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

NCT04064346 | Terminated Phase 3 Results DMC FDA Drug

• 1 other identifier: PA-ADPKD-301
• Study Type: interventional
• Target: 12
• Locations: 8 countries
• Sites: 43

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.

Conditions

Autosomal Dominant Polycystic Kidney; ADPKD

Outcome Measures

Primary Outcomes (2)

• Annualized Change in Estimated Glomerular Filtration Rate (eGFR) - Part 1

  The annualized change in eGFR will be calculated from the Chronic Kidney Disease Epidemiology Collaboration eGFR creatinine equation refit without the race variable (CKD-EPIcr\_R) equation for serum creatinine from baseline (mean of 3 eGFR determinations obtained during Screening and Placebo Run-in Periods \[Visits 1a/1b (if required), Visit 2, and Visit 3\]) to final assessment (mean of 3 eGFR determinations obtained during Follow-up Period I or, for participants who discontinue treatment prior to Visit 22, during the Follow-up Period 8 to 28 days following study drug treatment discontinuation).

  Baseline to the end of Follow-up Period I (up to 71 weeks)

• Annualized Change in Estimated Glomerular Filtration Rate (eGFR) - Part 2

  The annualized change in eGFR will be calculated from the CKD-EPIcr\_R equation for serum creatinine from baseline (mean of 3 eGFR determinations obtained during obtained during Follow-up Period I) to final assessment (mean of 3 eGFR determinations obtained during Follow-up Period II or, for participants who discontinue treatment prior to Visit 43, during the Follow-up Period 8 to 28 days following study drug treatment discontinuation).

  Baseline to the end of Follow-up Period II (up to 64 weeks)

Secondary Outcomes (18)

• Number of Participants With Serum Alanine Aminotransferase (ALT) Levels >3 × the Upper Limit of Normal (ULN) - Part 1

  From the end of the Single-blind Lixivaptan Titration Period to the end of Follow-up Period I (maximum of 102 days)

• Number of Participants With Serum ALT Levels >3 × the ULN - Part 2

  Duration of the Lixivaptan Re-titration Period and the Maintenance Treatment Period (56 weeks) and Follow-up Period II (4 weeks)

• eGFR Slope - Part 1

  Baseline to the end of Double-blind Randomized Treatment Period (up to 67 weeks), with changes from baseline calculated every 4 weeks during the Double-blind Randomized Treatment Period

• eGFR Slope - Part 2

  Baseline to the end of the Maintenance Treatment Period (up to 60 weeks), with changes from baseline calculated every 4 weeks during the Maintenance Treatment Period

• Height-adjusted Total Kidney Volume (htTKV) - Part 1

  Baseline to the end of Follow-up Period I (up to 71 weeks)

Study Arms (2)

Lixivaptan

EXPERIMENTAL

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

Drug: Lixivaptan

Placebo

PLACEBO COMPARATOR

Matching placebo capsules BID

Drug: Placebo

Interventions

Lixivaptan DRUG

Oral vasopressin V2 receptor antagonist

Lixivaptan

Placebo DRUG

Matching placebo

Placebo

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Palladio Biosciences: lead
• Centessa Pharmaceuticals plc: collaborator

Study Sites (43)

Nephrology Associates, PC - Greystone

Hoover, Alabama, 35242, United States

Location

Nephrology Consultants, LLC

Huntsville, Alabama, 35805-4104, United States

Location

Arizona Kidney Disease & Hypertension Center - Scottsdale / Pima

Scottsdale, Arizona, 85258, United States

Location

JEM Research Institute

Atlantis, Florida, 33462, United States

Location

Elixia at Florida Kidney Physicians - Southeast

Fort Lauderdale, Florida, 33308, United States

Location

Qway Research

Hialeah, Florida, 33010, United States

Location

South Florida Nephrology Associates PA

Lauderdale Lakes, Florida, 33313-1600, United States

Location

Total Research Group, LLC

Miami, Florida, 33126, United States

Location

Innovation Medical Research Center, Inc

Palmetto Bay, Florida, 33157, United States

Location

Florida Kidney Physicians - Tampa

Tampa, Florida, 33615, United States

Location

Clinical Site Partners, LLC

Winter Park, Florida, 32789, United States

Location

Tufts Medical Center, Inc,

Boston, Massachusetts, 02111, United States

Location

St Clair Nephrology Research, LLC

Roseville, Michigan, 48066, United States

Location

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

Clinical Research Consultants, LLC

Kansas City, Missouri, 64111, United States

Location

Angel City Research, Inc

Morrisville, North Carolina, 27560, United States

Location

Northeast Clinical Research Center, LLC

Bethlehem, Pennsylvania, 18107, United States

Location

Brown Medicine - Brown Physicians Patient Center

Riverside, Rhode Island, 02915-2235, United States

Location

Knoxville Kidney Center LLC

Knoxville, Tennessee, 37923, United States

Location

Prolato Clinical Research Center (PCRC)

