Polycystic Kidney Disease, Adult
Conditions
Brief summary
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.
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.
Interventions
DRUGLixivaptan
Oral vasopressin V2 receptor antagonist
Sponsors
Centessa Pharmaceuticals plc
Palladio Biosciences
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Single group, open-label study
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 120 days (from Screening to the end of the Maintenance Treatment Period) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 120 days (from Screening to the end of the Maintenance Treatment Period) | 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. |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 140 days (from Screening to the end of the Follow-up Period) | Number of participants with TEAEs during the Lixivaptan Re-titration Period, the Maintenance Treatment Period, or the Follow-up Period. |
| Number of Participants With Potentially Clinically Important Clinical Laboratory Findings | 140 days (from Screening to the end of the Follow-up Period) | 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. |
| 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 | 120 days (from Screening to the end of the Maintenance Treatment Period) | 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. |
| Number of Participants With Potentially Clinically Important 12-lead Electrocardiogram (ECG) Findings | 140 days (from Screening to the end of the Follow-up Period) | 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). |
| Annualized Change in Estimated Glomerular Filtration Rate (eGFR) From Baseline to Final Assessment | 140 days (from Screening to the end of the Follow-up Period) | 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. |
| Number of Participants With Potentially Clinically Important Vital Signs Findings | 140 days (from Screening to the end of the Follow-up Period) | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Enrolled Participants All participants who were enrolled in this study were included in this group. | 0 |
| Total | 0 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Maintenance Treatment Period | Sponsor Termination of Study | 1 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 1 | 0 / 1 |
| other Total, other adverse events | 1 / 1 | 0 / 1 |
| serious Total, serious adverse events | 0 / 1 | 0 / 1 |
Outcome results
Primary
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.
Time frame: 120 days (from Screening to the end of the Maintenance Treatment Period)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| All Enrolled Participants | 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 | 0 Participants |
Secondary
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.
Time frame: 140 days (from Screening to the end of the Follow-up Period)
Population: The annualized change in eGRF is provided for the only participant enrolled at the time of early termination of the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| All Enrolled Participants | Annualized Change in Estimated Glomerular Filtration Rate (eGFR) From Baseline to Final Assessment | 14.6 mL/min/1.73m^2 | Standard Deviation 0 |
Secondary
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.
Time frame: 120 days (from Screening to the end of the Maintenance Treatment Period)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| All Enrolled Participants | 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 | 0 Participants |
Secondary
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.
Time frame: 120 days (from Screening to the end of the Maintenance Treatment Period)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| All Enrolled Participants | 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 | 0 Participants |
Secondary
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).
Time frame: 140 days (from Screening to the end of the Follow-up Period)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| All Enrolled Participants | Number of Participants With Potentially Clinically Important 12-lead Electrocardiogram (ECG) Findings | Lixivaptan Re-titration and Maintenance Treatment Periods | 0 Participants |
| All Enrolled Participants | Number of Participants With Potentially Clinically Important 12-lead Electrocardiogram (ECG) Findings | Follow-up Period | 0 Participants |
Secondary
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.
Time frame: 140 days (from Screening to the end of the Follow-up Period)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| All Enrolled Participants | Number of Participants With Potentially Clinically Important Clinical Laboratory Findings | Lixivaptan Re-titration and Maintenance Treatment Periods | 0 Participants |
| All Enrolled Participants | Number of Participants With Potentially Clinically Important Clinical Laboratory Findings | Follow-up Period | 0 Participants |
Secondary
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.
Time frame: 140 days (from Screening to the end of the Follow-up Period)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| All Enrolled Participants | Number of Participants With Potentially Clinically Important Vital Signs Findings | Lixivaptan Re-titration and Maintenance Treatment Periods | 0 Participants |
| All Enrolled Participants | Number of Participants With Potentially Clinically Important Vital Signs Findings | Follow-up Period | 0 Participants |
Secondary
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.
Time frame: 140 days (from Screening to the end of the Follow-up Period)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| All Enrolled Participants | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Follow-up Period | 0 Participants |
| All Enrolled Participants | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Lixivaptan Re-titration and Maintenance Treatment Periods | 1 Participants |