Efficacy and Safety of Lixivaptan in the Treatment of Autosomal Dominant Polycystic Kidney Disease
Condition: Autosomal Dominant Polycystic Kidney; ADPKD
MeSH terms: Arthrogryposis; Kidney Diseases; Polycystic Kidney Diseases; Polycystic Kidney, Autosomal Dominant
Intervention: Lixivaptan; Placebo
Intervention description: Oral vasopressin V2 receptor antagonist; Matching placebo
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: 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.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking description: Sponsor - identical appearing active and placebo capsules in Part 1; all active capsules in Part 2
Enrollment: 12.0
Sex: All
Minimum age: 18 Years
Maximum age: 60 Years
Healthy volunteers: No

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.
    

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.