Effect of tolvaptan in Japanese patients with autosomal dominant polycystic kidney disease: a post hoc analysis of TEMPO 3:4 and TEMPO Extension Japan.
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ABSTRACT: Background
Autosomal dominant polycystic kidney disease (ADPKD) is a progressive condition that eventually leads to end-stage renal disease. A phase 3 trial of tolvaptan (TEMPO 3:4; NCT00428948) and its open-label extension (TEMPO Extension Japan: TEMPO-EXTJ; NCT01280721) were conducted in patients with ADPKD. In this post hoc analysis, effects on renal function and the safety profile of tolvaptan were assessed over a long-term period that included the 3-year TEMPO 3:4 and the approximately 3-year TEMPO-EXTJ trials.Methods
Patients from Japanese trial sites who completed TEMPO 3:4 were offered participation in TEMPO-EXTJ. Patients whose efficacy parameters were measured at year 2 in TEMPO-EXTJ for efficacy evaluation were included. The annual slope of the estimated glomerular filtration rate (eGFR) and growth in total kidney volume (TKV) were analyzed.Results
In patients who received tolvaptan in TEMPO 3:4 and TEMPO-EXTJ, the annual slope of eGFR (mL/min/1.73 m2) was - 3.480 in TEMPO 3:4 and - 3.417 in TEMPO-EXTJ, with no apparent effect of an approximately 3.6-month off-treatment interval between the two trials. In patients who received a placebo in TEMPO 3:4 before initiating tolvaptan in TEMPO-EXTJ, the slope of eGFR was significantly less steep from TEMPO 3:4 (- 4.287) to TEMPO-EXTJ (- 3.364), a difference of 0.923 (P = 0.0441).Conclusion
The TEMPO-EXTJ trial supports a sustained beneficial effect of tolvaptan on eGFR. In patients who received a placebo in TEMPO 3:4, initiation of tolvaptan in TEMPO-EXTJ was associated with a significant slowing of eGFR decline.
SUBMITTER: Muto S
PROVIDER: S-EPMC8357671 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:AimThe aim of this trial (ClinicalTrials.gov identifier: NCT01280721) was to investigate the long-term safety profile of tolvaptan in Japanese patients with autosomal dominant polycystic kidney disease (ADPKD).MethodsThis open-label multicenter trial was conducted to examine adverse drug reactions (ADRs) related to tolvaptan up to an additional 3 years in 135 Japanese patients who participated in the Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and its Outcomes (TEMPO) 3:4 trial at doses of 60-120 mg/d. Blood samples were collected at baseline; at weeks 1, 2, and 3; at month 3; and every 3 months thereafter.ResultsIn total, 134/135 (>99%) patients experienced ADRs. The most frequent ADRs were thirst (77.0%), pollakiuria (57.0%), polyuria (37.8%), and hyperuricemia (14.8%). Any unexpected ADRs were not reported in this trial. Most ADRs occurred early during treatment. Fourteen patients (10.4%) experienced hepatic events, and 8 (5.9%) experienced >3-fold increases above the upper limits of normal in serum alanine aminotransferase or aspartate aminotransferase levels between 3 and 9 months following tolvaptan initiation, which recovered after drug interruption. Of the 8 patients, 7 (5.2%) were previously allocated to the placebo arm in the TEMPO 3:4 trial and 4 (3.0%) discontinued due to the hepatic events. One patient (0.7%) was previously allocated to tolvaptan and experienced similar events in the TEMPO 3:4 trial. None of the hepatic ADRs met Hy's Law laboratory criteria.ConclusionADRs observed in this extension trial were similar to those identified in the TEMPO 3:4 trial and hepatic events were not progressive.
