Efficacy and Safety of Lixivaptan in the Treatment of Autosomal Dominant Polycystic Kidney Disease

NCT ID: NCT04064346

Last Updated: 2023-02-06

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 12 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-10-28
• Study Completion Date: 2022-08-03

Brief Summary

This is a Phase 3 trial consisting of a 2-arm, double-blind, placebo-controlled, randomized phase (Part 1) followed by a single-arm open-label phase (Part 2) to demonstrate the efficacy and safety of lixivaptan in participants with autosomal dominant polycystic kidney disease (ADPKD). Part 1 of the trial is designed to demonstrate the efficacy of lixivaptan in slowing the decline in kidney function as measured by the difference in estimated glomerular filtration rate (eGFR) between the lixivaptan-treated and placebo-treated participants. Part 2 of the study is designed to provide confirmation of the durability of this effect. Additionally, both parts of the study will contribute to understanding the safety of lixivaptan, particularly any effects on liver chemistry tests.

Detailed Description

Part 1: Approximately 2250 participants with ADPKD will be screened in order to qualify the 1350 individuals who will proceed through the Placebo Run-in Period, the Lixivaptan Titration Period, and then be randomized to receive lixivaptan or placebo in the Double-blind, Randomized Treatment Period. Throughout Part 1 the study drug will look identical regardless of whether it is placebo or lixivaptan.

After meeting entry criteria during screening, participants will enter a 1-week single-blind, Placebo Run-in Period to obtain select baseline measurements. This will be followed by a 5- to 6-week single-blind dose titration period during which lixivaptan administered twice daily (BID) will be titrated to the highest tolerated dose (the Lixivaptan Titration Period). The starting dose (Level 1) will be 50 mg BID) and this will be increased weekly through Levels 2 (100 mg BID), 3 (150mg BID), and 4 (200 mg BID). The minimum dose to enter the next period, the Double-blind, Randomized Treatment Period, is Level 2 (100 mg BID). Those participants successfully titrated and tolerating the drug will then be randomized (each participant has a 2/3 chance of receiving lixivaptan and a 1/3 chance of receiving placebo) to either continue receiving lixivaptan or switch immediately to matching placebo in a double-blind manner. All dosing throughout the study will be 4 capsules BID. Depending on the study period, treatment arm to which the participant is randomized, and current dose level, the set of 4 capsules may be all placebo, all active or a combination of active and placebo. Double-blind treatment will continue for 52 weeks after which study drug will be held, and final assessments obtained off-treatment over 3 visits starting on the 8th day after the last dose of double-blind study drug through the 28th day after the last dose of study drug.

For Part 1 summaries after randomization, the analysis results will be presented by 2 treatment groups: lixivaptan and placebo.

Part 2: All participants entering Part 1, who have not discontinued due to an adverse event or withdrawn consent, will continue into Part 2 of the study, and will proceed through the Lixivaptan Re-titration Period and a Maintenance Treatment Period.

The Lixivaptan Re-titration Period will be a 2- to 4-week period during which dosing with lixivaptan will start at Level 1 (50 mg BID) for all participants and will be increased weekly until the dose level of lixivaptan, or the inferred lixivaptan dose level for participants randomized to placebo treatment, taken at the end of the Double-blind, Randomized Treatment Period in Part 1 is achieved. Lixivaptan treatment will continue for 52 weeks during the Maintenance Treatment Period after which study drug will be held, and final assessments obtained off-treatment over 3 visits starting on the 8th day after the last dose of lixivaptan through the 28th day after the last dose of lixivaptan.

Since all participants in Part 2 are treated with lixivaptan, the summaries for Part 2 will be presented in the following treatment cohorts and overall (treatment cohorts combined):

• Part1/Part2 - placebo/lixivaptan: all participants in Part 2 who were randomized into the placebo treatment group in Part 1.
• Part1/Part2 - lixivaptan/lixivaptan: all participants in Part 2 who were randomized into the lixivaptan treatment group in Part 1.

Conditions

Autosomal Dominant Polycystic Kidney; ADPKD

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Lixivaptan

Lixivaptan capsules, 100-200 mg twice a day (BID)

Group Type: EXPERIMENTAL

Lixivaptan

Intervention Type: DRUG

Oral vasopressin V2 receptor antagonist

Placebo

Matching placebo capsules BID

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Matching placebo

Interventions

Lixivaptan

Oral vasopressin V2 receptor antagonist

Intervention Type: DRUG

Placebo

Matching placebo

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Diagnosis of ADPKD by appropriate imaging or genetic testing.
• Mayo Clinic MRI imaging classification of 1C, 1D or 1E.
• eGFR ≥25 mL/min/1.73 m2 and ≤90 mL/min/1.73 m^2.
• Body mass index between 18 and 40 kg/m^2.
• Control of hypertension consistent with the 2021 Kidney Disease: Improving Global Outcomes guidelines without a diuretic and with an angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) unless not considered medically appropriate.
• 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.

