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

NCT04152837 | Terminated Phase 3 Results FDA Drug

• 1 other identifier: PA-ADPKD-303
• Study Type: interventional
• Target: 7
• Locations: 1 country
• Sites: 6

Brief Summary

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.

Conditions

Polycystic Kidney Disease, Adult; ADPKD

Outcome Measures

Primary Outcomes (1)

• Number of Participants Who Develop Serum Alanine Aminotransferase (ALT) Levels >3 × ULN During the Titration or Maintenance Periods Assessed to be Related to Lixivaptan and Result in Discontinuation of Lixivaptan Treatment

  Number of participants who develop serum ALT levels \>3 x ULN which are assessed by the independent Hepatic Events Review Committee (HERC) to be at least probably related to lixivaptan and result in the discontinuation of lixivaptan treatment. The independent HERC, after reviewing demographic, medical and medication history, safety data and other relevant data of participants who develop liver abnormalities, will determine the probable causality for liver chemistry test abnormalities of concern and the relatedness to lixivaptan using the Drug-Induced Liver Injury Network probability criteria (Fontana et al., 2009). The normal range of ALT was defined as 0-55 U/L.

  Up to 58 weeks

Secondary Outcomes (7)

• Number of Participants Who Develop Serum ALT Levels >5 × ULN During the Titration or Maintenance Periods Assessed to be Related to Lixivaptan and Result in Discontinuation of Lixivaptan Treatment

  Up to 58 weeks

• Number of Participants Who Develop Serum ALT Levels >3 × ULN During the Titration or Maintenance Periods Assessed to be Related to Lixivaptan and Result in Dose Reduction of Lixivaptan Treatment

  Up to 58 weeks

• Number of Participants With Treatment-emergent Adverse Events (TEAEs)

  Up to 62 weeks

• Number of Participants With Potentially Clinically Important Clinical Laboratory Findings

  Up to 62 weeks

• Number of Participants With Potentially Clinically Important Vital Signs Findings

  Up to 62 weeks

Study Arms (1)

Lixivaptan

EXPERIMENTAL

Lixivaptan oral capsules, 100-200 mg twice daily

Drug: Lixivaptan

Interventions

Lixivaptan DRUG

Oral vasopressin V2 receptor antagonist

Lixivaptan

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

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.

Sponsors & Collaborators

• Palladio Biosciences: lead
• Centessa Pharmaceuticals plc: collaborator

Study Sites (6)

University of California Los Angeles

Los Angeles, California, 90025, United States

Location

University of Chicago Medicine & Biological Sciences

Chicago, Illinois, 60637, United States

Location

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

Brookview Hills Research Associates, LLC

Winston-Salem, North Carolina, 27103, United States

Location

Northeast Clinical Research Center, LLC

Bethlehem, Pennsylvania, 18107, United States

Location

Nephrology Associates of Northern Virginia, Inc.

Fairfax, Virginia, 22033, United States

Location

Related Publications (1)

• Fontana RJ, Watkins PB, Bonkovsky HL, Chalasani N, Davern T, Serrano J, Rochon J; DILIN Study Group. Drug-Induced Liver Injury Network (DILIN) prospective study: rationale, design and conduct. Drug Saf. 2009;32(1):55-68. doi: 10.2165/00002018-200932010-00005.

  PMID: 19132805 BACKGROUND

MeSH Terms

Conditions

Polycystic Kidney, Autosomal Dominant

Interventions

lixivaptan

Condition Hierarchy (Ancestors)

Polycystic Kidney Diseases; Kidney Diseases, Cystic; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Abnormalities, Multiple; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Ciliopathies; Genetic Diseases, Inborn

Limitations and Caveats

Efficacy and safety results are limited by the early termination of the trial and the small number of subjects. Early termination was due to a sponsor decision for reasons unrelated to safety.

Results Point of Contact

• Title: Milena Kanova
• Organization: Centessa Pharmaceuticals

milena.kanova@centessa.com

+44 7780 430583

Study Officials

• Arlene Chapman, MD

  University of Chicago, Chicago, IL USA

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: GT60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Open-label, single treatment group

Study Record Dates

• First Submitted: October 31, 2019
• First Posted: November 5, 2019
• Study Start: September 2, 2020
• Primary Completion: July 29, 2022
• Study Completion: July 29, 2022
• Last Updated: April 10, 2023
• Results First Posted: April 10, 2023

Record last verified: 2023-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (6)