| S-EPMC5661830 | biostudies-literature
Project description:BackgroundTolvaptan slows kidney function decline in patients with autosomal dominant polycystic kidney disease (ADPKD) who are at risk of rapid progression. Given that treatment requires commitment to long-term use, we evaluated the effects of tolvaptan discontinuation on the trajectory of ADPKD progression.MethodsThis was a post hoc analysis of pooled data from two clinical trials of tolvaptan (TEMPO 2:4 [NCT00413777] and TEMPO 3:4 [NCT00428948]), an extension trial (TEMPO 4:4 [NCT01214421]), and an observational study (OVERTURE [NCT01430494]) that enrolled patients from the other trials. Individual subject data were linked longitudinally across trials to construct analysis cohorts of subjects with a tolvaptan treatment duration > 180 days followed by an off-treatment observation period of > 180 days. For inclusion in Cohort 1, subjects were required have ≥ 2 outcome assessments during the tolvaptan treatment period and ≥ 2 assessments during the follow-up period. For Cohort 2, subjects were required to have ≥ 1 assessment during the tolvaptan treatment period and ≥ 1 assessment during the follow-up period. Outcomes were rates of change in estimated glomerular filtration rate (eGFR) and total kidney volume (TKV). Piecewise-mixed models compared changes in eGFR or TKV in the on-treatment and post-treatment periods.ResultsIn the Cohort 1 eGFR population (n = 20), the annual rate of eGFR change (in mL/min/1.73 m2) was -3.18 on treatment and -4.33 post-treatment, a difference that was not significant (P = 0.16), whereas in Cohort 2 (n = 82), the difference between on treatment (-1.89) and post-treatment (-4.94) was significant (P < 0.001). In the Cohort 1 TKV population (n = 11), TKV increased annually by 5.18% on treatment and 11.69% post-treatment (P = 0.06). In Cohort 2 (n = 88), the annual TKV growth rates were 5.15% on treatment and 8.16% post-treatment (P = 0.001).ConclusionsAlthough limited by small sample sizes, these analyses showed directionally consistent acceleration in measures of ADPKD progression following the discontinuation of tolvaptan.
| S-EPMC10286436 | biostudies-literature
Project description:Background and objectivesTolvaptan is approved to slow kidney function decline in adults with autosomal dominant polycystic kidney disease (ADPKD) at risk of rapid progression. Because in vitro studies indicated that the tolvaptan oxobutyric acid metabolite inhibits organic anion-transporting polypeptide (OATP)1B1 and OATP1B3, United States prescribing information advises avoiding concurrent use with OATP1B1/1B3 substrates, including hepatic hydroxymethyl glutaryl-CoA reductase inhibitors (statins). This post hoc analysis of the pivotal phase 3 tolvaptan trials (Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes [TEMPO] 3:4 trial [NCT00428948] and Replicating Evidence of Preserved Renal Function: an Investigation of Tolvaptan Safety and Efficacy in ADPKD [REPRISE] trial [NCT02160145]) examined the safety of concurrent tolvaptan/statin use.Design, setting, participants, & measurementsThe trials randomized a combined total of 2815 subjects with early- to late-stage ADPKD to tolvaptan (n=1644) or placebo (n=1171) for 3 years (TEMPO 3:4) and 1 year (REPRISE). Statin use was unrestricted, and 597 subjects (21.2% overall; 332 [20.2%] tolvaptan, 265 [22.6%] placebo) received statins. Statin use (duration, dose change, statin change, permanent discontinuation), incidences of statin-related adverse events, and hepatic transaminase elevations were determined for subjects who received tolvaptan+statin, placebo+statin, tolvaptan alone, and placebo alone.ResultsNo differences in statin use parameters between tolvaptan- and placebo-treated subjects were observed. No statistically significant increases in commonly reported statin-related adverse events (e.g., musculoskeletal disorders, gastrointestinal symptoms) were seen between subjects receiving tolvaptan+statin and placebo+statin. For example, in TEMPO 3:4, frequencies were 5.4% and 7.8%, respectively, for myalgia (difference -2.4%; 95% confidence interval, -11.2% to 6.4%) and 9.3% and 7.8%, respectively, for abdominal pain (difference 1.5%; -7.9% to 10.9%). In an analysis that excluded participants concurrently using allopurinol, the frequency of alanine transaminase or aspartate transaminase >3× upper limit of normal in the pooled study populations was 3.6% for the tolvaptan+statin group and 2.3% for the placebo+statin group (difference 1.4%; -2.0% to 4.7%).ConclusionsTolvaptan has been used safely in combination with statins in clinical trials.PodcastThis article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2020_04_06_CJN.08170719.mp3.
