGFR (b). Values for change from baseline (as percent TKV or 2 TKV trended upward or downward as expected (Table 4). ml/min per 1.73 m per year) are plotted, and dotted lines representing Over 3 years, mean TKV increased by 98 ml (5.3%, from a linear regression of group trend were drawn. (c) These subjects’ annualized change in eGFR (by MDRD formula) and the annualized 1635 to 1734 ml) in the all completers tolvaptan-treated percent change in TKV were plotted, and the entire data set’s correlation group, compared with 300 ml (19%, from 1422 to 1722 ml) (r ϭϪ0.21, P Ͻ 0.01) was evaluated. Dashed lines marking a zero in the matched control group. These TKV changes were all change in TKV and eGFR parameters are drawn, creating quadrants significantly different between the groups at each yearly representing improvement in both parameters (A), improvement in assessment. In contrast, eGFR declined from a mean of 61.6 eGFR but worsened TKV (B), worsened eGFR but improved TKV (C), to 55.9 for all completers treated subjects and from 61.9 to and worsening in both parameters (D) are shown. The data point circled 55.4 ml/min per 1.73 m2 for matched controls. Although represents the subject in whom compliance with tolvaptan was not the difference between groups in the mean change at year supported by tolvaptan metabolite data. Clin J Am Soc Nephrol 6: 2499–2507, October, 2011 Tolvaptan in ADPKD, Higashihara et al. 2505
Table 4. Change in mean TKV and eGFR in all completing subjects by visit
Control Tolvaptan
Mean % Mean % Group Difference; N N a Mean SD Change SD Mean SD Change SD P-value
TKV (ml) Baseline 102 1422 724.8 51 1635 977.5 Month 12 100 1515 776.3 4.8 7.0 51 1644 983.7 0.8 7.3 Ϫ4.41 (Ϫ0.71 to Ϫ8.11); P ϭ 0.02 Month 24 95 1660 896.7 13.8 11.0 51 1670 1015 1.6 8.5 Ϫ12.5 (Ϫ8.79 to Ϫ16.2); P Ͻ 0.0001 Month 36 102 1722 945.5 19.0 15.9 51 1733 1052 5.3 11.0 Ϫ14.3 (Ϫ10.6 to Ϫ18.0); P Ͻ 0.0001
Mean Mean Group Difference; N N a Mean SD Change SD Mean SD Change SD P-Value eGFR ml/min per 1.73 m2b Baseline 102 61.9 19.1 51 61.6 20.1 Month 12 100 59.4 22.1 Ϫ2.6 8.5 49 60.0 22.2 Ϫ1.5 12.8 1.0 (Ϫ2.3 to 4.3); P ϭ 0.54 Month 24 100 56.2 22.1 Ϫ5.6 8.4 50 59.3 21.5 Ϫ2.6 8.8 2.9 (Ϫ0.4 to 6.1); P ϭ 0.09 Month 36 101 55.4 22.3 Ϫ6.8 10.5 51 55.9 21.1 Ϫ5.7 9.2 1.1 (Ϫ2.2 to 4.4); P ϭ 0.50
TKV, total kidney volume; eGFR, estimated GFR; MDRD, Modification of Diet in Renal Disease. a Values in parentheses are 95% confidence interval. b eGFR by MDRD ϭ 186 ϫ (SCr) Ϫ 1.154 ϫ (age) Ϫ 0.203 ϫ (0.742 if female) ϫ (1.21 if African American or 0.808 if Japanese).
3 in eGFR was only 1.1 ml/min per 1.73 m2, the maximum before the premorning dose (the time point where the drug difference was 3.1 ml/min per 1.73 m2 at year 2, reflecting would have least affected urine osmolality) at the maxi- 2 a high degree of variability of average eGFR over time and mally tolerated dose for TEMPO4 and at 15/15 mg/d for yielding nonsignificant differences between the groups at 156-05-002 were 228 and 310 mOsm/kg per H2O, respec- 1, 2, or 3 years. Results were similar when using data from tively; below or near serum osmolality (290 mOsm/kg per all subjects (Supplemental Table 4). H2O). In comparison to recently published data on water- The slopes for TKV and eGFR were significantly and loaded ADPKD subjects, this spot-urine value reflects the negatively correlated. Greater increases in TKV were cor- maximum urine osmolality, rather than a 24-hour integra- related with greater declines in eGFR, with lesser changes tion of osmolality, which would be a lower value (17). for both occurring in the tolvaptan-treated patients (r ϭ Tolvaptan had a strong effect on TKV growth, consistent Ϫ0.21, P Ͻ 0.01) (Figure 3c). with a potent effect on cyst growth. Data from the 2-month 2 2 Separate analyses of the TEMPO4 North American (Sup- time point in the TEMPO4 study and 6-month time point in plemental Tables 5 and 6) and 156-05-002 Japanese com- the 156-05-002 study suggest an early decrease in TKV, pleters yielded similar results for trends in TKV (both likely attributable to changes in cyst fluid secretion (18). groups showing significance; LMM group difference 0.97, Beyond this 2- to 6-month period, TKV growth appears to Ͻ 2 95% CI 0.95 to 0.98, P 0.001, for TEMPO4; 0.935, 95% CI resume, but at a substantially slower rate than in the un- 0.92 to 0.95, P Ͻ 0.001, for 156-05-002) and eGFR (signifi- treated subjects. 2 cant only for the larger TEMPO4 cohort). The results of our analysis showed significant effect of Only eight subjects were not receiving antihypertensive tolvaptan on the rate (slope) of eGFR decline. MMRM therapy at baseline. Three became hypertensive during the analysis using data limited to annual visits, however, was 3 years of treatment. The small number of subjects in the not significant for change in eGFR at year 1 or year 3, with nonhypertensive category at baseline prevented useful only a trend toward significance at year 2. The high phys- analyses of effects on hypertension progression. iologic variability of GFR compared with TKV and the lower sensitivity of the MMRM compared with the slope Discussion analysis may account for the different results. Cyst growth progressed more slowly in the tolvaptan- The results also showed a significant negative correla- treated patients than in historical controls. Eighty-one per- tion between annualized slope of TKV and slope of eGFR cent of subjects completed 3 years of treatment. Although (r ϭϪ0.21, P Ͻ 0.01). In Figure 3c, subjects treated with all of the participants experienced AEs and six participants tolvaptan cluster near zero change for both parameters. withdrew from the study because of AEs, most were mild The only subjects without an increase in TKV or a decline 2 to moderate in severity. Of 39 TEMPO4 study completers, in eGFR were treated with tolvaptan (quadrant A). More 92% were eligible and enrolled in an extension of open- control subjects tended to worsen in both (TKV increase label treatment. and eGFR decline) in number and extent (quadrant D). Fifty-one subjects treated with tolvaptan for 3 years were Likewise, the mean change in eGFR over 3 years of treat- compared with 102 untreated, matched ADPKD controls. ment with tolvaptan was marginally less than in the con-
