Tolvaptan for Polycystic Kidney Disease
Recruiting in Palo Alto (17 mi)
+23 other locations
Age: < 65
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 3
Recruiting
Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.
Must not be taking: CYP3A4 inducers, Vasopressin agonists
Disqualifiers: Premature birth, Anuria, Liver dysfunction, others
No Placebo Group
Pivotal Trial (Near Approval)
Prior Safety Data
Approved in 3 Jurisdictions
Trial Summary
What is the purpose of this trial?The primary objective of this study is to evaluate the safety of tolvaptan in pediatric subjects with autosomal recessive polycystic kidney disease (ARPKD)
Will I have to stop taking my current medications?
The trial requires that you stop taking certain medications, such as those that induce CYP3A4, vasopressin agonists, and other treatments for PKD cysts. If you are on these medications, you may need to stop them to participate in the trial.
What data supports the effectiveness of the drug Tolvaptan for treating Polycystic Kidney Disease?
The research on Tolvaptan in patients with idiopathic membranous nephropathy (a kidney condition) suggests that certain markers in the body might predict how well a patient responds to the drug, indicating its potential effectiveness in treating kidney-related conditions.
12345How is the drug Tolvaptan unique in treating polycystic kidney disease?
Tolvaptan is unique because it is the first approved drug specifically for slowing the progression of autosomal dominant polycystic kidney disease (ADPKD) by blocking the vasopressin V2 receptor, which helps reduce kidney cyst growth and slow kidney function decline. Unlike other treatments, it directly targets the mechanism that promotes cyst growth, offering a novel approach to managing this condition.
678910Eligibility Criteria
This trial is for infants and children from 28 days old to under 18 years with ARPKD. Participants need informed consent from parents or guardians, must be able to follow the trial's procedures, and not have been born prematurely if under 12 weeks old. They can't join if they require dialysis, have had a kidney transplant, severe anemia or heart issues, electrolyte imbalances, are on certain other medications including experimental drugs for PKD or CYP3A4 inducers.Inclusion Criteria
My guardian can consent to the trial and I can follow all trial requirements.
Ability to provide written informed assent from all subjects old enough per local laws to provide assent
I am under 18 years old and have been diagnosed with ARPKD.
Exclusion Criteria
Your platelet count is less than 50,000 per microliter.
I am taking medications that affect liver enzyme levels.
My baby was born at or before 32 weeks and is now between 28 days and less than 12 weeks old.
+24 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive tolvaptan either as a suspension or tablets for 18 months
18 months
Follow-up
Participants are monitored for safety and effectiveness after treatment
4-6 months
Participant Groups
The study tests the safety of Tolvaptan in tablet and suspension forms in young patients with autosomal recessive polycystic kidney disease (ARPKD). It aims to see how well these pediatric subjects tolerate the medication.
2Treatment groups
Experimental Treatment
Group I: Tolvaptan TabletsExperimental Treatment1 Intervention
Tolvaptan tablets will be administered orally as split-dose regimens (15/7.5 mg, 30/15 mg, and 45/15 mg) upon awakening and 8 hours later (twice daily) based on weight if able to swallow tablets. Treatment duration is 18 months.
Group II: Tolvaptan SuspensionExperimental Treatment1 Intervention
Tolvaptan suspension will be administered orally or via feeding/nasogastric tube at doses of 0.15 mg/kg once daily in the AM, 0.30 mg/kg once daily in the AM, 0.5 mg/kg once daily in the AM, 0.75 mg/kg split dose (0.5 mg/kg AM and 0.25 mg/kg 8 hours later), and 1 mg/kg split dose (0.67 mg/kg AM and 0.33 mg/kg 8 hours later) based on age. Treatment duration is 18 months.
Tolvaptan is already approved in United States, United States, European Union for the following indications:
🇺🇸 Approved in United States as Samsca for:
- Hyponatremia
- Syndrome of Inappropriate Antidiuretic Hormone (SIADH)
- Heart Failure
🇺🇸 Approved in United States as Jynarque for:
- Autosomal Dominant Polycystic Kidney Disease (ADPKD)
🇪🇺 Approved in European Union as Jinarc for:
- Autosomal Dominant Polycystic Kidney Disease (ADPKD)
- Hyponatremia
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Riley Hospital for ChildrenIndianapolis, IN
Johns Hopkins Pediatric SpeciaBaltimore, MD
C.S. Mott Children's HospitalAnn Arbor, MI
Children's National Medical CenterWashington, United States
More Trial Locations
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Who Is Running the Clinical Trial?