| S-EPMC7269222 | biostudies-literature
Project description:BackgroundThe TEMPO 3:4 Trial results suggested that tolvaptan had no effect compared with placebo on albuminuria in autosomal-dominant polycystic kidney disease (ADPKD) patients. However, the use of categorical 'albuminuria events' may have resulted in a loss of sensitivity to detect changes. The aim of this study is to investigate the effects of tolvaptan on albuminuria as a continuous variable.MethodsPost hoc analysis of a 3-year prospective, blinded randomized controlled trial, including 1375 ADPKD patients. Albuminuria was measured in a spot morning urine sample prior to tolvaptan dosing and expressed as albumin-to-creatinine ratio (ACR).ResultsBaseline median (interquartile range) ACR was 3.2 (1.7-7.1) mg/mmol. Of note, 47.9% of ADPKD patients had normal, 48.7% moderately increased and 3.4% severely increased ACR. Subjects with higher baseline ACR had higher blood pressure and total kidney volume (TKV) and lower estimated glomerular filtration rate (eGFR). During follow-up, higher baseline ACR was associated with more rapid eGFR loss (P < 0.0001 for trend), but not with rate of growth in TKV. During the 3-year trial, ACR rose in placebo- and decreased in tolvaptan-treated patients (+0.23 versus -0.40 mg/mmol). The difference ACR increased over time, reaching a maximum of 24% at Month 36 (P < 0.001). At that time only a minor difference in blood pressure was observed (mean arterial pressure -1.9 mmHg for tolvaptan). The decrease in ACR was similar in all subgroups investigated, and remained after withdrawal of study drug. The beneficial effect of tolvaptan on TKV growth and eGFR loss was stronger in patients with higher baseline ACR.ConclusionsIn ADPKD, higher baseline albuminuria was associated with more eGFR loss. Tolvaptan decreased albuminuria compared with placebo, independent of blood pressure. Treatment efficacy of tolvaptan on changes in TKV and eGFR was more readily detected in patients with higher albuminuria.
| S-EPMC6367945 | biostudies-literature
Project description:It is unknown whether early diagnosis of autosomal dominant polycystic kidney disease (ADPKD) can enable earlier management and improve outcomes. We conducted a post hoc analysis of data from the TEMPO 3:4 trial. Subjects were stratified by ADPKD diagnosis at age ≤18 (childhood diagnosis [CD]) or>18 (adulthood diagnosis [AD]). Groups were compared for baseline characteristics and total kidney volume (TKV) growth and estimated glomerular filtration rate (eGFR) decline over 3 years. 294 CD and 1148 AD subjects were analyzed. At inclusion, CD subjects were younger (mean age 34.2 versus 39.8 years; p < 0.0001) and had better eGFR (mean ± SD 87.4 ± 23.9 versus 80.1 ± 20.7 mL/min/1.73 m2; p < 0.0001), while CD had more severe Mayo risk classification (p < 0.0001) and more PKD1 mutations (p = 0.003). No statistical differences were found in TKV or eGFR change. At study end, placebo-treated CD subjects had better eGFR than projected by a prediction equation (mean difference ±SD for observed versus predicted eGFR: 2.18 ± 10.7 mL/min/1.73 m2; p = 0.0475). However, these results are not confirmed when excluding stage 1 CKD. Whether CD subjects, despite their risk profile, have a slower disease course than predicted remains inconclusive. Future studies are needed to confirm that early diagnosis and management can alter the disease course of ADPKD.