Efficacy of tolvaptan in blocking the vasopressin V2 recep- trol even although the tolvaptan group had larger kidneys tor was evident in that the group median trough Uosm at baseline. The CRISP study suggested that both TKV and 2506 Clinical Journal of the American Society of Nephrology
renal function worsen more quickly for those with larger and cooperation during the several years of these studies; kidney volumes (7). In the current study, TKV was 13% the study investigators, coordinators, Radiology Centers lower at baseline in the control compared with the tolvap- and other staff; the TEMPO scientific advisors: Akira tan group, a difference that should have favored slower Hishida (Hamamatsu University, Shizuoka, Japan); Fumi- growth and functional decline. On the other hand, the take Gejyo, M.D. (Nigata University, Niigata, Japan); mean age of the control group was 5 years younger (37 Toshiaki Nitatori, M.D. (Kyorin University School of Med- versus 42 years), and younger subjects with larger kidneys icine, Mitaka, Tokyo); the TEMPO Independent Data Mon- grew most rapidly in the CRISP study (7). TKV growth itoring Committee members: Sidney Goldstein, M.D. rates in the whole CRISP cohort averaged 5.3% to 9.5% and (Henry Ford Hospital, Detroit, MI); Benjamin Cowley, 5.2% to 6.8% per year for Ͻ30- and Ն30-year-old subjects, M.D. (University of Oklahoma, Oklahoma City, OK); respectively, more than three times that observed for the Masafumi Fukagawa, M.D., Ph.D. (Tokai University group receiving tolvaptan (1.7%/yr) (7) in this study. Thus, School of Medicine, Isehara City, Japan); Roser Torra, M.D. TKV and renal function appear to be linked, and treatment (Fundacio Puigvert, Barcelona, Spain); Lee-Jen Wei, Ph.D. to slow the rate of TKV growth appears to be accompanied (Harvard School of Public Health, Boston, MA): the Otsuka by a slower rate of decline in renal function. and CRO project managers, Data Monitors, Data Manag- This study has limitations. Twelve of 51 (approximately ers, Programmers; Osamu Sato and Tadashi Okada (Ot- 25%) of the tolvaptan-treated patients were Japanese, suka Pharmaceutical Corporation, Tokyo, Japan); and the whereas both of the matched-control patient cohorts were radiologists at Central Reading Facilities (Biovisiq, Osaka, predominantly Caucasian (approximately 90%) with only Japan, and Perceptive, Billerica, MA). approximately 1% Asian. It should be noted, however, that the tolvaptan effects on TKV and eGFR are also significant Appendix when matched control comparisons are restricted to the 2 156-04-250 TEMPO4 Principle Investigators (PI), North American patients (Supplemental Tables 5 and 6). Subinvestigators (SI), and Radiologists (R): United States Another limitation is that controls were not studied con- William Bennett (PI), Michael Walczyk (SI), Northwest currently. This is less likely to have influenced TKV com- Renal Clinic, Inc., Portland, OR; Jon Blumenfeld* (PI), parisons (because controls derived exclusively from con- Stephanie Donahue (SI), Martin Prince* (R), Rogosin Insti- temporaneous CRISP) than eGFR comparisons using tute,* New York, NY, and Weill Medical College; W. Kline controls from CRISP (65% of patients) and from the MDRD Bolton (PI), Mitchell Rosner (SI), Clinical Research Center (35% of patients) conducted almost two decades earlier. A at the University of Virginia, Charlottesville, VA; Arlene sensitivity analysis using only CRISP eGFR-matched con- Chapman (PI), Frederick Rahbari-Oskoui (SI), Diego Mar- trols for all subjects in both studies provides a poorer tin (R), Emory Midtown Hospital, Atlanta, GA; Charles baseline match, but yields equally significant results for Edelstein (PI), Tomas Berl (SI), Janis Cicerchi (SI), Brian L. Ϫ Ϫ 2 ϭ eGFR ( 1.7 versus 1.0 ml/min/1.73 m per year [P Burke (R), University of Colorado Denver, Aurora, CO; 0.01, LMM group difference 1.1, 95% CI 0.23 to 2.0] using Michael Koren (PI), Susan N. Greco (SI), Jeffry Jacqmein Ϫ Ϫ only CRISP controls as compared with 1.7 versus 2.0 (SI), Darlene Bartilucci (SI), Mark Frisk (R), Jacksonville 2 ϭ ml/min/1.73 m per year [P 0.02, LMM group difference Center for Clinical Research, Jacksonville, FL; Gerald 0.95, 95% CI 0.13 to 1.8] using CRISP and MDRD controls). Schulman (PI), Julia Lewis (SI), Thomas Golper (SI), Ron- Given these limitations, the results of the current study, ald Arildsen (R), Vanderbilt University Medical Center, while promising, should be viewed cautiously. Nashville, TN; Suzanne Swan (PI), Courtney Cannon (SI), To be clinically meaningful, the 15% to 65% or 0.3- to James Cunningham–R. Davita Clinical Research, Minneap- 2 1.4-ml/min per 1.73 m per year advantage would need to be olis, MN; Vicente Torres (PI), Marie Hogan (SI), Fernando sustained over a period of many more years. Confirming this Fervenza (SI), James Glockner (R), Mayo Clinic, Rochester, degree of benefit in the ongoing 1445-subject, placebo-con- MN; Terry Watnick (PI), Sharon Turban (SI), Katarzyna J. trolled ADPKD trial (NCT00428948) are needed to provide Macura (R), John Hopkins School of Medicine, Baltimore, the evidence necessary to establish a causal link between this MD; Franz Winklhofer (PI), Judson Bertsch (SI), Connie therapy’s ability to slow kidney volume expansion with pres- Wang (SI), Louis Wetzel (R), University of Kansas Medical ervation of kidney function. Center, Kansas City, KS.