Otsuka Pharmaceutical Development & Commercialization, Inc.Lead Sponsor
References
Different Effects of Tolvaptan in Patients with Idiopathic Membranous Nephropathy with Nephrotic Syndrome. [2018]This case report discusses the clinical indication for immunosuppressants in patients with idiopathic membranous nephropathy (IMN). Because this disease occasionally shows spontaneous remission, it is necessary to determine the predictive values for a therapeutic effect in order to provide appropriate treatment. Two distinct cases described herein illustrate the different effects of tolvaptan in responders and non-responders, according to the pre-treatment levels of AQP-2 immunostaining in the samples from renal biopsy and urinary levels of AQP-2 and osmolality, suggesting that these values may be useful predictors of response to tolvaptan in patients with nephrotic IMN.
Cyclosporine A treatment in patients with Alport syndrome: a single-center experience. [2018]Limited and discordant data are available on cyclosporine A (CsA) treatment for proteinuria in Alport syndrome (AS). To address this lack of consistent data, we have studied 15 AS patients (14 males; mean age 15.3 +/- 6.0 years) treated with CsA. Patient selection criteria included a urinary protein/creatinine ratio > or =1 mg/mg and a creatinine clearance >40 ml/min/1.73 m(2). CsA treatment was started at an initial dose of 5 mg/kg/day and subsequently adjusted to reach target C2 levels of 500 ng/ml. Renal function, proteinuria, and blood pressure were monitored. Blood pressure was treated to avoid the administration of angiotensin converting enzyme or angiotensin receptor blockers for the first 2 years of therapy. The average follow-up was 3.5 years. Five patients had chronic renal failure at the beginning of treatment, of whom three and one reached end-stage renal failure within 1 and 3 years, respectively. In the remaining 11 patients, the glomerular filtration rate declined by 11 +/- 6% within 6 months, but remained stable thereafter. Proteinuria decreased by 63 +/- 21% from baseline, but returned nearly to baseline after 2.5 years of follow-up. Based on these results, we suggest that CsA is effective in reducing proteinuria in patients with Alport syndrome but that this effect is temporary. Our data do not support the use of CsA therapy for proteinuric patients with AS, particularly if they have chronic renal failure.
Conversion from Brand-Name Neoral to the Generic Ciqorin in Stable Renal Transplant Recipients. [2017]Transplant physicians and patients are often reluctant to change to generic versions of immunosuppressive drugs with a narrow therapeutic index, such as ciclosporin (CsA). Thus, in routine follow-up for kidney transplant patients receiving CsA maintenance immunosuppressive therapy in our center, we evaluated the exchangeability of the brand name, Neoral, and the recently approved CsA generic formulation, Ciqorin.
Low-dose cyclosporine treatment in Chinese nephrotic patients with idiopathic membranous nephropathy: An uncontrolled study with prospective follow-up. [2013]The optimal dose of cyclosporine A (CsA) in treatment of nephrotic proteinuria in idiopathic membranous nephropathy (IMN) remains inconclusive. We evaluated the efficacy and safety of low-dose CsA combined with low-dose prednisone as induction therapy for Chinese nephrotic patients with IMN.
Benefits of cyclosporine absorption profiling in nephrotic syndrome: preprandial once-daily administration of cyclosporine microemulsion improves slow absorption and can standardize the absorption profile. [2013]Cyclosporine is known to improve proteinuria in nephrotic syndrome (NS), but is also associated with drug-related renal impairment. In this case series, therapeutic drug monitoring using the absorption profile was applied to adults with NS to investigate the efficacy and safety of once-daily administration of cyclosporine microemulsion (CSAME).
Tolvaptan: A Review in Autosomal Dominant Polycystic Kidney Disease. [2020]Tolvaptan [Jynarque® (USA); Jinarc® (EU, Canada); Samsca® (Japan)] is a highly selective vasopressin V2 receptor antagonist approved for the treatment of autosomal dominant polycystic kidney disease (ADPKD). In the phase III TEMPO 3:4 trial, 3 years' treatment with tolvaptan slowed the increase in total kidney volume (TKV) and the decline in renal function relative to placebo. The composite secondary endpoint of time to investigator-assessed clinical progression also favoured tolvaptan over placebo. Although tolvaptan did not demonstrate a sustained disease-modifying effect on TKV over the longer term in the TEMPO 4:4 extension trial, the effect of tolvaptan in slowing renal function decline was maintained for a further 2 years. The phase III REPRISE trial confirmed the efficacy of tolvaptan in patients with later-stage ADPKD. Most of the adverse events commonly observed with tolvaptan (e.g. polyuria, nocturia, polydipsia, thirst) are consistent with its pharmacological activity. In the TEMPO trials, tolvaptan was also associated with idiosyncratic hepatotoxicity which was reversible on discontinuation of the drug. Although the use of tolvaptan requires careful consideration and balancing of benefits and risks, it provides a valuable treatment option to slow the progression of ADPKD in patients at risk of or with evidence of rapidly progressing disease.
