Multicenter, open-label, extension trial to evaluate the long-term efficacy and safety of early versus delayed treatment with tolvaptan in autosomal dominant polycystic kidney disease: the TEMPO 4:4 Trial

Vicente E Torres, Arlene B Chapman, Olivier Devuyst, Ron T Gansevoort, Ronald D Perrone, Ann Dandurand, John Ouyang, Frank S Czerwiec, Jaime D Blais, TEMPO 4:4 Trial Investigators, Vicente E Torres, Arlene B Chapman, Olivier Devuyst, Ron T Gansevoort, Ronald D Perrone, Ann Dandurand, John Ouyang, Frank S Czerwiec, Jaime D Blais, TEMPO 4:4 Trial Investigators

Abstract

Background: In TEMPO 3:4, the vasopressin V2 receptor antagonist tolvaptan slowed total kidney volume (TKV) growth and estimated glomerular filtration rate (eGFR) decline relative to placebo.

Methods: TEMPO 4:4 was designed to provide an additional 2 years of data on the long-term safety and efficacy of tolvaptan in subjects completing TEMPO 3:4. The objective was to assess the disease-modifying effects of tolvaptan on TKV and eGFR end-points including change from baseline over the combined duration of TEMPO 3:4 and TEMPO 4:4, and non-inferiority of slopes during TEMPO 4:4.

Results: Of the 1445 subjects randomized to TEMPO 3:4, 871 (60.3%) enrolled in TEMPO 4:4. Percent changes in TKV from TEMPO 3:4 baseline to TEMPO 4:4 Month 24 were 29.9% and 31.6% (prior tolvaptan versus prior placebo, P = 0.38). Adjusting for baseline covariates improved the TKV treatment difference at Month 24 in TEMPO 4:4 from -1.70% to - 4.15% between the groups (P = 0.04). Slopes of TKV growth during TEMPO 4:4 were higher in early- versus delayed-treatment groups (6.16% versus 4.96% per year, P = 0.05). Analysis of secondary eGFR endpoints demonstrated a persistent effect on eGFR (3.15 mL/min/1.73 m2, P < 0.001), and non-inferiority in eGFR slopes. The safety profile on exposure to tolvaptan in TEMPO 4:4 was similar to that in TEMPO 3:4.

Conclusions: The results of TEMPO 4:4 support a sustained disease-modifying effect of tolvaptan on eGFR. The lack of a sustained treatment difference on TKV may be accounted for by limitations of the trial design, including loss of randomization and baseline imbalances ensuing TEMPO 3:4. The safety profile was similar to that observed in TEMPO 3:4.

Trial registration: ClinicalTrials.gov NCT00428948.

© The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA.

Figures

FIGURE 1
FIGURE 1
Subject disposition in TEMPO 4:4.
FIGURE 2
FIGURE 2
Percentage change in TKV from TEMPO 3:4 baseline to TEMPO 4:4 Month 24 visit. Open circles and triangles represent off-treatment time points. Break in treatment from TEMPO 3:4 to TEMPO 4:4 ranged from 13 to 829 days from the Month 36 visit in TEMPO 3:4.
FIGURE 3
FIGURE 3
Change in eGFR from the TEMPO 3:4 baseline to the Month 24 visit of TEMPO 4:4. The inter-trial period is plotted as a 5-month interval, which approximates the 80th percentile of the treatment holiday (range 13–829 days). Open circles and triangles represent off-treatment time points.
FIGURE 4
FIGURE 4
Change from baseline in TKV and eGFR by gender. (A) Percentage change in TKV from TEMPO 3:4 baseline to Month 24 in TEMPO 4:4 for males (left panel) and females (right panel). (B) Change in eGFR from TEMPO 3:4 baseline to Month 24 in TEMPO 4:4 for males (left panel) and females (right panel). Open circles and triangles represent off-treatment time points.
FIGURE 5
FIGURE 5
Percentage change from baseline in TKV when adjusted for covariates. Open circles and triangles represent off-treatment time points. Blue and gray symbols are slightly offset for ease of interpretation. The following variables were included in an unstructured variance covariance matrix with fixed factors as in the primary analysis with the addition of copeptin and baseline covariates of age, gender, gender visit interaction, eGFR, eGFR visit interaction and urine ACR.
FIGURE 6
FIGURE 6
Change from baseline in TKV and eGFR by imaging classification. (A) Percentage change in TKV from TEMPO 3:4 baseline to Month 24 in TEMPO 4:4 for subjects in class 2A–B and 1B (left panel) and class 1C, D, E (right panel). (B) Change in eGFR from TEMPO 3:4 baseline to Month 24 in TEMPO 4:4 for subjects in class 2A–B and 1B (left panel) and class 1C, D, E (right panel). Open circles and triangles represent off-treatment time points.
FIGURE 7
FIGURE 7
Change from baseline in TKV and eGFR by genotype. (A) Percentage change in TKV from TEMPO 3:4 baseline to Month 24 in TEMPO 4:4 for subjects with PKD2 (left panel), PKD1 non-truncating (NT, middle panel) and PKD1 truncating (T, right panel) genotypes. (B) Change in eGFR from TEMPO 3:4 baseline to Month 24 in TEMPO 4:4 for subjects PKD2 (left panel), PKD1 non-truncating (NT, middle panel) and PKD1 truncating (T, right panel) genotypes. Open circles and triangles represent off-treatment time points.
FIGURE 8
FIGURE 8
Change from baseline in TKV and eGFR by CKD stage. (A) Percent change in TKV from TEMPO 3:4 baseline to Month 24 in TEMPO 4:4 for subjects in CKD 1 (left panel) and CKD 2/3 (right panel). (B) Change in eGFR from TEMPO 3:4 baseline to Month 24 in TEMPO 4:4 for subjects in CKD 1 (left panel) and CKD 2/3 (right panel). Open circles and triangles represent off-treatment time points.

