Roll-over Study to Assess Safety of Lixivaptan in Participants With ADPKD Who Completed Study PA-ADPKD-303

PA-ADPKD-304: A Phase 3, Open-label, Roll-over Study to Assess Long-term Safety of Lixivaptan in Participants With Autosomal Dominant Polycystic Kidney Disease Who Completed Study PA-ADPKD-303: The ALERT Study

This is a Phase 3, open-label, roll-over study to demonstrate the continued hepatic and non-hepatic safety and renal efficacy of lixivaptan in participants with ADPKD who previously experienced abnormal liver chemistry test results while treated with tolvaptan, were permanently discontinued from the drug for that reason, and subsequently completed study PA-ADPKD-303, the open-label lead-in study with lixivaptan.

Study Overview

• Status: Terminated
• Conditions: Polycystic Kidney Disease, Adult
• Intervention / Treatment: Drug: Lixivaptan

Detailed Description

This is a Phase 3, open-label, roll-over study to demonstrate the continued hepatic and non-hepatic safety and renal efficacy of lixivaptan in participants with ADPKD who previously experienced abnormal liver chemistry test results while treated with tolvaptan that resulted in permanent discontinuation of tolvaptan for that reason, and subsequently completed study PA-ADPKD-303, the open-label lead-in study with lixivaptan.

Assessments completed during the final 4 visits of PA-ADPKD-303, the lead-in study, will serve as the screening and baseline assessments for this roll-over study. Evaluation of eligibility will be completed at Visit 1 of this study, following signing of informed consent. Participants satisfying all study entry criteria at Visit 1 will be considered enrolled following completion of all Visit 1 study procedures and will be dispensed lixivaptan treatment to start the Lixivaptan Re-titration Period (1 to 2 weeks). During the Lixivaptan Re-titration Period, participants will have their dose of lixivaptan re-established based on the dose they were receiving at the completion of the lead-in study. Participants will continue on lixivaptan treatment for up to 104 weeks during the Maintenance Treatment Period and will be assessed at a study visit every 12 weeks. In between the quarterly study visits, participants will be required to have blood drawn for liver chemistry determinations every 4 weeks. At the end of 104 weeks, lixivaptan treatment will be stopped, and participants will enter a 4-week Follow-up Period during which final assessments of safety and efficacy will be obtained over 3 visits during a 28-day period.

• Study Type: Interventional
• Enrollment (Actual): 1
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Bethlehem, Pennsylvania, United States, 18107
      • Northeast Clinical Research Center, LLC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Male or female participants with ADPKD who completed study PA-ADPKD-303
• Continued control of hypertension without the use of a diuretic
• Continued adherence to prohibitions on concomitant medications stated in the study PA-ADPKD-303 protocol
• 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:

• Any contraindication to continued treatment with lixivaptan
• 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
• Hypovolemia on physical examination at Screening

• The following laboratory results based on serum drawn at Visit 24 of PA-ADPKD-303:

  • Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) values >1.5 × ULN
  • Total bilirubin values >1.5 × ULN
• eGFR <20 mL/min/1.73 m^2 based on laboratory results from Visit 26 of PA-ADPKD-303
• A finding at Screening that precludes safe participation in the study or participants who are likely to be non-compliant with study procedures in the opinion of the Investigator or medical monitor

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Lixivaptan; Lixivaptan capsules 100-200mg twice daily	Drug: Lixivaptan; Oral vasopressin V2 receptor antagonist