General Acknowledgments 156-05-002 Investigators: Japan) The CRISP and MDRD studies were conducted by the Yasuhiko Iino (PI), Nippon Medical School Hospital, To- CRISP and MDRD investigators and supported by the kyo; Kouju Kamata (PI), Hisato Sakamoto (SI), Kitasato National Institute of Diabetes and Digestive and Kidney University Hospital, Sagamihara, Kanagawa; Koichi Ka- Diseases (NIDDK). The data from the CRISP and MDRD mura (PI), National Hospital Organization Chiba-East studies reported here were supplied by the NIDDK Central Hospital, Chiba; Tatsuhiko Kanno (PI), Hidetomo Naka- Repositories. The analyses presented in this publication moto (SI), Musashi Ranzan Hospital, Ranzan-machi, were not prepared in collaboration with Investigators of Saitama; Satoru Muto (PI), Mitsuko Yasuda (SI), Shigeo the CRISP and MDRD studies and does not necessarily Horie (SI), Hisamitsu Ide (SI), Teikyo University Hospital, reflect the opinions or views of the CRISP and MDRD Tokyo; Yukio Naya (PI), Naoki Nihei (PI), Kazuhiro Araki studies, the NIDDK Central Repositories, or the NIDDK. (SI), Chiba University Hospital, Chiba; Kosaku Nitta (PI), We acknowledge the contributions of the volunteer sub- Ken Tsuchiya (SI), Junko Arai (SI), Tokyo Women’s Med- jects who have and continue to patiently offer their time ical University Hospital, Tokyo; Takatsugu Okegawa (PI), Clin J Am Soc Nephrol 6: 2499–2507, October, 2011 Tolvaptan in ADPKD, Higashihara et al. 2507
Eiji Higashihara (SI), Kyorin University Hospital, Mitaka, Harris PC, Klahr S, Bennett WM, Hirschman GN, Meyers Tokyo; Kenmei Takaichi (PI), Yoshifumi Ubara (SI), Tora- CM, Zhang X, Zhu F, Miller JP: Volume progression in poly- nomon Hospital, Tokyo; Yusuke Tsukamoto (PI), To- cystic kidney disease. N Engl J Med 354: 2122–2130, 2006 8. Grantham JJ, Chapman AB, Torres VE: Volume progression in mokazu Okado (SI), Michio Kuwahara (SI), Mikiko Ayata autosomal dominant polycystic kidney disease: The major (SI), Shigeru Takada (SI), Seiji Inoshita (SI), Tamaki Kuy- factor determining clinical outcomes. Clin J Am Soc Nephrol ama (SI), Tomoki Asai (SI), Shuwa General Hospital, Ka- 1: 148–157, 2006 sukabe, Saitama. 9. USDA: Develop biomarkers to aid in the development of therapies for polycystic kidney disease (PKD). In: Key FDA critical path activities under way in 2007. Washington, D.C., Funding and Disclosures 2 U.S. Department of Health and Human Services Food and The TEMPO4 trial was funded by Otsuka Pharmaceutical De- Drug Administration, June 2008, page 5 velopment & Commercialization, Inc; the 002 trial was funded by 10. Klahr S, Levey A, Beck G, Caggiula A, Hunsicke L, Kusek J, Otsuka Pharmaceutical, Ltd.; the CRISP and MDRD trials were Striker G: The effects of dietary protein restriction and blood- funded by the U.S. National Institutes of Health; Dr. Higashihara pressure control on the progression of chronic renal disease. N Engl J Med 330: 877–884, 1994 reports having served as a consultant to Otsuka. Dr. Torres reports 11. Ravine D, Gibson RN, Walker RG, Sheffield LJ, Kincaid- having served as a consultant to Hoffman La-Roche, Primrose, Smith P, Danks DM: Evaluation of ultrasonographic diagnos- and Amgen, receiving grants/research support from Otsuka and tic criteria for autosomal dominant polycystic kidney disease Novartis. Dr. Chapman reports having served as a consultant to 1. Lancet 343: 824–827, 1994 Otsuka and Novartis. Dr. Grantham reports having served as a 12. Stevens L, Greene T, Levey A: Surrogate endpoints for clini- consultant to Otsuka and receiving grants/research support from cal trials of kidney disease progression. Clin J Am Soc Neph- rol 1: 874–884, 2006 Otsuka. Dr. Bae reports having served as a consultant to Otsuka. 13. Klahr S, Breyer J, Beck G, Dennis V, Hartman J, Roth D, Dr. Watnik reports serving as an investigator for the Otsuka Steinman T, Wang S, Yamamoto M: Dietary protein restric- Tolvaptan Program, holding a patent in area of ADPKD genetics, tion, blood pressure control, and the progression of polycys- licensed to Athena Laboratories through Johns Hopkins Univer- tic kidney disease modification of diet in renal disease study sity (JHU) for which her and her spouse’s royalties are managed group. J Am Soc Nephrol 5: 2037–2047, 1995 14. Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hen- by JHU and donated to the Polycystic Kidney Disease Research driksen S, Kusek JW, Van Lente F: Using standardized serum Foundation. Drs. Horie and Nutahara have served as consultants creatinine values in the modification of diet in renal disease and investigators for Otsuka. Drs. Ouyang and Czerwiec and Ms. study equation for estimating glomerular filtration rate. Ann Krasa are employees of Otsuka. No other potential conflict of Intern Med 145: 247–254, 2006 interest relevant to this article was reported. 15. Horio M, Imai E, Yasuda Y, Watanabe T, Matsuo S: Modifica- tion of the CKD epidemiology collaboration (CDK-EPI) equa- tion for Japanese: Accuracy and use for population estimates. References Am J Kidney Dis, 56: 32–38, 2010 1. Grantham JJ: Clinical practice. Autosomal dominant polycys- 16. Sarnak MJ, Greene T, Wang X, Beck G, Kusek JW, Collins AJ, tic kidney disease. N Engl J Med 359: 1477–1485, 2008 Levey AS: The effect of a lower target blood pressure on the 2. Gabow P: Autosomal dominant polycystic kidney disease. progression of kidney disease: Long-term follow-up of the N Engl J Med 329: 323–342, 1993 modification of diet in renal disease study. Ann Intern Med 3. Dalgaard OZ: Bilateral polycystic disease of the kidneys: A 142: 342–351, 2005 follow-up of two hundred and eighty-four patients and their 17. Wang CJ, Creed C, Winklhofer FT, Grantham JJ: Water pre- families. Acta Med Scand 328: 1–255, 1957 scription in autosomal dominant polycystic kidney disease: A 4. Torres VE, Harris PC, Pirson Y: Autosomal dominant polycys- pilot study. Clin J Am Soc Nephrol 6: 192–197, 2011 tic kidney disease. Lancet 369: 1287–1301, 2007 18. Irazabal MV, Torres VE, Hogan MC, Glockner J, King BF, Of- 5. Bajwa ZH, Gupta S, Warfield CA, Steinman TI: Pain manage- stie TJ, Krasa HB, Ouyang J, Czerwiec FS: Short-term effects ment in polycystic kidney disease. Kidney Int 60: 1631– of tolvaptan on renal function and volume in patients with 1644, 2001 autosomal dominant polycystic kidney disease. Kidney Int 6. Torres VE: Vasopressin in chronic kidney disease: An ele- 80: 295–301, 2011 phant in the room? Kidney Int 76: 925–928, 2009 7. Grantham JJ, Torres VE, Chapman AB, Guay-Woodford LM, Published online ahead of print. Publication date available at Bae KT, King BF, Jr, Wetzel LH, Baumgarten DA, Kenney PJ, www.cjasn.org.
