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

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Brief Title

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

Official Title

A 2-Year, Phase 3 Study of the Efficacy and Safety of Lixivaptan in Participants With Autosomal Dominant Polycystic Kidney Disease Consisting of a 1-year Double-blind, Placebo-controlled, Randomized Phase and a 1-year Open-label Phase

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 renal 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 2000 participants with ADPKD will be screened in order to qualify the
      1200 individuals who will then be randomized to receive lixivaptan or placebo. Each
      participant has a 2/3 chance of receiving lixivaptan and a 1/3 chance of receiving placebo.
      After meeting entry criteria during screening, participants will begin receiving treatment
      with study drug. At some point during Part 1, all participants will receive placebo and all
      participants will receive lixivaptan. The dose will be adjusted to the highest level that is
      tolerated and that dose will be continued for the rest of Part 1. Similarly, at some point
      participants will be randomized to lixivaptan or placebo. Throughout Part 1 the study drug
      will look identical regardless of whether it is placebo or lixivaptan. After 58-59 weeks, the
      administration of study drug will be paused, and final eGFR assessments for Part 1 will be
      obtained during 3 follow-up visits starting over a period of 28 days.

      Part 2: All participants entering Part 1 will continue into Part 2 of the study and be
      treated with the active drug, lixivaptan, for an additional 54-56 weeks unless study drug was
      previously discontinued for a safety reason or a participant withdraws consent. At the end of
      that time, study drug will be discontinued, and final eGFR assessments for Part 2 will be
      obtained during 3 follow-up visits starting over a period of 28 days.
    

Study Phase

Phase 3

Study Type

Interventional


Primary Outcome

Estimated Glomerular Filtration Rate (eGFR) - Part 1

Secondary Outcome

 Serum alanine aminotransferase (ALT) levels

Condition

Polycystic Kidney Disease, Adult

Intervention

Lixivaptan

Study Arms / Comparison Groups

 Lixivaptan - Part 1 and Part 2
Description:  Lixivaptan capsules, 100-200 mg twice a day (BID)

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

1200

Start Date

October 28, 2021

Completion Date

April 2026

Primary Completion Date

February 2025

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 m2

          -  Body mass index (BMI) between 18 and 40 kg/m2

          -  Control of hypertension consistent with KDIGO guidelines without a diuretic

          -  Willing to practice acceptable methods of birth control (both males who have partners
             of child-bearing potential and females of childbearing potential)

        Exclusion Criteria:

          -  Known sensitivity or idiosyncratic reaction to any compound present in lixivaptan and
             related compounds.

          -  Hypovolemia or inability to perceive thirst

          -  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, venglustat, demeclocycline,
             or mammalian target of rapamycin (mTOR) kinase inhibitors (e.g. everolimus, sirolimus,
             etc.) 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 chronic diuretic use

          -  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, renal 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 electrocardiogram (ECG) findings that could pose a safety risk to the
             subject.

          -  Positive test results for hepatitis B surface antigen (HBsAg) or hepatitis C (HCV).

          -  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 since treatment
             inception.

          -  History of clinically significant drug or alcohol abuse in the past 2 years.

          -  Contraindication to or interference with MRI assessments.

          -  Malignancy within the past 5 years except for those not considered to affect
             participant survival.
      

Gender

All

Ages

18 Years - 60 Years

Accepts Healthy Volunteers

No

Contacts

Vicente Torres, MD, PhD, 267-609-7553, [email protected]

Location Countries

Canada

Location Countries

Canada

Administrative Informations


NCT ID

NCT04064346

Organization ID

PA-ADPKD-301


Responsible Party

Sponsor

Study Sponsor

Palladio Biosciences


Study Sponsor

Vicente Torres, MD, PhD, Principal Investigator, Mayo Clinic


Verification Date

November 2021