Safety of Lixivaptan in Subjects Previously Treated With Tolvaptan for Autosomal Dominant Polycystic Kidney Disease

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Brief Title

Safety of Lixivaptan in Subjects Previously Treated With Tolvaptan for Autosomal Dominant Polycystic Kidney Disease

Official Title

An Open-Label Study of Lixivaptan in Subjects With Autosomal Dominant Polycystic Kidney Disease Who Previously Experienced Abnormal Liver Chemistry Test Results While Receiving Tolvaptan: The ALERT Study

Brief Summary

      This is a Phase 3, open-label, repeat-dose study designed to assess liver safety, non-liver
      safety, and efficacy in subjects 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 subjects will be enrolled and treated with lixivaptan for
      52 weeks following titration to an optimal dose.
    

Detailed Description

      This is a Phase 3, open-label, repeat-dose study designed to assess liver safety, non-liver
      safety, and efficacy in subjects who previously experienced liver chemistry test
      abnormalities while treated with tolvaptan and were permanently discontinued from the drug
      for that reason. Up to 50 subjects will be enrolled. Evaluations will include frequent
      testing of liver chemistry (every week during the Baseline and Titration Periods and every 4
      weeks during the Maintenance Period), physical examinations, vital signs, safety labs (serum
      chemistry, hematology, urinalysis), estimated glomerular filtration rate (eGFR), urine
      specific gravity and osmolality determinations and trough serum concentration of lixivaptan.
      After meeting entry criteria during a 1-3 week Screening Period that can extend up to 8 weeks
      for medication adjustment, subjects will enter a 3 week no study treatment Baseline Period to
      obtain baseline measurements followed by a 3-6 week Titration Period during which lixivaptan
      administered twice daily (BID) will be titrated to a dose that is tolerated and results in a
      reduced trough urine specific gravity (or the maximum dose level). The minimum dose to enter
      the Maintenance Period is 100 mg BID. Treatment will continue for up to 52 weeks (12 months)
      after which study drug will be held, and final assessments obtained during the Follow-up
      Period of 4 weeks. The total study duration will be up to approximately 73 weeks (16.8
      months).
    

Study Phase

Phase 3

Study Type

Interventional


Primary Outcome

Abnormal ALT Values

Secondary Outcome

 Proportion of subjects reporting at least one adverse event

Condition

Polycystic Kidney Disease, Adult

Intervention

Lixivaptan

Study Arms / Comparison Groups

 Lixivaptan
Description:  Lixivaptan oral capsules, 100-200 mg twice daily

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

50

Start Date

September 2, 2020

Completion Date

November 2022

Primary Completion Date

October 2022

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.

          -  Baseline eGFR > 20 ml/min/1.73 m2.

          -  Body mass index (BMI) between 18 and 35 kg/m2 (inclusive) at the time of Screening.

          -  Documented history of:

               -  At least 2 elevated alanine aminotransferase (ALT) levels, 1 ALT level >2 times
                  (x) the upper limit of normal (ULN) and 1 ALT level >3 x ULN while the subject
                  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

               -  At least 2 elevated ALT levels, 1 ALT level >2 x the subject's stable baseline
                  level and 1 ALT level >3 x the subject's stable baseline level while the subject
                  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 tolvaptan 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
             subject) without the use of a diuretic in concert with Kidney Disease: Improving
             Global Outcomes (KDIGO) "Clinical Practice Guideline for the Management of Blood
             Pressure in Chronic Kidney Disease".

        Exclusion Criteria:

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

          -  Hypovolemia or inability to perceive thirst

          -  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.

          -  Prior use of tolvaptan within the past 3 months or until a previously elevated ALT
             level has returned to ≤1 x ULN.

          -  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 3 months

          -  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, transplanted 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.

          -  Clinically significant liver disease or impairment or active chronic hepatitis at
             Screening.

          -  Elevated baseline levels of serum ALT or total bilirubin.

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

Gender

All

Ages

18 Years - 65 Years

Accepts Healthy Volunteers

No

Contacts

, 267-609-7553, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT04152837

Organization ID

PA-ADPKD-303


Responsible Party

Sponsor

Study Sponsor

Palladio Biosciences


Study Sponsor

, , 


Verification Date

April 2021