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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04152837
Recruitment Status : Recruiting
First Posted : November 5, 2019
Last Update Posted : September 23, 2020
Sponsor:
Information provided by (Responsible Party):
Palladio Biosciences

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.

Condition or disease Intervention/treatment Phase
Polycystic Kidney Disease, Adult Drug: Lixivaptan Phase 3

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).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: Open-label, single treatment group
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : September 2, 2020
Estimated Primary Completion Date : October 2022
Estimated Study Completion Date : November 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Kidney Diseases

Arm Intervention/treatment
Experimental: Lixivaptan
Lixivaptan oral capsules, 100-200 mg twice daily
Drug: Lixivaptan
Oral vasopressin V2 antagonist




Primary Outcome Measures :
  1. Abnormal ALT Values [ Time Frame: 52 weeks ]
    Proportion of subjects who develop alanine aminotransferase (ALT) levels >3 x ULN adjudicated to be related to lixivaptan and resulted in discontinuation of the study drug


Secondary Outcome Measures :
  1. Proportion of subjects reporting at least one adverse event [ Time Frame: 52 weeks ]
    Number and percent of subjects who develop at least 1 adverse event during treatment

  2. Abnormal Total Bilirubin Values [ Time Frame: 52 weeks ]
    Proportion of subjects who develop total bilirubin levels >2 x ULN during treatment with lixivaptan

  3. Renal Function [ Time Frame: 52 weeks ]
    Change from baseline in estimated glomerular filtration rate (eGFR)

  4. Systolic Blood Pressure (SBP) [ Time Frame: 52 weeks ]
    Change from baseline in SBP

  5. Serum Sodium Concentration [ Time Frame: 52 weeks ]
    Change from baseline in serum sodium concentration



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04152837


Contacts
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Contact: Neil Shusterman, MD 267-609-7553 ClinicalTrials@palladiobio.com
Contact: Elaine Richardson 267-609-7553 ClinicalTrials@palladiobio.com

Locations
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United States, Michigan
St. Clair Nephrology Recruiting
Roseville, Michigan, United States, 48066
Contact: Rosemarie Henschel    313-432-6273    RHenschel@scsp.net   
Principal Investigator: Marjana Dimitrijevic, MD         
United States, North Carolina
Brookview Hills Research Associates, LLC Recruiting
Winston-Salem, North Carolina, United States, 27103
Contact: Cindy Vanhoy    336-245-6320    CVanhoy@brookviewhills.com   
Principal Investigator: Gregory Greenwood, MD         
United States, Pennsylvania
Northeast Clinical Research Center, LLC Recruiting
Bethlehem, Pennsylvania, United States, 18107
Contact: Stephanie Hanzl       steph.hanzl@necresearch.org   
Principal Investigator: Nelson Kopyt, DO         
United States, Virginia
Nephrology Associates of Northern Virginia, Inc. Recruiting
Fairfax, Virginia, United States, 22033
Contact: Musirah Khan    703-961-0565 ext 224    musirah.khan@nanvonline.com   
Principal Investigator: Amadshah Mirkhel, MD         
Sponsors and Collaborators
Palladio Biosciences
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Responsible Party: Palladio Biosciences
ClinicalTrials.gov Identifier: NCT04152837    
Other Study ID Numbers: PA-ADPKD-303
First Posted: November 5, 2019    Key Record Dates
Last Update Posted: September 23, 2020
Last Verified: September 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Kidney Diseases
Polycystic Kidney Diseases
Polycystic Kidney, Autosomal Dominant
Urologic Diseases
Kidney Diseases, Cystic
Abnormalities, Multiple
Congenital Abnormalities
Ciliopathies
Genetic Diseases, Inborn