The fourth leading cause of end-stage renal disease (ESRD) in adults is autosomal dominant polycystic kidney disease (ADPKD). In the TEMPO (Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Disease and its Outcomes) 3:4 trial, patients with early ADPKD (defined as estimated creatinine clearance ≥60 ml/min), tolvaptan reduced kidney growth as well as decline in estimated glomerular filtration rate (eGFR). The eGFR benefit persisted with an additional 2 years of open-label tolvaptan treatment (TEMPO 4:4 study).
There were no anticipated idiosyncratic hepatocellular toxic effects in the two trials. Monitoring occurred once every 4 months; two patients in the TEMPO 3:4 trial and one in the TEMPO 4:4 trial had evidence of potentially serious drug-induced liver injury. Vicente E. Torres, MD, and colleagues recently conducted the REPRISE (Replicating Evidence of Preserved Renal Function: An Investigation of Tolvaptan Safety and Efficacy in ADPKD) trial.
The phase 3, randomized withdrawal, multicenter, placebo-controlled, double-blind trial included patients with ADPKD with late stage chronic kidney disease (CKD) (stage 2 to early stage 4). The trial was designed to determine the efficacy and safety of tolvaptan in patients with more advanced ADPKD with the use of more frequent monitoring for toxic effects in the liver. Results were reported online in the New England Journal of Medicine [doi:10.1056/NEJMoa1710030].
The primary end point of interest was the change in eGFR from baseline to follow-up, with adjustment for the exact duration that each patient participated in the study (interpolated to 1 year). Safety assessments were conducted monthly.
The final study included 1370 patients who were randomly assigned to receive tolvaptan (n=683) or placebo (n=687). The month 12 visit was completed by 95.8% of patients in the tolvaptan group and 95.9% of those in the placebo group. Of the 1370 patients in the total cohort, 97.2% (n=1331) were included in the primary efficacy analysis, 99.4% (n=1362) were included in the key secondary efficacy analysis, and 99.7% (n=1366) were included in the safety analysis. The two patient groups were balanced at baseline in terms of demographic and clinical characteristics. The patients had CKD stage 3a (30.1%), stage 3b (45.2%), or stage 4 (19.5%).
At the end of the single-blind tolvaptan period, 82.3% of the total cohort (n=1128/1370) were receiving a daily dose of 90 mg in the morning and 30 mg in the afternoon; 17.7% (n=242) were receiving 60 mg in the morning and 30 mg in the afternoon. Patients in the placebo group who completed the trial were taking mock morning and afternoon doses of 90 mg and 30 mg, respectively.
At 1 year, following adjustment for the duration of the trial for each patient, the mean change in eGFR was –2.34 mL/min/1.73 m2 (95% confidence interval [CI], –2.81 to –1.87) in the tolvaptan group, compared with –3.61 mL/min/1.73 m2 (95% CI, –4.08 to –3.14) in the placebo group. Decline in eGFR at 1 year was slower with tolvaptan compared with placebo (difference, 1.27 mL/min/1.73 m2; 95% CI, 0.86-1.68; P<.001).
The robustness of the primary analysis was confirmed by prespecified sensitivity analyses. Prespecified subgroup analyses demonstrated a beneficial effect of tolvaptan across subgroups that included sex, baseline eGFR, stage of CKD (other than stage 2), and in subgroups of patients by age (≤55 years of age) and patients who were white. The beneficial effects were not seen in patients >55 years of age, those who were nonwhite, and those who had CKD stage 2.
The key secondary end point (slope of the change in eGFR derived from individual slopes for each patient, adjusting for the duration of the observations and with interpolation to 1 year), was –3.16 mL/min/1.73 m2 in the tolvaptan group (95% CI, –3.43 to –2.89), compared with –4.17 mL/min/1.73 m2 in the placebo group (95% CI, –4.45 to –3.89). In subgroup analyses, there was a beneficial effect of tolvaptan in subgroups defined according to sex, baseline eGFR, stage of CKD (with the exception of stage 2 CKD), and geographic region. There was also a benefit in patients ≤55 years of age and patients who were white. There was no beneficial effect in smaller subgroups of patients who were >55 years of age, those who were nonwhite, and those with CKD stage 2.
The rates of new or worsening adverse events did not differ between the tolvaptan and placebo groups during the double-blind period (85.3% and 82.3%, respectively). During the single-blind tolvaptan period, the rates of new or worsening adverse events were higher than the rates among patients who received tolvaptan during the double-blind period. Following randomization, patients in the tolvaptan group had higher rates of polyuria, nocturia, thirst, polydipsia, dry mouth, diarrhea, and fatigue.
Elevations in the alanine aminotransferase level (to >3 times the upper limit of the normal range) occurred in 5.6% of the tolvaptan group (n=38/681) and in 1.2% in the placebo group (n=8/685). The elevations were reversible after stopping tolvaptan. There were no elevations detected in the bilirubin level of more than twice the upper limit of the normal range.
Study limitations cited by the authors included selecting participants mainly on the basis of eGFR, possibly limiting the trial population of patients who would have rapid progression of disease, and the short duration of the trial.
In conclusion, the researchers said, “The results of the present trial showed that tolvaptan slowed the progressive loss of renal function in patients with ADPKD at stages that were more advanced than those of the patients who were included in the TEMPO 3:4 trial. Monthly monitoring of liver-enzyme levels probably reduced the frequency of drug-induced liver injury. The long-term effectiveness of treatment with tolvaptan remains to be determined.”
- Researchers conducted a study to determine the efficacy and safety of tolvaptan in patients with late-stage autosomal dominant polycystic kidney disease.
- The change from baseline in estimated glomerular filtration rate was –2.34 mL/min/1.73 m2 in the tolvaptan group compared with –3.61 m:/min/1.73 m2 in the placebo group.
- Elevations seen in the tolvaptan group in alanine aminotransferase level were reversible after stopping tolvaptan; there were no elevations in the bilirubin level of more than twice the upper limit of the normal range detected.