| S-EPMC7062834 | biostudies-literature
Project description:Introduction:In the randomized placebo-controlled Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and its Outcomes (TEMPO) 3:4 trial, tolvaptan slowed kidney growth and renal function decline in subjects with autosomal dominant polycystic kidney disease (ADPKD). Consistent with its primary pharmacologic activity, tolvaptan use was commonly associated with aquaretic adverse events (AAEs) attributable to excess free water clearance. Methods:A post hoc analysis of tolvaptan-related discontinuations from the pivotal randomized controlled trial TEMPO 3:4 and its open-label extension TEMPO 4:4. Results:In total, 750 of 961 tolvaptan-treated subjects (78%) in TEMPO 3:4 reported at least one AAE. Of these 750 subjects, 72 (10%) discontinued because of an AAE (aquaretic-discontinued group) and 573 (76%) continued (aquaretic-continued group). The aquaretic-discontinued subjects were younger, had better baseline renal function, and had higher fasting urine osmolality than aquaretic-continued subjects. Of the 750 subjects reporting an AAE, 105 (14%) discontinued for another reason (non-aquaretic-discontinued group). Compared to non-aquaretic-discontinued subjects, aquaretic-discontinued subjects were more commonly male, had better baseline renal function, and discontinued the study drug faster. After 3 years of therapy, 75% of tolvaptan subjects indicated that they could tolerate their current dose for the rest of their lives, compared to 85% of placebo subjects. These findings were corroborated by results in the open-label extension trial TEMPO 4:4. Discussion:In this study, AAEs were common but well tolerated in ADPKD patients on tolvaptan. ADPKD patients in earlier stages of disease progression may be more sensitive to aquaretic symptoms, which may help in guiding tolvaptan dosing and titration decisions in the future.
| S-EPMC5733681 | biostudies-literature
Project description:BackgroundThe course of autosomal dominant polycystic kidney disease (ADPKD) is often associated with pain, hypertension, and kidney failure. Preclinical studies indicated that vasopressin V(2)-receptor antagonists inhibit cyst growth and slow the decline of kidney function.MethodsIn this phase 3, multicenter, double-blind, placebo-controlled, 3-year trial, we randomly assigned 1445 patients, 18 to 50 years of age, who had ADPKD with a total kidney volume of 750 ml or more and an estimated creatinine clearance of 60 ml per minute or more, in a 2:1 ratio to receive tolvaptan, a V(2)-receptor antagonist, at the highest of three twice-daily dose regimens that the patient found tolerable, or placebo. The primary outcome was the annual rate of change in the total kidney volume. Sequential secondary end points included a composite of time to clinical progression (defined as worsening kidney function, kidney pain, hypertension, and albuminuria) and rate of kidney-function decline.ResultsOver a 3-year period, the increase in total kidney volume in the tolvaptan group was 2.8% per year (95% confidence interval [CI], 2.5 to 3.1), versus 5.5% per year in the placebo group (95% CI, 5.1 to 6.0; P<0.001). The composite end point favored tolvaptan over placebo (44 vs. 50 events per 100 follow-up-years, P=0.01), with lower rates of worsening kidney function (2 vs. 5 events per 100 person-years of follow-up, P<0.001) and kidney pain (5 vs. 7 events per 100 person-years of follow-up, P=0.007). Tolvaptan was associated with a slower decline in kidney function (reciprocal of the serum creatinine level, -2.61 [mg per milliliter](-1) per year vs. -3.81 [mg per milliliter](-1) per year; P<0.001). There were fewer ADPKD-related adverse events in the tolvaptan group but more events related to aquaresis (excretion of electrolyte-free water) and hepatic adverse events unrelated to ADPKD, contributing to a higher discontinuation rate (23%, vs. 14% in the placebo group).ConclusionsTolvaptan, as compared with placebo, slowed the increase in total kidney volume and the decline in kidney function over a 3-year period in patients with ADPKD but was associated with a higher discontinuation rate, owing to adverse events. (Funded by Otsuka Pharmaceuticals and Otsuka Pharmaceutical Development and Commercialization; TEMPO 3:4 ClinicalTrials.gov number, NCT00428948.).
