Abstract | BACKGROUND: DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In a phase 3, multicenter, double-blind, placebo-controlled, 3-year trial, 1445 patients with ADPKD (age 18-50 years), with total kidney volume (TKV) ≥750 ml and estimated creatinine clearance ≥60 ml/min, were randomly assigned 2:1 to split-dose tolvaptan (45/15, 60/30, or 90/30 mg daily as tolerated) or placebo. The primary endpoint was annualized rate of TKV change. Secondary endpoints included a composite endpoint of time to multiple composite ADPKD-related events (worsening kidney function, kidney pain, hypertension, and albuminuria) and rate of kidney function decline. RESULTS:
Tolvaptan reduced annualized TKV growth by 1.99%, 3.12%, and 2.61% per year (all P<0.001; subgroup-treatment interaction, P=0.17) and eGFR decline by 0.40 in CKD1 (P=0.23), 1.13 in CKD2 (P<0.001) and 1.66 ml/min per 1.73 m(2) per year in CKD3 (P<0.001) with a trend for a positive subgroup-treatment interaction (P=0.07) across CKD1, CKD2 and CKD3. ADPKD-related events were less frequent in tolvaptan recipients than in placebo recipients among those with CKD1 (hazard ratio [HR], 0.83; 95% confidence interval [95% CI], 0.70-0.98; P=0.03) and those with CKD 3 (HR, 0.71; 95% CI, 0.57-0.89; P=0.003), but not among those with CKD2 (HR, 1.02; 95% CI, 0.85-1.21; P=0.86). Aquaresis-related adverse events (more frequent in the tolvaptan group) and ADPKD-related adverse events (more frequent in the placebo group) were not associated with CKD stage. Hypernatremia events in tolvaptan-treated patients with CKD3 and plasma aminotransferase elevations in tolvaptan-treated patients across CKD stages 1-3 occurred more frequently than in placebo recipients. CONCLUSIONS: This post hoc analysis suggests clinically similar beneficial effects of tolvaptan in ADPKD across CKD stages 1-3.
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Authors | Vicente E Torres, Eiji Higashihara, Olivier Devuyst, Arlene B Chapman, Ronald T Gansevoort, Jared J Grantham, Ronald D Perrone, John Ouyang, Jaime D Blais, Frank S Czerwiec, TEMPO 3:4 Trial Investigators |
Journal | Clinical journal of the American Society of Nephrology : CJASN
(Clin J Am Soc Nephrol)
Vol. 11
Issue 5
Pg. 803-811
(05 06 2016)
ISSN: 1555-905X [Electronic] United States |
PMID | 26912543
(Publication Type: Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial)
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Copyright | Copyright © 2016 by the American Society of Nephrology. |
Chemical References |
- Antidiuretic Hormone Receptor Antagonists
- Benzazepines
- Tolvaptan
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Topics |
- Adult
- Albuminuria
(etiology)
- Antidiuretic Hormone Receptor Antagonists
(adverse effects, therapeutic use)
- Benzazepines
(adverse effects, therapeutic use)
- Disease Progression
- Double-Blind Method
- Female
- Glomerular Filtration Rate
(drug effects)
- Humans
- Hypernatremia
(chemically induced)
- Hypertension
(etiology)
- Kidney
(diagnostic imaging, pathology)
- Magnetic Resonance Imaging
- Male
- Middle Aged
- Organ Size
(drug effects)
- Pain
(etiology)
- Polycystic Kidney, Autosomal Dominant
(complications, drug therapy, physiopathology)
- Severity of Illness Index
- Tolvaptan
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