Tolvaptan for Polycystic Kidney Disease

Recruiting at 42 trial locations

Overseen By Otsuka Contact Center Otsuka Call Center

Age: < 65

Sex: Any

Trial Phase: Phase 3

Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.

Must not be taking: CYP3A4 inducers, Vasopressin agonists

Disqualifiers: Premature birth, Anuria, Liver dysfunction, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 18 months

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the safety of tolvaptan as a potential treatment for children and teens with autosomal recessive polycystic kidney disease (ARPKD). ARPKD causes cysts (fluid-filled sacs) to develop in the kidneys, which can lead to kidney damage. The trial will test tolvaptan in two forms: a liquid suspension and tablets, both taken daily for 18 months. Eligible participants have been diagnosed with ARPKD but do not have other kidney conditions or complications like abnormal liver function. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to a potentially groundbreaking treatment.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that tolvaptan has been studied for safety in individuals with a condition similar to ARPKD, known as ADPKD. In past studies, most participants tolerated tolvaptan well, though some experienced side effects, including impacts on liver function. Therefore, regular safety checks are crucial during treatment. The FDA has already approved tolvaptan for adults with ADPKD, indicating its safety is well-documented. However, this trial focuses on children with ARPKD, so results might differ. Always consult the trial team for the most current safety information. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Tolvaptan for polycystic kidney disease because it offers a unique approach to treatment. Unlike current standard options like blood pressure medications and pain relievers, Tolvaptan specifically targets vasopressin receptors to slow the growth of kidney cysts. This mechanism directly addresses cyst development, which is a root cause of the disease, rather than just managing symptoms. Additionally, Tolvaptan is available in both suspension and tablet forms, providing flexibility in administration and potentially improving patient adherence. This targeted action and versatility make Tolvaptan a promising candidate for managing polycystic kidney disease more effectively.

What evidence suggests that tolvaptan might be an effective treatment for polycystic kidney disease?

Research has shown that tolvaptan can slow the worsening of kidney function in people with polycystic kidney disease, which is crucial for those affected. Tolvaptan targets a specific part of the kidney, slowing the growth of kidney cysts. In this trial, participants will receive either the liquid suspension or tablet form of tolvaptan. Patients taking tolvaptan have experienced a slower decline in kidney function, as measured by the estimated glomerular filtration rate (eGFR). This benefit has been observed in both clinical trials and everyday use. ^{3 4 5 6 7}

Who Is on the Research Team?

Olga Sergeyeva, MD

Principal Investigator

[e-mail]

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Tolvaptan

Trial Overview 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.

How Is the Trial Designed?

Group I: Tolvaptan Tablets Experimental Treatment 1 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 Suspension Experimental Treatment 1 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, 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

Who Is Running the Clinical Trial?

Otsuka Pharmaceutical Development & Commercialization, Inc.

Lead Sponsor

Trials

271

Recruited

170,000+

John Kraus

Otsuka Pharmaceutical Development & Commercialization, Inc.

Chief Medical Officer since 2023

MD, PhD

Tarek Rabah

Otsuka Pharmaceutical Development & Commercialization, Inc.

Chief Executive Officer since 2022

BS in Biology and BA in Business from the American University of Beirut, MBA from McGill University

Published Research Related to This Trial

Tolvaptan is the first approved medication in Europe for delaying the progression of autosomal dominant polycystic kidney disease (ADPKD) in adults with early-stage chronic kidney disease, showing significant efficacy in reducing kidney volume growth and slowing renal function decline over 3 years in the phase III TEMPO 3:4 trial.

While tolvaptan is effective, it can cause side effects related to its mechanism of action, such as increased urination and thirst, as well as potential liver enzyme elevations, which are reversible upon stopping the medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tolvaptan: A Review in Autosomal Dominant Polycystic Kidney Disease. Blair, HA., Keating, GM.[2018]

In a study involving 10 stable kidney transplant patients, switching from the brand-name immunosuppressant Neoral to the generic version Ciqorin showed similar pharmacokinetic profiles, indicating that the two formulations can be considered exchangeable.

Renal function remained stable throughout the study, with no significant changes in glomerular filtration rate or other health parameters, providing reassurance about the safety of using the generic formulation in place of the brand-name drug.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Conversion from Brand-Name Neoral to the Generic Ciqorin in Stable Renal Transplant Recipients. Cortinovis, M., Gotti, E., Trillini, M., et al.[2017]

In a study of 15 patients with Alport syndrome treated with cyclosporine A (CsA) over an average of 3.5 years, proteinuria decreased significantly by 63%, indicating that CsA can effectively reduce protein levels in urine.

However, the reduction in proteinuria was temporary, as levels returned nearly to baseline after 2.5 years, and the treatment did not prevent further decline in renal function, especially in patients with chronic renal failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cyclosporine A treatment in patients with Alport syndrome: a single-center experience. Massella, L., Muda, AO., Legato, A., et al.[2018]

In the phase III TEMPO 3:4 trial, tolvaptan significantly slowed the increase in total kidney volume and the decline in renal function over 3 years compared to placebo, making it an effective treatment for autosomal dominant polycystic kidney disease (ADPKD).

While tolvaptan did not show a long-term effect on kidney volume in the TEMPO 4:4 extension trial, it continued to slow renal function decline for an additional 2 years, although it is associated with common side effects like increased urination and potential liver toxicity that requires monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tolvaptan: A Review in Autosomal Dominant Polycystic Kidney Disease. Blair, HA.[2020]

In a study involving 13 patients with autosomal dominant polycystic kidney disease (ADPKD), the addition of hydrochlorothiazide significantly reduced the excessive urine output caused by tolvaptan, improving quality of life and kidney injury markers.

While metformin also reduced urine volume, it did not show improvements in kidney damage markers or quality of life, indicating that hydrochlorothiazide may be the more effective option for managing tolvaptan's side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of Hydrochlorothiazide and Metformin on Aquaresis and Nephroprotection by a Vasopressin V2 Receptor Antagonist in ADPKD: A Randomized Crossover Trial. Kramers, BJ., Koorevaar, IW., van Gastel, MDA., et al.[2023]

In patients with idiopathic membranous nephropathy (IMN), the response to the immunosuppressant tolvaptan may be predicted by pre-treatment levels of AQP-2 immunostaining and urinary AQP-2 and osmolality, as shown in two distinct case studies.

The findings suggest that assessing these biomarkers could help tailor treatment strategies for IMN, especially since the disease can sometimes resolve on its own.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Different Effects of Tolvaptan in Patients with Idiopathic Membranous Nephropathy with Nephrotic Syndrome. Tanaka, A., Nakamura, T., Sato, E., et al.[2018]

In a case series of 20 adults with nephrotic syndrome, once-daily administration of cyclosporine microemulsion (CSAME) effectively eliminated severe nephrotic symptoms after 6 months without causing renal impairment, as indicated by stable serum creatinine and blood urea nitrogen levels.

Therapeutic drug monitoring allowed for dose adjustments based on absorption profiles, leading to a significant reduction in the mean dose of cyclosporine while maintaining efficacy, suggesting that preprandial administration enhances drug absorption and could be a standard practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Benefits of cyclosporine absorption profiling in nephrotic syndrome: preprandial once-daily administration of cyclosporine microemulsion improves slow absorption and can standardize the absorption profile. Takeda, A., Horike, K., Onoda, H., et al.[2013]

In a pilot study of 12 patients with autosomal dominant polycystic kidney disease (ADPKD) who have been on tolvaptan for 10 years, strong adherence to the medication was reported, with a median adherence score of 23.5 out of 25.

While patients were highly satisfied with the information about tolvaptan's action and usage, 42% expressed dissatisfaction regarding the information about potential side effects, highlighting the need for improved patient education on the risks associated with tolvaptan therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

10-Year Evaluation of Adherence and Satisfaction with Information about Tolvaptan in ADPKD: A Single-Center Pilot Study. Schirutschke, H., Gross, P., Paliege, A., et al.[2022]

Tolvaptan, a vasopressin V2-receptor antagonist, was successfully used in a neonate with severe autosomal dominant polycystic kidney disease (ADPKD), demonstrating its potential for managing this condition in children despite being unlicensed for pediatric use.

The treatment resulted in significant cost savings and positive clinical outcomes, including reduced blood pressure and expected aquaresis, while highlighting the importance of a multidisciplinary approach and the need for better pediatric formulations in medicine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TOLVAPTAN USE IN SEVERE NEONATAL AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD): THE PHARMACEUTICAL CHALLENGE. Olalekan, K., Fox, A., Gilbert, R.[2017]

In a study of 18 Chinese patients with idiopathic membranous nephropathy (IMN) and nephrotic proteinuria, low-dose cyclosporine A (CsA) combined with low-dose prednisone resulted in remission in 68.8% of patients, demonstrating its efficacy as an induction therapy.

The treatment was generally safe, with manageable adverse effects such as hypertension and hyperuricemia, indicating that low-dose CsA can be a viable option even for patients who did not respond to other immunosuppressive therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low-dose cyclosporine treatment in Chinese nephrotic patients with idiopathic membranous nephropathy: An uncontrolled study with prospective follow-up. Li, J., Zhang, YM., Qu, Z., et al.[2013]

Citations

1. otsuka-us.com otsuka-us.com/discover/articles-1188

Otsuka's JYNARQUE™ (tolvaptan) Approved by U.S. FDA ... The result of the key secondary composite endpoint was driven by effects on worsening kidney function and kidney pain events. In contrast, there ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9926647/

Design of two ongoing clinical trials of tolvaptan in the ... Vasopressin V2 receptor antagonists were shown to slow cystic development and preserve kidney function in rodent models orthologous to human ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT02160145

NCT02160145 | Efficacy and Safety of Tolvaptan in ... The purpose of the study is to determine whether tolvaptan is effective and safe for the treatment of late-stage chronic kidney disease due to autosomal ...

4. jynarquehcp.com jynarquehcp.com/documents/Evidence-Based-Leave-Behind-Time-to-ESKD.pdf

common clinical question about JYNARQUE® (tolvaptan) JYNARQUE is indicated to slow kidney function decline in adults at risk of rapidly progressing autosomal dominant polycystic kidney disease (ADPKD). Page 2 ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12002913/

Effectiveness of Tolvaptan for Autosomal Dominant Polycystic ... Tolvaptan was associated with slower eGFR decline in routine clinical practice, consistent with the results of controlled trials.

6. jynarquehcp.com jynarquehcp.com/clinical-information/safety-profile

Safety Profile | HCP JYNARQUE® (tolvaptan) tablets The safety profile of JYNARQUE® (tolvaptan) has been evaluated in the 2 largest clinical trials of patients with ADPKD · DISCONTINUATION RATES WITH JYNARQUE.

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2018/204441lbl.pdf

JYNARQUE (tolvaptan) tablets for oral use - accessdata.fda.gov JYNARQUE is indicated to slow kidney function decline in adults at risk of rapidly progressing autosomal dominant polycystic kidney disease (ADPKD). 2. DOSAGE ...