| S-EPMC3760207 | biostudies-literature
Project description:Backgroundand objectives The Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes 3:4 study demonstrated a significant beneficial effect of the vasopressin V2 receptor antagonist tolvaptan on rates of kidney growth and eGFR decline in autosomal dominant polycystic kidney disease (ADPKD). This post hoc analysis was performed to reassess the primary and secondary efficacy endpoints by CKD stage at baseline.Design, setting, participants, & measurementsIn 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.ResultsTolvaptan 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.ConclusionsThis post hoc analysis suggests clinically similar beneficial effects of tolvaptan in ADPKD across CKD stages 1-3.
| S-EPMC4858477 | biostudies-literature
Project description:Chinese translationIn the TEMPO (Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes) trial, tolvaptan significantly reduced expansion of kidney volume and loss of kidney function.To determine how the benefits of tolvaptan seen in TEMPO may relate to longer-term health outcomes, such as progression to end-stage renal disease (ESRD) and death, and cost-effectiveness.A decision-analytic model.Published literature from 1993 to 2012.Persons with early autosomal dominant polycystic kidney disease.Lifetime.Societal.Patients received tolvaptan therapy until death, development of ESRD, or liver complications or no tolvaptan therapy.Median age at ESRD onset, life expectancy, discounted quality-adjusted life-years and lifetime costs (in 2010 U.S. dollars), and incremental cost-effectiveness ratios.Tolvaptan prolonged the median age at ESRD onset by 6.5 years and increased life expectancy by 2.6 years. At $5760 per month, tolvaptan cost $744 100 per quality-adjusted life-year gained compared with standard care.For patients with autosomal dominant polycystic kidney disease that progressed more slowly, the cost per quality-adjusted life-year gained was even greater for tolvaptan.Although TEMPO followed patients for 3 years, the main analysis assumed that clinical benefits persisted over patients' lifetimes.Assuming that the benefits of tolvaptan persist in the longer term, the drug may slow progression to ESRD and reduce mortality rates. However, barring an approximately 95% reduction in price, cost-effectiveness does not compare favorably with many other commonly accepted medical interventions.National Institutes of Health and Agency for Healthcare Research and Quality.
| S-EPMC3981098 | biostudies-literature
Project description:Autosomal dominant polycystic kidney disease (ADPKD), a frequent cause of end-stage renal disease, has no cure. V2-specific vasopressin receptor antagonists delay disease progression in animal models.This is a prospectively designed analysis of annual total kidney volume (TKV) and thrice annual estimated GFR (eGFR) measurements, from two 3-year studies of tolvaptan in 63 ADPKD subjects randomly matched 1:2 to historical controls by gender, hypertension, age, and baseline TKV or eGFR. Prespecified end points were group differences in log-TKV (primary) and eGFR (secondary) slopes for month 36 completers, using linear mixed model (LMM) analysis. Sensitivity analyses of primary and secondary end points included LMM using all subject data and mixed model repeated measures (MMRM) of change from baseline at each year. Pearson correlation tested the association between log-TKV and eGFR changes.Fifty-one subjects (81%) completed 3 years of tolvaptan therapy; all experienced adverse events (AEs), with AEs accounting for six of 12 withdrawals. Baseline TKV (controls 1422, tolvaptan 1635 ml) and eGFR (both 62 ml/min per 1.73 m(2)) were similar. Control TKV increased 5.8% versus 1.7%/yr for tolvaptan (P < 0.001, estimated ratio of geometric mean 0.96 [95% confidence interval 0.95 to 0.97]). Corresponding annualized eGFR declined: -2.1 versus -0.71 ml/min per 1.73 m(2)/yr (P = 0.01, LMM group difference 1.1 ml/min per 1.73 m(2)/yr [95% confidence interval 0.24 to 1.9]). Sensitivity analyses including withdrawn subjects were similar, whereas MMRM analyses were significant at each year for TKV and nonsignificant for eGFR. Increasing TKV correlated with decreasing eGFR (r = -0.21, P < 0.01).ADPKD cyst growth progresses more slowly with tolvaptan than in historical controls, but AEs are common.
| S-EPMC3359559 | biostudies-literature