10-Year Evaluation of Adherence and Satisfaction with Information about Tolvaptan in ADPKD: A Single-Center Pilot Study. [2022]Tolvaptan is the only approved drug for the treatment of autosomal dominant polycystic kidney disease (ADPKD) and causes significant polyuria with secondary polydipsia. Up to now, there is no study that examines tolvaptan adherence and satisfaction with information received about tolvaptan in ADPKD patients 10 years after starting tolvaptan therapy.
Effects of Hydrochlorothiazide and Metformin on Aquaresis and Nephroprotection by a Vasopressin V2 Receptor Antagonist in ADPKD: A Randomized Crossover Trial. [2023]The vasopressin V2 receptor antagonist tolvaptan is the only drug that has been proven to be nephroprotective in autosomal dominant polycystic kidney disease (ADPKD). Tolvaptan also causes polyuria, limiting tolerability. We hypothesized that cotreatment with hydrochlorothiazide or metformin may ameliorate this side effect.
Tolvaptan: A Review in Autosomal Dominant Polycystic Kidney Disease. [2018]Tolvaptan (Jinarc(®)) is a highly selective vasopressin V2 receptor antagonist indicated for use in patients with autosomal dominant polycystic kidney disease (ADPKD). Tolvaptan is the first pharmaceutical agent to be approved in Europe for delaying the progression of ADPKD in adults with stage 1-3 chronic kidney disease at initiation of treatment. In the large phase III TEMPO 3:4 trial in adults with ADPKD, 3 years' treatment with oral tolvaptan significantly reduced growth in total kidney volume and slowed renal function decline relative to placebo. Tolvaptan was also associated with a significantly lower rate of events for the composite secondary endpoint of time to investigator-assessed clinical progression relative to placebo, an effect that was largely attributable to reductions in the risk of worsening renal function and the risk of worsening kidney pain. Many of the most common adverse events in the tolvaptan group were related to its aquaretic mechanism of action (e.g. polyuria, nocturia, polydipsia and thirst). Tolvaptan was also associated with idiosyncratic elevations of liver enzymes which were reversible on discontinuation of the drug. Although the use of tolvaptan requires careful consideration and balancing of benefits and risks, current evidence suggests that tolvaptan is a promising new treatment option for patients with ADPKD.
TOLVAPTAN USE IN SEVERE NEONATAL AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD): THE PHARMACEUTICAL CHALLENGE. [2017]Unlicensed medications are used all the time in the management of diseases in childhood. Tolvaptan (Jinarc®) is a vasopressin V2-receptor antagonist licensed for use to slow the progression of cyst development and renal insufficiency of ADPKD in adults with CKD stage 1 to 3 with evidence of rapidly progressing disease. Studies of animal models implicate the antidiuretic hormone arginine vasopressin and its messenger cyclic adenosine monophosphate (cAMP) as promoters of kidney-cyst cell proliferation and luminal fluid secretion. The suppression of vasopressin release by means of high water intake, genetic elimination of vasopressin, and vasopressin V2-receptor blockade all reduce the cyst burden and protect kidney function1 A Phase 3 trial showed that Tolvaptan, as compared with placebo, slowed down the increase in total kidney volume and decline in kidney function in adults (average 39 yrs) with ADPKD over a 3-year period.2 ADPKD is the most common form of polycystic kidney disease (PKD) typically late in onset and results from mutation of either of two genes: PKD1 and PKD2. Autosomal recessive polycystic kidney (ARPKD), the other form of PKD, is 20 times less common, presents primarily in infancy and childhood, is typically more severe, and commonly associated with hypertension. ARPKD results from mutation of PKHD1. In spite of these differences, there is growing evidence to suggest that ADPKD and ARPKD are more related than previously suspected.3 Bilineal inheritance of PKD1 abnormalities has been reported to cause extremely severe disease resembling ARPKD.4 The use of Tolvaptan in the management of PKD in children is therefore expected to become more important.