Title
The ELiSA Study - Evaluation of Lixivaptan in Subjects With Autosomal Dominant Polycystic Kidney Disease
A Phase 2, Open-Label, Multi-Center Study to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of Lixivaptan in Subjects With Autosomal Dominant Polycystic Kidney Disease
Phase
Phase 2Lead Sponsor
Palladio BiosciencesStudy Type
InterventionalStatus
Completed Results PostedIndication/Condition
Autosomal Dominant Polycystic Kidney DiseaseIntervention/Treatment
LixivaptanStudy Participants
31This is a Phase 2, open-label, parallel-group, multiple dose study designed to evaluate the pharmacokinetics, pharmacodynamics, safety and tolerability of multiple doses of lixivaptan in Autosomal Dominant Polycystic Kidney Disease subjects with chronic kidney disease (CKD) in stages CKD1, CKD2 or CKD3.
Therapeutic interventions aimed at counterbalancing the effect of vasopressin and/or normalizing intracellular levels of cAMP may be effective in delaying disease progression in autosomal dominant polycystic kidney disease (ADPKD).
The primary objectives of this study in subjects with ADPKD are:
To characterize the safety and tolerability of lixivaptan following multiple doses in ADPKD subjects with relatively preserved kidney function (chronic kidney disease CKD1 and CKD2) and moderately impaired renal function (CKD3).
The secondary objectives of this study are:
To characterize the PK profile of lixivaptan and its major metabolites following multiple doses of lixivaptan in ADPKD subjects with relatively preserved kidney function (CKD1 and CKD2) and moderately impaired renal function (CKD3).
To characterize the pharmacodynamic effect of lixivaptan on urine output, urine osmolality, total kidney volume, serum vasopressin, and serum creatinine following multiple doses of lixivaptan in ADPKD subjects with relatively preserved kidney function (CKD1 and CKD2) and moderately impaired renal function (CKD3).
Oral low dose lixivaptan in participants with CKD1 or CKD2
Oral high dose lixivaptan in participants with CKD1 or CKD2
Oral high dose lixivaptan in participants with CKD3
Oral low dose lixivaptan in participants with CKD3
Inclusion Criteria: Male or female, between 18 and 65 years of age at the time of screening Estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m2 with eGFR calculated by the CKD EPI equation Diagnosed with ADPKD by modified Ravine criteria Considered by Investigator to be in good health relative to underlying CKD status and clinically stable with respect to underlying CKD Exclusion Criteria: Known sensitivity or idiosyncratic reaction to lixivaptan, its related compounds such as benzazepines (e.g., tolvaptan, conivaptan, benazepril, fenoldopam, or mirtazapine), or any compound listed as being present in the study formulation Women who are pregnant or breast feeding Subjects have taken tolvaptan, oral or intravenous antibiotics, or any investigational drug or used an investigational device within 30 days or 5 half-lives, whichever is longer, prior to first study dose Subject has a transplanted kidney, or absence of a kidney Subjects with clinically significant incontinence, overactive bladder, or urinary retention (e.g., benign prostatic hyperplasia) Subjects with clinically significant liver disease, or clinically significant liver function abnormalities or serology other than that expected for ADPKD with cystic liver disease at baseline Subjects with any clinically significant concomitant disease or condition other than ADPKD (including treatment for such conditions) that, in the opinion of the Investigator, could either interfere with the study drug or pose an unacceptable risk to the subject
| Event Type | Organ System | Event Term | High Dose Lixivaptan / CKD1 or CKD2 | Low Dose Lixivaptan / CKD1 or CKD2 | High Dose Lixivaptan / CKD3 | Low Dose Lixivaptan / CKD3 |
|---|
The number of study participants who experience clinically meaningful laboratory findings, relating to clinical chemistry, hematology, and urinalysis, during the study will be counted and summarized by cohort.
The pharmacokinetic parameter Cmax, the highest concentration of WAY-141624 measured in plasma after multiple doses of drug, will be calculated from the observed concentration of WAY-141624 and summarized by cohort.
The pharmacokinetic parameter Cmax, the highest concentration of WAY-138451 measured in plasma after multiple doses of drug, will be calculated from the observed concentration of WAY-138451 and summarized by cohort.
The pharmacokinetic parameter Cmax, the highest concentration of WAY-138758 measured in plasma after multiple doses of drug, will be calculated from the observed concentration of WAY-138758 and summarized by cohort.
The pharmacokinetic parameter tmax, the time taken to reach the highest concentration of lixivaptan in plasma after multiple doses of drug, will be calculated from the observed concentration of lixivaptan and summarized by cohort.
The pharmacokinetic parameter tmax, the time taken to reach the highest concentration of WAY-141624 in plasma after multiple doses of drug, will be calculated from the observed concentration of WAY-141624 and summarized by cohort.
The pharmacokinetic parameter tmax, the time taken to reach the highest concentration of WAY-138451 in plasma after multiple doses of drug, will be calculated from the observed concentration of WAY-138451 and summarized by cohort.
The pharmacokinetic parameter tmax, the time taken to reach the highest concentration of WAY-138758 in plasma after multiple doses of drug, will be calculated from the observed concentration of WAY-138758 and summarized by cohort.
The pharmacokinetic parameter AUC(0-last) for lixivaptan will be calculated using the linear trapezoidal rule for increasing values and the log trapezoidal rule for decreasing values, summarized by cohort.
The pharmacokinetic parameter AUC(0-last) for WAY-141624 will be calculated using the linear trapezoidal rule for increasing values and the log trapezoidal rule for decreasing values and summarized by cohort.