References

    1. Ong AC, Devuyst O, Knebelmann B. et al. Autosomal dominant polycystic kidney disease: the changing face of clinical management. Lancet 2015; 385: 1993–2002
    1. Chapman AB, Devuyst O, Eckardt KU. et al. Autosomal dominant polycystic kidney disease (ADPKD): executive summary from a kidney disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int 2015; 88: 17–27
    1. Grantham JJ, Mulamalla S, Swenson-Fields KI.. Why kidneys fail in autosomal dominant polycystic kidney disease. Nat Rev Nephrol 2011; 7: 556–566
    1. Gattone VH, Wang X, Harris PC. et al. Inhibition of renal cystic disease development and progression by a vasopressin V2 receptor antagonist. Nat Med 2003; 9: 1323–1326
    1. Torres VE, Wang X, Qian Q. et al. Effective treatment of an orthologous model of autosomal dominant polycystic kidney disease. Nat Med 2004; 10: 363–364
    1. Wang X, Wu Y, Ward CJ. et al. Vasopressin directly regulates cyst growth in polycystic kidney disease. J Am Soc Nephrol 2008; 19: 102–108
    1. Torres VE, Harris PC.. Strategies targeting cAMP signaling in the treatment of polycystic kidney disease. J Am Soc Nephrol 2014; 25: 18–32
    1. Torres VE, Chapman AB, Devuyst O. et al. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med 2012; 367: 2407–2418
    1. Non-Inferiority Clinical Trials to Establish Effectiveness: Guidance for Industry, Food and Drug Administration, Division of Drug Information, Office of Communications, Center for Drug Evaluation and Research
    1. Gansevoort RT, Meijer E, Chapman AB. et al. Albuminuria and tolvaptan in autosomal-dominant polycystic kidney disease: results of the TEMPO 3:4 Trial. Nephrol Dial Transplant 2016; 31: 1887–1894
    1. Gansevoort R, van Gastel M, Chapman A. et al. Copeptin, a surrogate for Vasopressin, predicts disease progression and Tolvaptan treatment efficacy in ADPKD. Results of the TEMPO 3:4 trial. J Am Soc Nephrol 2016; 27: 34A
    1. Irazabal MV, Blais JD, Perrone RP. et al. Prognostic enrichment design in clinical trials for ADPKD: The TEMPO 3:4 clinical trial. Kidney Int Rep 2016; 1: 213–220
    1. Cornec-Le Gall E. Can we further enrich ADPKD clinical trials for rapidly progressive patients? Application of the PROPKD score in the TEMPO trial. J Am Soc Nephrol 2016; 27: 766A.
    1. Torres VE, Higashihara E, Devuyst O. et al. Effect of tolvaptan in autosomal dominant polycystic kidney disease by CKD stage: results from the TEMPO 3:4 Trial. Clin J Am Soc Nephrol 2016; 11: 803–811
    1. Watkins PB, Lewis JH, Kaplowitz N. et al. Clinical pattern of tolvaptan-associated liver injury in subjects with autosomal dominant polycystic kidney disease: analysis of clinical trials database. Drug Saf 2015; 38: 1103–13
    1. Bhattaram VA, Siddiqui O, Kapcala LP. et al. Endpoints and analyses to discern disease-modifying drug effects in early Parkinson's disease. Am Assoc Pharm Sci J 2009; 11: 456–464
    1. Irazabal MV, Torres VE, Hogan MC. et al. Short-term effects of tolvaptan on renal function and volume in patients with autosomal dominant polycystic kidney disease. Kidney Int 2011; 80: 295–301
    1. Boertien WE, Meijer E, de Jong PE, et al.Short-term effects of tolvaptan in individuals with autosomal dominant polycystic kidney disease at various levels of kidney function. Am J Kidney Dis 2015; 65: 833–841
    1. Reif GA, Yamaguchi T, Nivens E. et al. Tolvaptan inhibits ERK-dependent cell proliferation, Cl(-) secretion, and in vitro cyst growth of human ADPKD cells stimulated by vasopressin. Am J Physiol Renal Physiol 2011; 301: F1005–F1013
    1. Grantham JJ, Torres VE, Chapman AB. et al. Volume progression in polycystic kidney disease. N Engl J Med 2006; 354: 2122–2130
    1. Chapman AB, Bost JE, Torres VE. et al. Kidney volume and functional outcomes in autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol 2012; 7: 479–486
    1. Bankir L, Bouby N, Ritz E.. Vasopressin: a novel target for the prevention and retardation of kidney disease? Nat Rev Nephrol 2013; 9: 223–239

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi