Tolvaptan for Polycystic Kidney Disease

Recruiting at 39 trial locations

Overseen By Otsuka Contact Center Otsuka Call Center

Age: < 18

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 transplant, 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: 24 months

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests how well the medication tolvaptan works for children with autosomal recessive polycystic kidney disease (ARPKD), a rare kidney condition. The main goal is to determine if tolvaptan can reduce the need for treatments like dialysis or a kidney transplant. Babies between 28 days and less than 12 weeks old, with large kidneys and multiple kidney cysts, might be suitable candidates. The trial aims to provide new insights into managing this challenging condition early in life. As a Phase 3 trial, it represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

The trial does not specify if you must stop all current medications, but you cannot take certain medications like diuretics, vasopressin agonists, or those that affect liver enzymes. Check with the trial team about your specific medications.

Is there any evidence suggesting that tolvaptan is likely to be safe for humans?

Research has shown that tolvaptan is generally well-tolerated by people with autosomal dominant polycystic kidney disease (ADPKD). Studies have demonstrated its effectiveness and safety for long-term use. For instance, one study found that tolvaptan can help slow the decline in kidney function, with most patients tolerating it well. However, some experienced side effects, such as increased liver enzymes, indicating potential liver stress.

Another study examined tolvaptan's safety and found it mostly well-tolerated, with liver-related side effects as the main concern. Therefore, monitoring liver function during treatment is important. Despite these concerns, tolvaptan has been successfully used to manage ADPKD, and its benefits in slowing kidney disease progression are well-documented.

These findings provide reassurance about tolvaptan's safety, especially since it is already approved for another kidney condition. Participants should still discuss potential risks with their doctor. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Most treatments for polycystic kidney disease focus on managing symptoms and slowing disease progression, often involving blood pressure medications or pain relievers. But Tolvaptan works differently, targeting the vasopressin V2 receptor to directly reduce the growth of kidney cysts. Researchers are excited about Tolvaptan because it specifically addresses the underlying cause of cyst development, offering a more targeted approach than current options. This unique mechanism of action provides hope for slowing down kidney damage more effectively.

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

Research has shown that tolvaptan, the treatment under study in this trial, can slow the loss of kidney function in people with autosomal dominant polycystic kidney disease (ADPKD). In these studies, tolvaptan slowed the worsening of kidney function. Although the research mainly focuses on ADPKD, tolvaptan's mechanism—reducing cyst growth in the kidneys—suggests potential benefits for autosomal recessive polycystic kidney disease (ARPKD) as well. The treatment decreases fluid buildup in kidney cysts, helping to maintain stable kidney function over time. This offers hope that tolvaptan could also be effective for ARPKD, but further research is needed to confirm this. ^{6 7 8 9 10}

Who Is on the Research Team?

Olga Sergeyeva, MD

Principal Investigator

Otsuka Pharmaceutical Development & Commercialization, Inc.

Are You a Good Fit for This Trial?

This trial is for infants aged between 28 days and less than 12 weeks with autosomal recessive polycystic kidney disease (ARPKD). They should have specific symptoms like enlarged kidneys and multiple cysts. Babies born prematurely or those needing dialysis, with liver issues, low platelets, severe anemia, or electrolyte imbalances can't participate.

Inclusion Criteria

Ability for parent or guardian to provide written, informed consent prior to initiation of any trial-related procedures, and ability to comply with all the requirements of the trial

I have ARPKD with enlarged kidneys, kidney cysts, and a history of low or no amniotic fluid.

My child is between 28 days and less than 12 weeks old.

Exclusion Criteria

Taking any other experimental medications

I have or might have imbalances in my body's sodium and potassium levels.

I have severe high blood pressure in the veins of my liver.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive tolvaptan for 24 months to evaluate its effect on delaying the need for renal replacement therapy

24 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

What Are the Treatments Tested in This Trial?

Interventions

• Tolvaptan

Trial Overview The study tests if Tolvaptan can help delay the need for dialysis in young children with ARPKD. It aims to see how effective this medication is at managing their kidney function over time.

How Is the Trial Designed?

Group I: Tolvaptan (OPC-41061) Experimental Treatment 1 Intervention

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

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 92 patients with autosomal dominant polycystic kidney disease (ADPKD) treated with tolvaptan over an average of 2.4 years, a significant decrease in urinary AQP2 levels was observed within the first month, indicating the drug's effectiveness in inhibiting vasopressin's action.

The initial reduction in urinary AQP2 was strongly correlated with improvements in kidney function, as measured by changes in total kidney volume and estimated glomerular filtration rate, suggesting that monitoring AQP2 levels could help predict renal prognosis during tolvaptan treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Urinary Aquaporin 2 as a Potential Indicator Predicting Tolvaptan Response in Patients With ADPKD. Makabe, S., Manabe, S., Kataoka, H., et al.[2022]

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]

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 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 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]

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]

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]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40242785/

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

2. clinicaltrials.gov clinicaltrials.gov/study/NCT02729662

NCT02729662 | Efficacy of Tolvaptan on ADPKD Patients Based on the results of a study entitled "The Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes ( ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S259005952500024X

Effectiveness of Tolvaptan for Autosomal Dominant ... Trial data have demonstrated that tolvaptan slows kidney function decline in patients with autosomal dominant polycystic kidney disease who are ...

4. jynarquehcp.com jynarquehcp.com/documents/Long-Term-Data.pdf

common clinical question about JYNARQUE® (tolvaptan) Dominant Polycystic Kidney Disease and Its Outcomes. JYNARQUE® (tolvaptan) has demonstrated effectiveness in slowing kidney function decline in the 2 ...

5. uspharmacist.com uspharmacist.com/article/evaluating-treatments-for-autosomal-dominant-pkd-1

Evaluating Treatments for Autosomal Dominant PKD Tolvaptan, while effective in slowing disease progression by lowering an increase in total kidney volume and kidney function decline compared ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9035348/

An update on the use of tolvaptan for autosomal dominant ... In the TEMPO (Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and its Outcomes) 3:4 study, tolvaptan reduced eGFR ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT00428948

Study Details | NCT00428948 | Tolvaptan Phase 3 Efficacy ... This study's purpose is to evaluate the long-term safety and efficacy of tolvaptan versus placebo in patients with ADPKD.

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11664107/

Tolvaptan safety in autosomal-dominant polycystic kidney ... Tolvaptan is a vasopressin V2 receptor antagonist which has proven to be an effective and mostly well-tolerated agent for the treatment of autosomal-dominant ...

9. sciencedirect.com sciencedirect.com/science/article/pii/S2590059524001468

Tolvaptan and Autosomal Dominant Polycystic Kidney ... The results showed a statistically significant reduction in kidney function decline with tolvaptan. Extrapolating this 5-year data to a 35-year disease ...

10. journals.lww.com journals.lww.com/kidney360/abstract/9900/long_term_experience_of_tolvaptan__is.712.aspx

Long-term Experience of Tolvaptan: Is Hepatotoxicity Still... This review summarizes data regarding hepatic safety from clinical trials and presents data from established risk mitigation programs and real-world evidence.