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Who Develop Serum ALT Levels >3 × ULN During the Lixivaptan Re-titration or Maintenance Treatment Periods Assessed to be Related to Lixivaptan and Resulted in Discontinuation of Lixivaptan Treatment	Number of participants who develop serum alanine aminotransferase (ALT) levels >3 × the upper limit of normal (ULN) which are assessed by the independent Hepatic Events Review Committee (HERC) to be at least probably related to lixivaptan and resulted in discontinuation of lixivaptan treatment. The independent HERC, after reviewing demographic, medical and medication history, safety data and other relevant data of participants who develop liver abnormalities, will determine the probable causality for liver chemistry test abnormalities of concern and the relatedness to lixivaptan using the Drug-Induced Liver Injury Network probability criteria (Fontana et al., 2009). The normal range of ALT was defined as 0-55 U/L.	120 days (from Screening to the end of the Maintenance Treatment Period)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Who Develop Serum ALT Levels >5 x ULN During the Lixivaptan Re-titration or Maintenance Treatment Periods Assessed to be Related to Lixivaptan and Resulted in Discontinuation of Lixivaptan Treatment	Number of participants who develop serum ALT levels >5 × ULN which are assessed by the independent HERC to be at least probably related to lixivaptan and resulted in discontinuation of lixivaptan treatment. The independent HERC, after reviewing demographic, medical and medication history, safety data and other relevant data of participants who develop liver abnormalities, will determine the probable causality for liver chemistry test abnormalities of concern and the relatedness to lixivaptan using the Drug-Induced Liver Injury Network probability criteria (Fontana et al., 2009). The normal range of ALT was defined as 0-55 U/L.	120 days (from Screening to the end of the Maintenance Treatment Period)
Number of Participants Who Develop Serum ALT Values >3 × ULN During the Lixivaptan Re-titration or Maintenance Treatment Periods Assessed to be Related to Lixivaptan and Resulted in Dose Reduction of Lixivaptan Treatment	Number of participants who develop serum ALT levels >3 × ULN that were assessed by the independent HERC to be at least probably related to lixivaptan and resulted in dose reduction of lixivaptan treatment. The independent HERC, after reviewing demographic, medical and medication history, safety data and other relevant data of participants who develop liver abnormalities, will determine the probable causality for liver chemistry test abnormalities of concern and the relatedness to lixivaptan using the Drug-Induced Liver Injury Network probability criteria (Fontana et al., 2009). The normal range of ALT was defined as 0-55 U/L.	120 days (from Screening to the end of the Maintenance Treatment Period)
Number of Participants With Treatment-emergent Adverse Events (TEAEs)	Number of participants with TEAEs during the Lixivaptan Re-titration Period, the Maintenance Treatment Period, or the Follow-up Period.	140 days (from Screening to the end of the Follow-up Period)
Number of Participants With Potentially Clinically Important Clinical Laboratory Findings	Number of participants with clinical laboratory findings (non-hepatic clinical chemistry, hematology, and urinalysis) recorded during the Lixivaptan Re-titration Period, the Maintenance Treatment Period, or the Follow-up Period, and considered to be potentially clinically important.	140 days (from Screening to the end of the Follow-up Period)
Number of Participants With Potentially Clinically Important Vital Signs Findings	Number of participants with vital signs findings (heart rate, diastolic and systolic blood pressure, and weight) recorded during the Lixivaptan Re-titration Period, the Maintenance Treatment Period, or the Follow-up Period, and considered to be potentially clinically important.	140 days (from Screening to the end of the Follow-up Period)
Number of Participants With Potentially Clinically Important 12-lead Electrocardiogram (ECG) Findings	Number of participants with ECG findings recorded during the Lixivaptan Re-titration Period, the Maintenance Treatment Period, or the Follow-up Period, and considered to be potentially clinically important (defined as a QT interval corrected for heart rate according to Fridericia's formula [QTcF] ≥ 450 msec).	140 days (from Screening to the end of the Follow-up Period)
Annualized Change in Estimated Glomerular Filtration Rate (eGFR) From Baseline to Final Assessment	Baseline eGFR is defined as the mean of the 3 eGFR assessments obtained at Visits 25, 26 and 27 of study PA-ADPKD-303 (if any values are missing, the remaining values will be used to determine the baseline eGFR). The endpoint eGFR is defined as the mean of 3 eGFR assessments obtained during the Follow-up Period (if any values are missing, the remaining values will be used to determine the endpoint eGFR). The change in eGFR from Baseline to Final Assessment will be provided.	140 days (from Screening to the end of the Follow-up Period)

Collaborators and Investigators

• Sponsor: Palladio Biosciences
• Collaborators: Centessa Pharmaceuticals plc
• Investigators: Principal Investigator: Nelson Kopyt, DO, Northeast Clinical Research Center, LLC

Publications and helpful links

General Publications

• Fontana RJ, Watkins PB, Bonkovsky HL, Chalasani N, Davern T, Serrano J, Rochon J; DILIN Study Group. Drug-Induced Liver Injury Network (DILIN) prospective study: rationale, design and conduct. Drug Saf. 2009;32(1):55-68. doi: 10.2165/00002018-200932010-00005.

Study record dates

Study Major Dates

• Study Start (Actual): February 10, 2022
• Primary Completion (Actual): June 29, 2022
• Study Completion (Actual): July 29, 2022

Study Registration Dates

• First Submitted: January 7, 2022
• First Submitted That Met QC Criteria: January 7, 2022
• First Posted (Actual): January 26, 2022

Study Record Updates

• Last Update Posted (Actual): May 12, 2023
• Last Update Submitted That Met QC Criteria: April 17, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urologic Diseases; Congenital Abnormalities; Genetic Diseases, Inborn; Abnormalities, Multiple; Kidney Diseases, Cystic; Ciliopathies; Kidney Diseases; Polycystic Kidney Diseases; Polycystic Kidney, Autosomal Dominant
• Other Study ID Numbers: PA-ADPKD-304

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No