Houston, Texas, 77054-2854, United States

Location

Clinical Advancement Center, PLLC

San Antonio, Texas, 78212, United States

Location

Utah Kidney Research Institute

Salt Lake City, Utah, 84115, United States

Location

Nephrology Associates of Northern Virginia, Inc

Fairfax, Virginia, 22033, United States

Location

Renal Research - Gosford

Gosford, New South Wales, 2250, Australia

Location

University Multiprofile Hospital for Active Treatment

Pleven, 5809, Bulgaria

Location

University Multiprofile Hospital for Active Treatment - Kaspela

Plovdiv, 4001, Bulgaria

Location

Medical Center "Hipokrat - N"

Plovdiv, 4003, Bulgaria

Location

Kidney Center - Medical Center

Varna, 9000, Bulgaria

Location

Multi-Profile Hospital for Active Treatment Sveta Anna - Varna

Varna, 9002, Bulgaria

Location

Bajai Szent Rokus Korhaz

Baja, 6500, Hungary

Location

Semmelweis Egyetem

Budapest, 1083, Hungary

Location

Debreceni Egyetem

Debrecen, 4032, Hungary

Location

Bugat Pal Korhaz

Gyöngyös, 3200, Hungary

Location

University of Pecs

Pécs, 7622, Hungary

Location

SCM Spolka z o.o

Krakow, 31-559, Poland

Location

Provita Centrum Medyczne sp. z o.o.

Warsaw, 02-647, Poland

Location

Hospital Universitari de Bellvitge (HUB)

Barcelona, 8097, Spain

Location

Hospital Universitario Fundacion Jimenez Diaz

Madrid, 28040, Spain

Location

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

Ankara, 6340, Turkey (Türkiye)

Location

Bezmialem Vakif Universitesi Tip Fakultesi Hastanesi

Fatih, 34093, Turkey (Türkiye)

Location

Istanbul Universitesi - Cerrahpasa Tip Fakultesi Hastanesi (IUCTFH)

Fatih, 34098, Turkey (Türkiye)

Location

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

Kayseri, 38039, Turkey (Türkiye)

Location

Salford Royal NHS Foundation Trust

Salford, M6 8HD, United Kingdom

Location

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

Results Point of Contact

• Title: Milena Kanova
• Organization: Centessa Pharmaceuticals

milena.kanova@centessa.com

+44 7780 430583

Study Officials

• Vicente Torres, MD, PhD

  Mayo Clinic

  PRINCIPAL INVESTIGATOR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Sponsor - identical appearing active and placebo capsules in Part 1; all active capsules in Part 2
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Part 1: 1-week, single-blind, Placebo Run-in Period, followed by a 5- to 6-week single-blind Lixivaptan Titration Period, followed by a 52-week Double-blind, Randomized Treatment Period, with 2/3 participants randomized to receive lixivaptan, and 1/3 participants randomized to receive placebo (the parallel assignment part of the study). There will be a 28-day off-treatment period during which final assessments will be obtained 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 double-blind study drug. Part 2: 2- to 4-week Lixivaptan Re-titration Period, followed by a 52-week Maintenance Treatment Period. There will be a 28-day off-treatment period during which final assessments will be obtained over 3 visits starting on the 8th day after the last dose of study drug through the 28th day after the last dose of study drug.

Study Record Dates

• First Submitted: August 19, 2019
• First Posted: August 21, 2019
• Study Start: October 28, 2021
• Primary Completion: August 3, 2022
• Study Completion: August 3, 2022
• Last Updated: February 6, 2023
• Results First Posted: February 6, 2023

Record last verified: 2023-01

Data Sharing

• IPD Sharing: Will not share

Locations

TU (4); US (23); PL (2); BU (5); HU (5); AU (1); ES (2); GB (1)