Safety of Lixivaptan in Subjects Previously Treated With Tolvaptan for Autosomal Dominant Polycystic Kidney Disease

Stopped early · Phase 3

Conditions studied: Polycystic Kidney Disease, Adult, ADPKD

In brief

This is a Phase 3, open-label, repeat-dose study designed to assess liver safety, non-liver safety, and efficacy of lixivaptan in participants who previously experienced liver chemistry test abnormalities while treated with tolvaptan and were permanently discontinued from the drug for that reason. Up to 50 eligible participants will be enrolled and treated with lixivaptan for 52 weeks following titration to an optimal dose.

Key facts

Study ID

NCT04152837

Run by

Palladio Biosciences

People needed

7

Starts

2020-09-02

Expected to finish

2022-07-29

Last updated by the study team

2023-04-10

Who can join

Age: 18 and older, up to 65. Sex: any. Healthy volunteers: not accepted.

You may qualify if…

• Male or female, between 18 and 65 years of age (inclusive) at the time of Screening.
• Documented diagnosis of ADPKD by imaging or genetic analysis previously treated with tolvaptan for that indication.
• Screening eGFR ≥ 20 mL/min/1.73 m\^2.
• Body mass index (BMI) between 18 and 35 kg/m\^2 (inclusive) at the time of Screening.
• Documented history of:
• Based on upper limit of normal (ULN): At least 2 elevated alanine aminotransferase (ALT) levels; 1 ALT level >2 x ULN and 1 ALT level >3 x ULN while the participant was receiving tolvaptan, or within 4 weeks after tolvaptan discontinuation, with no other explanation for the ALT elevations. The 2 elevated ALT measurements could be recorded during the same instance of liver injury or during distinct instances; OR
• Based on the participant's stable baseline as determined by the Investigator: At least 2 elevated ALT levels; 1 ALT level >2 x the participant's stable baseline level and 1 ALT level >3 x the participant's stable baseline level while the participant was receiving tolvaptan, or within 4 weeks after tolvaptan discontinuation, with no other explanation for the ALT elevations; provided that at least one ALT elevation was >2 x ULN. The 2 elevated ALT measurements could be recorded during the same instance of liver injury or during distinct instances; OR
• A pattern of ALT elevations deemed by the Investigator to be consistent with tolvaptan liver injury with no other explanation for the ALT elevations and agreement of the medical monitor and sponsor.
• Permanent discontinuation of prior tolvaptan treatment because of the ALT abnormality.
• If re-challenge with tolvaptan was performed, the ALT level must have increased to >2 x ULN upon rechallenge or the ALT level was increasing but tolvaptan was stopped for patient safety reasons before it reached > 2 x ULN after having previously normalized.
• Appropriate control of hypertension including an angiotensin converting enzyme inhibitor or angiotensin receptor blocker (unless not considered appropriate for the participant) without the use of a diuretic in concert with Kidney Disease: Improving Global Outcomes "Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease".
• Willing to practice acceptable methods of birth control (both males who have partners of child-bearing potential and females of childbearing potential).
• Able to provide informed consent.

You may not qualify if…

• Known sensitivity or idiosyncratic reaction to any compound present in lixivaptan and related compounds.
• Hypovolemia at Screening.
• Abnormal serum sodium concentration at Screening.
• Subjects who have taken any investigational drug or used an investigational device within 30 days, or 5 half-lives, whichever is longer, prior to Screening.
• Subjects who are taking, have taken within the past 2 weeks, or are expected to be taking, strong or moderate CYP3A4 or CYP2C8 inhibitors or inducers including regular use of grapefruit juice, Seville oranges, or St. John's wort.
• Simvastatin at total daily doses >10 mg or amlodipine at total daily doses >5 mg.
• Use of tolvaptan within the 3 months prior to Screening or until a previously elevated ALT level has returned to ≤1 x ULN for at least 3 months.
• Use of lixivaptan or participation in a clinical study with lixivaptan within the 3 months prior to Screening.
• Use of conivaptan, somatostatin analogs (e.g., lanreotide, pasireotide, octreotide, etc.), metformin, nicotinamide, bardoxolone, venglustat, demeclocycline, or mammalian Target of Rapamycin (mTOR) kinase inhibitors (e.g., everolimus, sirolimus, etc.) to treat ADPKD within the 3 months prior to Screening.
• Requirement for chronic diuretic use.
• History of advanced diabetes (e.g., glycosylated hemoglobin [HgbA1c] >7.5%, and/or glycosuria by dipstick, significant proteinuria [>300 mcg albumin/mg creatinine]), other significant renal disease, transplanted kidney, recent kidney surgery within the 6 months prior to Screening (including cyst drainage or fenestration) or acute kidney injury within the 6 months prior to Screening.
• Clinically significant incontinence, overactive bladder, or urinary retention (e.g., benign prostatic hyperplasia).
• New York Heart Association Functional Class 3 or 4 heart failure or other significant cardiac or electrocardiogram (ECG) findings that could pose a safety risk to the participant.
• Clinically significant liver disease or impairment or active chronic hepatitis at Screening.
• Positive test results for hepatitis B surface antigen (HBsAg) or hepatitis C (HCV) antibody.
• History of infection with human immunodeficiency virus (HIV) unless the participant is stable and doing well on a non-CYP interacting anti-retroviral therapy (ART) regimen and who has not required more than 2 changes in their ART regimen.
• ALT or aspartate aminotransferase (AST) values >1.5 x ULN during Screening/Baseline.
• Total bilirubin values >1.0 x ULN during Screening/Baseline.
• History of drug or alcohol abuse in the 2 years prior to Screening.
• Any malignancy within the 5 years prior to Screening except for basal cell carcinoma successfully treated with local therapy.
• Medical history or findings that preclude safe participation in the study or who are likely to be non-compliant with study procedures in the opinion of the Investigator or medical monitor.

Where it is running

• University of California Los Angeles — Los Angeles, California, United States
• University of Chicago Medicine & Biological Sciences — Chicago, Illinois, United States
• Mayo Clinic — Rochester, Minnesota, United States
• Brookview Hills Research Associates, LLC — Winston-Salem, North Carolina, United States
• Northeast Clinical Research Center, LLC — Bethlehem, Pennsylvania, United States
• Nephrology Associates of Northern Virginia, Inc. — Fairfax, Virginia, United States

Full record on ClinicalTrials.gov

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