Exclusion Criteria

• Known sensitivity or idiosyncratic reaction to lixivaptan and/or its excipients.
• Hypovolemia.
• 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 or Seville oranges.
• Prior use of tolvaptan or lixivaptan within the past 2 months.
• Prior use of conivaptan, somatostatin analogs (e.g., lanreotide, pasireotide, octreotide, etc.), metformin, nicotinamide, bardoxolone, demeclocycline, or mammalian target of rapamycin kinase inhibitors (e.g., everolimus, sirolimus, etc.), or KetoCitra™ or any beta-hydroxybutyrate containing supplements to treat ADPKD within the past 2 months.
• Prior use of a sodium-glucose cotransporter 2 (SGLT2) inhibitor (e.g., canagliflozin, dapagliflozin, empagliflozin, etc.) within the past 2 months or expected need for initiation of treatment with a SGLT2 inhibitor during the study.
• Prior use of a hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor within the past 2 months or expected need for initiation of treatment with a HIF-PH inhibitor during the study.
• Requirement for ongoing diuretic use.
• Advanced diabetes (e.g., glycosylated hemoglobin >7.5%, and/or glycosuria by dipstick, significant proteinuria [>300 mcg albumin/mg creatinine]), other significant kidney disease, kidney cancer, transplanted kidney, single kidney, recent kidney surgery within the past 6 months (including cyst drainage or fenestration) or acute kidney injury within past 6 months.
• 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 ECG findings that could pose a safety risk to the subject.
• Positive test results for hepatitis B surface antigen or hepatitis C antibody.
• History of infection with human immunodeficiency virus unless the participant is clinically 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 since treatment inception.
• History of clinically significant drug or alcohol abuse in the past 2 years.
• Contraindications to or interference with MRI assessments.
• Malignancy within the past 5 years except for those not considered to affect participant survival.
• Medical history or findings that preclude safe participation in the trial or participants who are likely to be non-compliant with trial procedures in the opinion of the Investigator or medical monitor.
• Clinically significant liver disease or impairment or alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin values >1.2 x ULN during Screening. Note: This criterion will preliminarily be reviewed at Visit 2 based on Visit 1a and Visit 1b results (if Visit 1b is required). The criterion must be re-evaluated no later than Visit 3 when results for Visit 2 are available.
• Simvastatin at a total daily dose >10 mg or amlodipine at a total daily dose >5 mg.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Centessa Pharmaceuticals plc

INDUSTRY

Sponsor Role: collaborator

Palladio Biosciences

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Vicente Torres, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Mayo Clinic

Locations

Nephrology Associates, PC - Greystone

Hoover, Alabama, United States

Nephrology Consultants, LLC

Huntsville, Alabama, United States

Arizona Kidney Disease & Hypertension Center - Scottsdale / Pima

Scottsdale, Arizona, United States

JEM Research Institute

Atlantis, Florida, United States

Elixia at Florida Kidney Physicians - Southeast

Fort Lauderdale, Florida, United States

Qway Research

Hialeah, Florida, United States

South Florida Nephrology Associates PA

Lauderdale Lakes, Florida, United States

Total Research Group, LLC

Miami, Florida, United States

Innovation Medical Research Center, Inc

Palmetto Bay, Florida, United States

Florida Kidney Physicians - Tampa

Tampa, Florida, United States

Clinical Site Partners, LLC

Winter Park, Florida, United States

Tufts Medical Center, Inc,

Boston, Massachusetts, United States

St Clair Nephrology Research, LLC

Roseville, Michigan, United States

Mayo Clinic

Rochester, Minnesota, United States

Clinical Research Consultants, LLC

Kansas City, Missouri, United States

Angel City Research, Inc

Morrisville, North Carolina, United States

Northeast Clinical Research Center, LLC

Bethlehem, Pennsylvania, United States

Brown Medicine - Brown Physicians Patient Center

Riverside, Rhode Island, United States

Knoxville Kidney Center LLC

Knoxville, Tennessee, United States

Prolato Clinical Research Center (PCRC)

Houston, Texas, United States

Clinical Advancement Center, PLLC

San Antonio, Texas, United States

Utah Kidney Research Institute

Salt Lake City, Utah, United States

Nephrology Associates of Northern Virginia, Inc

Fairfax, Virginia, United States

Renal Research - Gosford

Gosford, New South Wales, Australia

University Multiprofile Hospital for Active Treatment

Pleven, , Bulgaria

University Multiprofile Hospital for Active Treatment - Kaspela

Plovdiv, , Bulgaria

Medical Center "Hipokrat - N"

Plovdiv, , Bulgaria

Kidney Center - Medical Center

Varna, , Bulgaria

Multi-Profile Hospital for Active Treatment Sveta Anna - Varna

Varna, , Bulgaria

Bajai Szent Rokus Korhaz

Baja, , Hungary

Semmelweis Egyetem

Budapest, , Hungary

Debreceni Egyetem

Debrecen, , Hungary

Bugat Pal Korhaz

Gyöngyös, , Hungary

University of Pecs

Pécs, , Hungary

SCM Spolka z o.o

Krakow, , Poland

Provita Centrum Medyczne sp. z o.o.

Warsaw, , Poland

Hospital Universitari de Bellvitge (HUB)

Barcelona, , Spain

Hospital Universitario Fundacion Jimenez Diaz

Madrid, , Spain

T.R. Ministry of Health Ankara Training and Research Hospital (Internal Disease, Division of Nephrology)

Ankara, , Turkey (Türkiye)

Bezmialem Vakif Universitesi Tip Fakultesi Hastanesi

Fatih, , Turkey (Türkiye)

Istanbul Universitesi - Cerrahpasa Tip Fakultesi Hastanesi (IUCTFH)

Fatih, , Turkey (Türkiye)

Erciyes Universitesi Tip Fakultesi (Erciyes University Faculty of Medicine) (Internal Medicine; Nephrology)

Kayseri, , Turkey (Türkiye)

Salford Royal NHS Foundation Trust

Salford, , United Kingdom

Countries

United States; Australia; Bulgaria; Hungary; Poland; Spain; Turkey (Türkiye); United Kingdom

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

PA-ADPKD-301

Identifier Type: -

Identifier Source: org_study_id