Supplemental Table 1 All Adverse Events Reported with Tolvaptan in North American & Japanese Subjects Number of Subjects Reporting AE (%) MedDRA Adverse Event Term 156-05-002 or TEMPO 15/15 mg/day 45/15 mg/day 90/30 mg/day N=17 N=22 N=24 Nasopharyngitis 13 (76) 2 (9) 1 (4) Thirst 9 (53) 8 (36) 16 (67) Pollakiuria 2 (12) 10 (46) 14 (58) Renal Pain 0 (0) 10 (46) 9 (38) Nocturia 2 (12) 9 (41) 3 (13) Upper Respiratory Tract Infection 2 (12) 1 (5) 9 (38) Polyuria 1 (6) 8 (36) 6 (25) Dizziness 2 (12) 8 (36) 4 (17) Contusion 6 (35) 1 (5) 0 (0) Fatigue 1 (6) 6 (27) 8 (33) Hypertension 5 (29) 4 (18) 4 (17) Abdominal Pain 1 (6) 3 (14) 7 (29) Diarrhea 2 (12) 2 (9) 7 (29) Blood Antidiuretic Hormone Increased* 5 (29) N/A N/A Urinary Tract Infection 1 (6) 3 (14) 6 (25) Sinusitis 2 (12) 3 (14) 6 (25) Headache 4 (24) 3 (14) 6 (25) Blood Uric Acid Increased 4 (24) 0 (0) 0 (0) Anemia 1 (6) 5 (23) 1 (4) Back Pain 3 (18) 5 (23) 3 (13) Dry Skin 2 (12) 5 (23) 2 (8) Dyspnea 0 (0) 1 (5) 5 (21) Constipation 1 (6) 0 (0) 5 (21) Dehydration 3 (18) 0 (0) 2 (8) Gastritis 3 (18) 0 (0) 0 (0) Palpitations 3 (18) 3 (14) 1 (4) Gastritis Erosive 3 (18) 0 (0) 0 (0) Vertigo 3 (18) 0 (0) 0 (0) Dental Caries 3 (18) 0 (0) 0 (0) Bronchitis 1 (6) 4 (18) 2 (8) Abdominal Distension 1 (6) 3 (14) 4 (17) Nausea 1 (6) 1 (5) 4 (17) Cough 0 (0) 0 (0) 4 (17) Edema Peripheral 1 (6) 3 (14) 3 (13) Hypotension 0 (0) 3 (14) 3 (13) Arthralgia 1 (6) 3 (14) 3 (13) Chest Pain 1 (6) 3 (14) 2 (8) Dry Eye 0 (0) 3 (14) 2 (8) Polydipsia 0 (0) 3 (14) 1 (4) Erythema 0 (0) 3 (14) 0 (0) Weight Increased 0 (0) 3 (14) 0 (0) Blood Creatinine Increased 2 (12) 1 (5) 3 (13) Viral Upper Respiratory Tract Infection 0 (0) 1 (5) 3 (13) Dyspepsia 0 (0) 1 (5) 3 (13) Dry Mouth 0 (0) 0 (0) 3 (13) Vomiting 0 (0) 1 (5) 3 (13) Insomnia 1 (6) 1 (5) 3 (13) Rash 0 (0) 0 (0) 3 (13) Muscle Spasms 0 (0) 0 (0) 3 (13) Anxiety 0 (0) 0 (0) 3 (13) Pain in Extremity 2 (12) 2 (9) 0 (0) Blood Triglycerides Increased 2 (12) 0 (0) 2 (8) Hyperuricemia 2 (12) 0 (0) 2 (8) Tinea Pedis 2 (12) 1 (5) 0 (0) Pharyngitis 2 (12) 0 (0) 1 (4) Musculoskeletal Pain 2 (12) 0 (0) 1 (4) Neck Pain 2 (12) 0 (0) 1 (4) Arthropod Sting 2 (12) 0 (0) 0 (0) Keratitis 2 (12) 0 (0) 0 (0) Gastric Polyps 2 (12) 0 (0) 0 (0) Malaise 2 (12) 0 (0) 0 (0) Muscle Injury 2 (12) 0 (0) 0 (0) Alanine Aminotransferase Increased 2 (12) 0 (0) 0 (0) Blood Cholesterol Increased 2 (12) 0 (0) 0 (0) Blood Glucose Increased 2 (12) 0 (0) 0 (0) Hemoglobin Decreased 2 (12) 0 (0) 0 (0) Blood Phosphorus Increased 2 (12) 0 (0) 0 (0) Spinal Osteoarthritis 2 (12) 0 (0) 0 (0) Intervertebral Disc Protrusion 2 (12) 0 (0) 0 (0) Intracranial Aneurysm 2 (12) 0 (0) 0 (0) Eczema 2 (12) 0 (0) 0 (0) Pruritus 2 (12) 0 (0) 0 (0) Upper Respiratory Tract Inflamation 2 (12) 0 (0) 0 (0) Flank Pain 0 (0) 2 (9) 2 (8) Influenza 1 (6) 2 (9) 1 (4) Flatulence 0 (0) 2 (9) 1 (4) Gastroenteritis Viral 0 (0) 2 (9) 1 (4) Otitis Media 0 (0) 2 (9) 1 (4) Nasal Congestion 0 (0) 2 (9) 1 (4) Atrial Fibrillation 0 (0) 2 (9) 0 (0) Umbilical Hernia 0 (0) 2 (9) 0 (0) Decreased Appetite 0 (0) 2 (9) 0 (0) Micturation Urgency 0 (0) 2 (9) 0 (0) Renal Failure Acute 0 (0) 2 (9) 0 (0) Menorrhagia 0 (0) 2 (9) 0 (0) Depression 1 (6) 0 (0) 2 (8) Abdominal Pain Upper 1 (6) 0 (0) 2 (8) Pneumonia 0 (0) 1 (5) 2 (8) Weight Decreased 0 (0) 1 (5) 2 (8) Hematuria 0 (0) 1 (5) 2 (8) Polycystic Liver Disease 0 (0) 0 (0) 2 (8) Food Poisoning 0 (0) 0 (0) 2 (8) Gastrointestinal Reflux Disease 0 (0) 0 (0) 2 (8) Early Satiety 0 (0) 0 (0) 2 (8) Mucosal Dryness 0 (0) 0 (0) 2 (8) Fungal Infection 0 (0) 0 (0) 2 (8) Viral Infection 0 (0) 0 (0) 2 (8) Incision Site Pain 0 (0) 0 (0) 2 (8) Hypertriglyceridemia 0 (0) 0 (0) 2 (8) Micturation Disorder 0 (0) 0 (0) 2 (8) Nephrolithiasis 0 (0) 0 (0) 2 (8) Dysmenorrhea 0 (0) 0 (0) 2 (8) Pharyngolaryngeal Pain 0 (0) 0 (0) 2 (8) Hemorrhoids 1 (6) 1 (5) 0 (0) Seasonal Allergy 1 (6) 1 (5) 0 (0) Skin Papilloma 1 (6) 1 (5) 0 (0) Breast Cyst 1 (6) 1 (5) 0 (0) Hyperkeratosis 1 (6) 1 (5) 0 (0) Diverticulitis 1 (6) 0 (0) 1 (4) Laceration 1 (6) 0 (0) 1 (4) Renal Impairment 1 (6) 0 (0) 1 (4) Arrhythmia 1 (6) 0 (0) 0 (0) Sinus Bradycardia 1 (6) 0 (0) 0 (0) Asthenopia 1 (6) 0 (0) 0 (0) Conjunctival Hemorrhage 1 (6) 0 (0) 0 (0) Conjunctivitis 1 (6) 0 (0) 0 (0) Eye Pruritis 1 (6) 0 (0) 