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

  • STATUS
    Recruiting
  • End date
    Nov 3, 2022
  • participants needed
    50
  • sponsor
    Palladio Biosciences
Updated on 3 May 2021
body mass index
hypertension
chronic kidney disease
renal disease
tolvaptan

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.

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).

Details
Condition Polycystic Kidney, Autosomal Dominant
Treatment Lixivaptan
Clinical Study IdentifierNCT04152837
SponsorPalladio Biosciences
Last Modified on3 May 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Is your age between 18 yrs and 65 yrs?
Gender: Male or Female
Do you have Polycystic Kidney, Autosomal Dominant?
Do you have any of these conditions: Do you have Polycystic Kidney, Autosomal Dominant??
Do you have any of these conditions: Do you have Polycystic Kidney, Autosomal Dominant??
Do you have any of these conditions: Do you have Polycystic Kidney, Autosomal Dominant??
Do you have any of these conditions: Do you have Polycystic Kidney, Autosomal Dominant??
Do you have any of these conditions: Do you have Polycystic Kidney, Autosomal Dominant??
Do you have any of these conditions: Do you have Polycystic Kidney, Autosomal Dominant??
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
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