Rationale and Design of a Clinical Trial Investigating Tolvaptan Safety and Efficacy in Autosomal Dominant Polycystic Kidney Disease.
BACKGROUND
In TEMPO 3:4, the vasopressin V2-receptor antagonist tolvaptan slowed kidney growth and function decline in autosomal dominant polycystic kidney disease (ADPKD) patients with relatively preserved kidney function.


METHODS
Prospective, phase 3b, multi-center, randomized-withdrawal, placebo-controlled, double-blind trial of tolvaptan in ADPKD patients with late stage 2 to early stage 4 chronic kidney disease (CKD). The primary endpoint was estimated glomerular filtration rate (eGFR) change from pre-treatment baseline to post-treatment follow-up. Secondary endpoints included annualized eGFR slope, incidence of ADPKD complications, and overall and hepatic safety profiles. Participants were 18-55 year-old ADPKD patients with baseline eGFR ≥25 and ≤65 mL/min/1.73 m2 or 56-65 year-old with eGFR ≥25 and ≤44 mL/min/1.73 m2 and evidence of eGFR decline >2.0 mL/min/1.73 m2 per year. Daily split doses of tolvaptan were titrated to tolerance (30/15, 45/15, 60/30, or 90/30 mg) and maintained for 12 months, after an 8-week pre-randomization period to screen out subjects unable to tolerate at least 60/30 mg for 3 weeks.


RESULTS
Of 1,495 subjects who entered the tolvaptan titration period, 125 (8.4%) discontinued the study before randomization. One thousand three hundred seventy subjects (684 tolvaptan, 686 placebo) from 213 centers across 21 countries were randomized. Baseline demographics were well balanced across treatment arms. Information collected during the study included eGFR, survey scores (PKD history and outcome), adverse events, vital signs, hematology, urinalysis, and serum chemistry tests.


CONCLUSIONS
Replicating Evidence of Preserved Renal Function: An Investigation of Tolvaptan Safety and Efficacy (REPRISE) determines whether tolvaptan administered over 1 year exhibits disease-modifying properties in ADPKD patients with late stage 2 to early stage 4 CKD, which provides an important therapeutic advancement for this difficult-to-treat disease.
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA.
Vicente E
VE
Torres
Olivier
O
Devuyst
Arlene B
AB
Chapman
Ron T
RT
Gansevoort
Ronald D
RD
Perrone
John
J
Ouyang
Jaime D
JD
Blais
Frank S
FS
Czerwiec
Olga
O
Sergeyeva
D000293:Adolescent; D000328:Adult; D000368:Aged; D001552:Benzazepines / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006801:Humans; D007668:Kidney / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D061214:Patient Safety; D016891:Polycystic Kidney, Autosomal Dominant / Q000188:drug therapy* / Q000503:physiopathology; D011446:Prospective Studies; D051436:Renal Insufficiency, Chronic / Q000150:complications; D012107:Research Design; D000077602:Tolvaptan; D016896:Treatment Outcome; D055815:Young Adult
D001552:Benzazepines; D000077602:Tolvaptan