0 (0) Abdominal Discomfort 1 (6) 0 (0) 0 (0) Enterocolitis 1 (6) 0 (0) 0 (0) Irritable Bowel Syndrome 1 (6) 0 (0) 0 (0) Periodontal Disease 1 (6) 0 (0) 0 (0) Periodontitis 1 (6) 0 (0) 0 (0) Gastrointestinal Telangiectasia 1 (6) 0 (0) 0 (0) Mass 1 (6) 0 (0) 0 (0) Inflammations 1 (6) 0 (0) 0 (0) Vessel Puncture Site Hematoma 1 (6) 0 (0) 0 (0) Anaphylactic Reaction 1 (6) 0 (0) 0 (0) Drug Hypersensitivity 1 (6) 0 (0) 0 (0) Acute Tonsillitis 1 (6) 0 (0) 0 (0) Hordeolum 1 (6) 0 (0) 0 (0) Paronychia 1 (6) 0 (0) 0 (0) Tonsillitis 1 (6) 0 (0) 0 (0) Urethritis 1 (6) 0 (0) 0 (0) Oral Herpes 1 (6) 0 (0) 0 (0) Clavicle Fracture 1 (6) 0 (0) 0 (0) Foot Fracture 1 (6) 0 (0) 0 (0) Head Injury 1 (6) 0 (0) 0 (0) Muscle Injury 1 (6) 0 (0) 0 (0) Tooth Injury 1 (6) 0 (0) 0 (0) Mouth Injury 1 (6) 0 (0) 0 (0) Wound 1 (6) 0 (0) 0 (0) Aspartate Aminotransferase Increased 1 (6) 0 (0) 0 (0) Blood Calcium Increased 1 (6) 0 (0) 0 (0) Blood Creatinine Phosphokinase 1 (6) 0 (0) 0 (0) Increased Blood Glucose Increased 1 (6) 0 (0) 0 (0) Blood Lactate Dehydrogenase Increased 1 (6) 0 (0) 0 (0) Blood Osmolality Decreased 1 (6) 0 (0) 0 (0) Blood Osmolality Increased 1 (6) 0 (0) 0 (0) Gamma-glutamyltransferase Increased 1 (6) 0 (0) 0 (0) Lymphocyte Count Decreased 1 (6) 0 (0) 0 (0) Monocyte Count Increased 1 (6) 0 (0) 0 (0) Neutrophil Count Increased 1 (6) 0 (0) 0 (0) Red Blood Cell Count Decreased 1 (6) 0 (0) 0 (0) White Blood Cell Count Decreased 1 (6) 0 (0) 0 (0) Blood Alkaline Phosphatase Decreased 1 (6) 0 (0) 0 (0) Urine Output Increased 1 (6) 0 (0) 0 (0) Lumbar Spinal Stenosis 1 (6) 0 (0) 0 (0) Amnesia 1 (6) 0 (0) 0 (0) Glossopharyngeal Neuralgia 1 (6) 0 (0) 0 (0) Hyperaesthesia 1 (6) 0 (0) 0 (0) Migrane 1 (6) 0 (0) 0 (0) Sciatica 1 (6) 0 (0) 0 (0) Subarachnoid Hemorrhage 1 (6) 0 (0) 0 (0) Arachnoid Cyst 1 (6) 0 (0) 0 (0) Adjustment Disorder with Depressed 1 (6) 0 (0) 0 (0) Mood Asthma 1 (6) 0 (0) 0 (0) Hemoptysis 1 (6) 0 (0) 0 (0) Rhinorrhea 1 (6) 0 (0) 0 (0) Oropharyngeal Pain 1 (6) 0 (0) 0 (0) Dyshydrosis 1 (6) 0 (0) 0 (0) Ingrowing Nail 1 (6) 0 (0) 0 (0) Urticaria 1 (6) 0 (0) 0 (0) Arthropod Bite 0 (0) 1 (5) 1 (4) Abdominal Pain Lower 0 (0) 1 (5) 1 (4) Hiatus Hernia 0 (0) 1 (5) 1 (4) Cyst 0 (0) 1 (5) 1 (4) Body Tinea 0 (0) 1 (5) 1 (4) Kidney Infection 0 (0) 1 (5) 1 (4) Tooth Infection 0 (0) 1 (5) 1 (4) Vulvovaginal Mycotic Infection 0 (0) 1 (5) 1 (4) Fall 0 (0) 1 (5) 1 (4) Radius Fracture 0 (0) 1 (5) 1 (4) Skin Laceration 0 (0) 1 (5) 1 (4) Cardiac Murmur 0 (0) 1 (5) 1 (4) Hyperlipidemia 0 (0) 1 (5) 1 (4) Dysgeusia 0 (0) 1 (5) 1 (4) Kidney Enlargement 0 (0) 1 (5) 1 (4) Renal Cyst Ruptured 0 (0) 1 (5) 1 (4) Dermatitis Contact 0 (0) 1 (5) 1 (4) Eosinophilia 0 (0) 1 (5) 0 (0) Tympanic Membrane Perforation 0 (0) 1 (5) 0 (0) Vertigo Positional 0 (0) 1 (5) 0 (0) Hypothyroidism 0 (0) 1 (5) 0 (0) Eye Swelling 0 (0) 1 (5) 0 (0) Ocular Hyperemia 0 (0) 1 (5) 0 (0) Vision Blurred 0 (0) 1 (5) 0 (0) Abdominal Hernia 0 (0) 1 (5) 0 (0) Gastrointestinal Disorder 0 (0) 1 (5) 0 (0) Reflux Esophagitis 0 (0) 1 (5) 0 (0) Chest Discomfort 0 (0) 1 (5) 0 (0) Irritability 0 (0) 1 (5) 0 (0) Edema 0 (0) 1 (5) 0 (0) Cholelithiasis 0 (0) 1 (5) 0 (0) Hepatomegaly 0 (0) 1 (5) 0 (0) Hypersensitivity 0 (0) 1 (5) 0 (0) Ear Infection 0 (0) 1 (5) 0 (0) Lower Respiratory Tract Infection 0 (0) 1 (5) 0 (0) Respiratory Tract Infection 0 (0) 1 (5) 0 (0) Rhinitis 0 (0) 1 (5) 0 (0) Tooth Abscess 0 (0) 1 (5) 0 (0) Joint Injury 0 (0) 1 (5) 0 (0) Limb Injury 0 (0) 1 (5) 0 (0) Rib Fracture 0 (0) 1 (5) 0 (0) Soft Tissue Injury 0 (0) 1 (5) 0 (0) Stress Fracture 0 (0) 1 (5) 0 (0) Blood Prolactin Increased 0 (0) 1 (5) 0 (0) Blood Urine Present 0 (0) 1 (5) 0 (0) Liver Function Test Abnormal 0 (0) 1 (5) 0 (0) Transaminases Increased 0 (0) 1 (5) 0 (0) Hypercholesterolemia 0 (0) 1 (5) 0 (0) Hypernatremia 0 (0) 1 (5) 0 (0) Plantar Faciitis 0 (0) 1 (5) 0 (0) Rotator Cuff Syndrome 0 (0) 1 (5) 0 (0) Acrochordon 0 (0) 1 (5) 0 (0) Lipoma 0 (0) 1 (5) 0 (0) Melanocytic Nevis 0 (0) 1 (5) 0 (0) Neuroma 0 (0) 1 (5) 0 (0) Pituitary Tumor Benign 0 (0) 1 (5) 0 (0) Seborrheic Keratosis 0 (0) 1 (5) 0 (0) Nystagmus 0 (0) 1 (5) 0 (0) Paraesthesia 0 (0) 1 (5) 0 (0) Parosmia 0 (0) 1 (5) 0 (0) Somnolence 0 (0) 1 (5) 0 (0) Tremor 0 (0) 1 (5) 0 (0) Abnormal Dreams 0 (0) 1 (5) 0 (0) Azotemia 0 (0) 1 (5) 0 (0) Breast Tenderness 0 (0) 1 (5) 0 (0) Dysfunctional Uterine Bleeding 0 (0) 1 (5) 0 (0) Menstruation Irregular 0 (0) 1 (5) 0 (0) Ovarian Cyst Rupture 0 (0) 1 (5) 0 (0) Pelvic Pain 0 (0) 1 (5) 0 (0) Rhinitis Alergic 0 (0) 1 (5) 0 (0) Sinus Congestion 0 (0) 1 (5) 0 (0) Sleep Apnea Syndrome 0 (0) 1 (5) 0 (0) Snoring 0 (0) 1 (5) 0 (0) Alopecia 0 (0) 1 (5) 0 (0) Cambell de Morgan Spots 0 (0) 1 (5) 0 (0) Dermatitis 0 (0) 1 (5) 0 (0) Psoriasis 0 (0) 1 (5) 0 (0) Seborrheic Dermatitis 0 (0) 1 (5) 0 (0) Skin Discoloration 0 (0) 1 (5) 0 (0) Orthostatic Hypotension 0 (0) 1 (5) 0 (0) Leukocytosis 0 (0) 0 (0) 1 (4) Splenomegaly 0 (0) 0 (0) 1 (4) Tachycardia 0 (0) 0 (0) 1 (4) Ventricular Extrasystoles 0 (0) 0 (0) 1 (4) Hyperparathyroidism Primary 0 (0) 0 (0) 1 (4) Hyperparathyroidism Secondary 0 (0) 0 (0) 1 (4) Ascites 0 (0) 0 (0) 1 (4) Breath Odor 0 (0) 0 (0) 1 (4) Epiploic Appendagitis 0 (0) 0 (0) 1 (4) Gastrointestinal Edema 0 (0) 0 (0) 1 (4) Rectal Hemorrhage 0 (0) 0 (0) 1 (4) Tooth Impacted 0 (0) 0 (0) 1 (4) Chills 0 (0) 0 (0) 1 (4) Dyscomfort 0 (0) 0 (0) 1 (4) Energy Increased 0 (0) 0 (0) 1 (4) Generalized Edema 0 (0) 0 (0) 1 (4) Granuloma 0 (0) 0 (0) 1 (4) Influenza Like Illness 0 (0) 0 (0) 1 (4) Localized Edema 0 (0) 0 (0) 1 (4) Pain 0 (0) 0 (0) 1 (4) Peripheral Coldness 0 (0) 0 (0) 1 (4) Pyrexia 0 (0) 0 (0) 1 (4) Temperature Intolerance 0 (0) 0 (0) 1 (4) Cholecystitis Chronic 0 (0) 0 (0) 1 (4) Alveolar Osteitis 0 (0) 0 (0) 1 (4) Cystitis 0 (0) 0 (0) 1 (4) Gastroenteritis 0 (0) 0 (0) 1 (4) Pyelonephritis 0 (0) 0 (0) 1 (4) Barotrauma 0 (0) 0 (0) 1 (4) Foreign Body in Eye 0 (0) 0 (0) 1 (4) Incisional Hernia 0 (0) 0 (0) 1 (4) Nerve Compression 0 (0) 0 (0) 1 (4) Wrist Fracture 0 (0) 0 (0) 1 (4) Grip Strength Decreased 0 (0) 0 (0) 1 (4) Kidney Palpable 0 (0) 0 (0) 1 (4) Lipids Increased 0 (0) 0 (0) 1 (4) Waist Circumference Increased 0 (0) 0 (0) 1 (4) Hypokalemia 0 (0) 0 (0) 1 (4) Bursitis 0 (0) 0 (0) 1 (4) Groin Pain 0 (0) 0 (0) 1 (4) Joint Range of Motion Decreased 0 (0) 0 (0) 1 (4) Musculoskeletal Chest Pain 0 (0) 0 (0) 1 (4) Osteoporosis 0 (0) 0 (0) 1 (4) Trigger Finger 0 (0) 0 (0) 1 (4) Malignant Melanoma In Situ 0 (0) 0 (0) 1 (4) Uterine Leiomyoma 0 (0) 0 (0) 1 (4) Hyperreflexia 0 (0) 0 (0) 1 (4) Sinus Headache 0 (0) 0 (0) 1 (4) Syncope 0 (0) 0 (0) 1 (4) Transient Ischemic Attack 0 (0) 0 (0) 1 (4) Visual Field Defect 0 (0) 0 (0) 1 (4) Libido Decreased 0 (0) 0 (0) 1 (4) Bladder Discomfort 0 (0) 0 (0) 1 (4) Renal Failure 0 (0) 0 (0) 1 (4) Erectile Dysfunction 0 (0) 0 (0) 1 (4) Menopausal Symptoms 0 (0) 0 (0) 1 (4) Ovarian Cyst 0 (0) 0 (0) 1 (4) Vaginal Dyscharge 0 (0) 0 (0) 1 (4) Dyspnea Exhertional 0 (0) 0 (0) 1 (4) Paranasal Sinus Hypersecretion 0 (0) 0 (0) 1 (4) Pharyngeal Erythema 0 (0) 0 (0) 1 (4) Postnasal Drip 0 (0) 0 (0) 1 (4) Productive Cough 0 (0) 0 (0) 1 (4) Night Sweats 0 (0) 0 (0) 1 (4) Petechiae 0 (0) 0 (0) 1 (4) Rash Macular 0 (0) 0 (0) 1 (4) Rash Papular 0 (0) 0 (0) 1 (4) Rash Puritic 0 (0) 0 (0) 1 (4) Skin Lesion 0 (0) 0 (0) 1 (4) Skin Plaque 0 (0) 0 (0) 1 (4) Flushing 0 (0) 0 (0) 1 (4)
Adverse Event is a new or worsening untoward symptom or sign occurring after receiving at least 1 dose of tolvaptan. 1Subjects receiving at least 1 dose from Japanese 156-05-002 (N=17) studies. 2Subjects receiving at least 1 dose from U.S. 156-04-250 “TEMPO” (N=46) who were randomized to separate dose groups. *N/A = Not Applicable since Antidiuretic Hormone (vasopressin) was not assessed in TEMPO
Supplemental Table 2 Details of Tolvaptan Subjects Withdrawing Prior to 36 months of Therapy. Subject Study ID & Reason for Comment Tolvaptan Dose Withdrawal 156-04-250-0012004 Adverse Event: 44 year old woman diagnosed with atrial fibrillation on day 60/30 mg/day Transient 144. Study drug was discontinued on day 147 for a transient Ischemic Attack ischemic attack which resolved 8 days later. The investigator assessed relationship to therapy as possible 156-04-250-0012043 Adverse Event: 28 year old woman placed on hormonal therapy for 45/15 mg/day Benign Pituitary dysfunctional uterine bleeding on day 103. She developed Tumor blurred vision on day 164 and was found to have a pituitary microadenoma on day 238. Study drug was discontinued on day 414. The investigator assessed relationship to therapy as possible 156-04-250-0032038 Subject 43 year old woman with a gradual increase in serum 60/30 mg/day Withdrew creatinine from a baseline of 2.4 mg/dL. On day 582, she Consent decided to pursue pre-emptive transplantation. Serum creatinine peaked at 3.2 mg/dL and was 3.0 mg/dL at study withdrawal. The investigator deemed the increase in serum creatinine to be unrelated to therapy. 156-04-250-0042039 Lost to Follow up 39 year old man with pollakiuria from day 1, worsening 60/30 mg/day nocturia on day 466 and worsening fatigue on day 467. He became non-compliant with study medication and was lost to follow-up. The investigator assessed relationship to therapy as probable for pollakiuria, possible for nocturia, and unlikely for fatigue. 156-04-250-0132005 Adverse Event: 48 year old woman with an increase in serum creatinine 45/15 mg/day Acute Renal from a baseline of 1.3-1.4 mg/dL to a peak 1.6-1.7 during Failure titration (day 24-26), which returned to 1.3 on treatment interruption (day 52) and increased to 1.6 after resuming therapy (day 69). Study drug was discontinued on day 69 and serum creatinine returned to 1.4 mg/dL after 27 days. The investigator deemed relationship to therapy as definite. 156-04-250-0132026 Adverse Event: 49 year old woman complained of left eye periorbital 45/15 mg/day Eye Swelling swelling on day 93 and of seasonal allergies on day 99. The eye swelling resolved after 140 days. She discontinued the trial at day 189. The investigator deemed relationship to therapy as probable. 156-04-250-0132033 Met Withdrawal 35 year old woman deemed to be non-compliant with study 45/15 mg/day Criteria medication and withdrawn from the study on day 173. 156-05-002-0010001 Adverse Event: 45 year old woman with an increase in serum creatinine 15/15 mg/day Renal from 0.79 mg/dL at baseline to 0.93 at day 7. She Impairment developed itching on the lower back on day 35 and 73. Study drug was suspended on day 95. Serum creatinine values during this time ranged between 0.90 and 1.03 mg/dL. Two months later the itching resolved and serum creatinine following discontinuation of therapy ranged between 0.83 and 0.92 mg/dL The investigator deemed the adverse event related to treatment. 156-05-002-0020001 Subject 33 years old man withdrawn at his request on day 658 15/15 mg/day Requested without having experienced adverse events. Withdrawal 156-05-002-0060002 Adverse Event: 38 year old woman suffered a subarachnoid hemorrhage 15/15 mg/day Subarachnoid due to a ruptured cerebral aneurysm on day 74 and died 18 hemorrhage days later. The event was assessed as not related to Supplemental Table 2 Details of Tolvaptan Subjects Withdrawing Prior to 36 months of Therapy. treatment. 156-05-002-0070001 Subject Met 44 year old man with an increase in the serum creatinine 15/15 mg/day Withdrawal from 2.13 mg/dL at screening and 1.88 mg/dL at baseline Criteria: Serum to 2.55 mg/dL on day 252. Study drug administration was creatinine 2.5 discontinued. One month later serum creatinine was 2.49 mg/dL mg/dL and remained high (2.55 and 2.57 mg/dL). Subject was withdrawn according to exclusion criteria. The increase was assessed as non-serious and possibly related to therapy. 156-05-002-0090002 Subject 40 year old woman withdrawn at her request on day 672 15/15 mg/day Requested without having experienced adverse events. Withdrawal
Supplemental Table 3 Annualized Progression Rate of TKV and eGFR
Projected Over 3 Years Data-in All Subjects
Annualized TKV Growth Rate1
Group N Annual Change Ratio of Geometric
%/year ( SD) Means p-value
(RGM, 95% CI) 1
TKV Control 126 5.8 (4.1) 0.96 <0.001 Tolvaptan 62 1.7 (9.2) (0.95-0.97)
Annualized eGFR Slope2
Group N Annual Change LS Mean Difference
mL/min/1.73m2/year ( SD) (mL/min/1.73m2/year, p-value
95% CI)
eGFR Control 126 -2.0 (3.2) 0.95 =0.02 Tolvaptan 63 -1.7 (11.9) (0.13-1.8)
N=Number of subjects, SD=Standard Deviation, CI=Confidence interval
1 Summary Statistics derived by regressing logarithm transformed TKV against time, and then exponential the regression slopes, p-value of Ratio of Geometric Means derived from testing time:treatment interaction using linear mixed model in which both intercept and slope are fixed and random effects. The Ratio of Geometric Means is an estimate of the ratio of the geometric mean of annualized growth rate of tolvaptan and control. 2 Summary Statistics derived by slope of change by regressing estimated GFR data against time by subject. LS Means Difference derived from testing the time treatment interaction using linear mixed model in which both intercept and slope are fixed and random effects. Matching criteria were gender, hypertension status, age and CKD-EPI eGFR (using coefficient of 0.813 if Japanese).15
Supplemental Table 4 Change in Mean TKV and eGFR in All Completing Subjects by Visit Control Tolvaptan
TKV N Mean SD Mean % SD N Mean SD Mean % SD Group Difference (95%CI) p-value mL Change Change
Baseline 126 1362 680.7 63 1649.0 939.3
Month 12 123 1448 731.2 5.0 6.6 54 1633.5 964.3 0.9 7.1 -4.67 (-1.28 to -8.06) p = 0.0071
Month 24 118 1579 843.0 13.8 10.6 51 1670.9 1015 1.6 8.5 -12.6 (-9.11 to -16.0) p < 0.0001
Month 36 126 1646 887.3 19.0 14.9 51 1733.5 1052 5.3 11.0 -14.3 (-10.9 to -17.7) p < 0.0001
eGFR N Mean SD Mean SD N Mean SD Mean SD Group Difference (95%CI) p-value ml/min/1.73m2 Change Change
Baseline 126 62.1 18.9 63 61.4 19.7
Month 12 123 60.4 21.6 -2.05 8.56 53 59.7 22.1 -1.68 12.3 0.4 (-2.7 to 3.5) p = 0.806
Month 24 123 56.7 22.4 -5.16 9.33 50 59.3 21.5 -2.55 8.82 2.3 (-0.9 to 5.4) p = 0.160
Month 36 125 55.8 22.4 -6.53 10.8 51 55.9 21.1 -5.70 9.23 0.7 (-2.4 to 3.9) p = 0.654 eGFR by MDRD = 186 x (Scr)-1.154x(age)-0.203 x (0.742 if female) x(1.21 if African American or 0.808 if Japanese).
Supplemental Table 5 Annualized Progression Rate of TKV and eGFR in
Completing Subjects Projected Over 3 Years (TEMPO only)
Annualized TKV Growth Rate1
Group N Annual Change Ratio of Geometric
%/year ( SD) Means p-value
(RGM, 95% CI)1
TKV Control 78 6.0 (4.4) 0.97 p<0.001 Tolvaptan 39 2.3 (3.5) (0.95 to 0.98)
Annualized eGFR Slope2
Group N Annual Change LS Mean Difference
mL/min/1.73m2/year ( SD) (mL/min/1.73m2/year, p-value
95% CI)
eGFR Control 78 -2.4 (3.3) 1.5 p=0.005 Tolvaptan 39 -0.6 (2.5) (0.46 to 2.53)
N=Number of subjects, SD=Standard Deviation, CI=Confidence interval
1 Summary Statistics derived by regressing logarithm transformed TKV against time, and then exponential the regression slopes, p-value of Ratio of Geometric Means derived from testing time:treatment interaction using linear mixed model in which both intercept and slope are fixed and random effects. The Ratio of Geometric Means is an estimate of the ratio of the geometric mean of annualized growth rate of tolvaptan and control. 2 Summary Statistics derived by slope of change by regressing estimated GFR data against time by subject. LS Means Difference derived from testing the time treatment interaction using linear mixed model in which both intercept and slope are fixed and random effects. eGFR by MDRD = 186 x (Scr)- 1.154x(age)-0.203 x (0.742 if female) x(1.21 if African American).
Supplemental Table 6 Annualized Progression Rate of TKV and eGFR
Projected Over 3 Years Data-in All Subjects (TEMPO only)
Annualized TKV Growth Rate1
Group N Annual Change Ratio of Geometric
%/year ( SD) Means p-value
(RGM, 95% CI)1
TKV Control 92 6.1 (4.4) 0.97 p<0.001 Tolvaptan 46 2.2 (10.5) (0.95 to 0.98)
Annualized eGFR Slope2
Group N Annual Change LS Mean Difference
mL/min/1.73m2/year ( SD) (mL/min/1.73m2/year, p-value
95% CI)
eGFR Control 92 -2.3 (3.3) 1.4 p = 0.006 Tolvaptan 46 -0.5 (9.4) (0.41 to 2.40)
N=Number of subjects, SD=Standard Deviation, CI=Confidence interval
1 Summary Statistics derived by regressing logarithm transformed TKV against time, and then exponential the regression slopes, p-value of Ratio of Geometric Means derived from testing time:treatment interaction using linear mixed model in which both intercept and slope are fixed and random effects. The Ratio of Geometric Means is an estimate of the ratio of the geometric mean of annualized growth rate of tolvaptan and control. 2 Summary Statistics derived by slope of change by regressing estimated GFR data against time by subject. LS Means Difference derived from testing the time treatment interaction using linear mixed model in which both intercept and slope are fixed and random effects. eGFR by MDRD = 186 x (Scr)- 1.154x(age)-0.203 x (0.742 if female) x(1.21 if African American).