Safety of Lixivaptan in Subjects Previously Treated With Tolvaptan for Autosomal Dominant Polycystic Kidney Disease
Condition: Polycystic Kidney Disease, Adult; ADPKD
MeSH terms: Kidney Diseases; Polycystic Kidney Diseases; Polycystic Kidney, Autosomal Dominant
Intervention: Lixivaptan
Intervention description: Oral vasopressin V2 receptor antagonist
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Intervention model description: Open-label, single treatment group
Masking: None (Open Label)
Enrollment: 7.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No

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.
    

Eligibility criteria:

        Inclusion Criteria:

          -  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.

        Exclusion Criteria:

          -  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.

          -  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.

          -  ALT or aspartate aminotransferase (AST) values >1.5 x ULN during Screening/Baseline.

          -  Total bilirubin values >1.0 x ULN during Screening/Baseline.

          -  History of drug or alcohol abuse in the 2 years prior to Screening.

          -  Any malignancy within the 5 years prior to Screening except for basal cell carcinoma
             successfully treated with local therapy.

          -  Medical history or findings that preclude safe participation in the study or who are
             likely to be non-compliant with study procedures in the opinion of the Investigator or
             medical monitor.