The pharmacokinetic parameter AUC(0-last) for WAY-138451 will be calculated using the linear trapezoidal rule for increasing values and the log trapezoidal rule for decreasing values and summarized by cohort.
The pharmacokinetic parameter AUC(0-last) for WAY-138758 will be calculated using the linear trapezoidal rule for increasing values and the log trapezoidal rule for decreasing values and summarized by cohort.
The pharmacokinetic parameter AUC(0-inf) for lixivaptan will be calculated using the linear trapezoidal rule for increasing values, the log trapezoidal rule for decreasing values, and extrapolated to infinity by addition of the last quantifiable observed concentration divided by the elimination rate constant and summarized by cohort.
The pharmacokinetic parameter AUC(0-inf) for WAY-141624 will be calculated using the linear trapezoidal rule for increasing values, the log trapezoidal rule for decreasing values, and extrapolated to infinity by addition of the last quantifiable observed concentration divided by the elimination rate constant and summarized by cohort.
The pharmacokinetic parameter AUC(0-inf) for WAY-138451 will be calculated using the linear trapezoidal rule for increasing values, the log trapezoidal rule for decreasing values, and extrapolated to infinity by addition of the last quantifiable observed concentration divided by the elimination rate constant and summarized by cohort.
The pharmacokinetic parameter AUC(0-inf) for WAY-138758 will be calculated using the linear trapezoidal rule for increasing values, the log trapezoidal rule for decreasing values, and extrapolated to infinity by addition of the last quantifiable observed concentration divided by the elimination rate constant and summarized by cohort.
The pharmacokinetic parameter t1/2 for lixivaptan, determined as ln2/apparent terminal elimination rate constant, will be calculated and summarized by cohort.
The pharmacokinetic parameter t1/2 for WAY-141624, determined as ln2/apparent terminal elimination rate constant, will be calculated and summarized by cohort.
The pharmacokinetic parameter t1/2 for WAY-138451, determined as ln2/apparent terminal elimination rate constant, will be calculated and summarized by cohort.
The pharmacokinetic parameter t1/2 for WAY-138758, determined as ln2/apparent terminal elimination rate constant, will be calculated and summarized by cohort.
The pharmacokinetic parameter λZ for lixivaptan will be determined by linear regression of the terminal points of the log-linear concentration-time curve. The Best Fit method utilized by WinNonlin will be used to identify the terminal linear phase of the concentration-time profile, with visual assessment and adjustment of the selected data points by the PK scientist if warranted. A minimum of 3 data points will be used for determination. Results will be summarized by cohort.
The pharmacokinetic parameter λZ for WAY-141624 will be determined by linear regression of the terminal points of the log-linear concentration-time curve. The Best Fit method utilized by WinNonlin will be used to identify the terminal linear phase of the concentration-time profile, with visual assessment and adjustment of the selected data points by the PK scientist if warranted. A minimum of 3 data points will be used for determination. Results will be summarized by cohort.
The pharmacokinetic parameter λZ for WAY-138451 will be determined by linear regression of the terminal points of the log-linear concentration-time curve. The Best Fit method utilized by WinNonlin will be used to identify the terminal linear phase of the concentration-time profile, with visual assessment and adjustment of the selected data points by the PK scientist if warranted. A minimum of 3 data points will be used for determination. Results will be summarized by cohort.
The pharmacokinetic parameter λZ for WAY-138758 will be determined by linear regression of the terminal points of the log-linear concentration-time curve. The Best Fit method utilized by WinNonlin will be used to identify the terminal linear phase of the concentration-time profile, with visual assessment and adjustment of the selected data points by the PK scientist if warranted. A minimum of 3 data points will be used for determination. Results will be summarized by cohort.
The pharmacokinetic parameter CL/F for lixivaptan, calculated as: Day 1 AM: dose divided by AUC(0-inf), or Day 7 AM: dose divided by AUC(0-last), will be summarized by cohort.
The pharmacokinetic parameter VZ/F for lixivaptan, calculated as CL/F divided by λZ, will be summarized by cohort.
The pharmacokinetic parameter RCmax for lixivaptan, calculated as [Cmax on Day 7]/[Cmax on Day 1], will be summarized by cohort.
The pharmacokinetic parameter RAUC(0-last) for lixivaptan, calculated as [AUC(0-last) on Day 7]/[AUC(0-last) on Day 1], will be summarized by cohort.
The pharmacokinetic parameter AUC(0-14) for lixivaptan will be calculated using the linear trapezoidal rule for increasing values and the log trapezoidal rule for decreasing values. The actual elapsed time for the nominal 14-hour sample will be used for the calculation. Results will be summarized by cohort.
The pharmacokinetic parameter AUC(0-14) for WAY-141624 will be calculated using the linear trapezoidal rule for increasing values and the log trapezoidal rule for decreasing values. The actual elapsed time for the nominal 14-hour sample will be used for the calculation. Results will be summarized by cohort.
The pharmacokinetic parameter AUC(0-14) for WAY-138451 will be calculated using the linear trapezoidal rule for increasing values and the log trapezoidal rule for decreasing values. The actual elapsed time for the nominal 14-hour sample will be used for the calculation. Results will be summarized by cohort.
The pharmacokinetic parameter AUC(0-14) for WAY-138758 will be calculated using the linear trapezoidal rule for increasing values and the log trapezoidal rule for decreasing values. The actual elapsed time for the nominal 14-hour sample will be used for the calculation. Results will be summarized by cohort.
The pharmacokinetic parameter MRCmax for WAY-141624 will be calculated and corrected for molecular weight of WAY-141624 and parent lixivaptan as: (Cmax,m/Cmax,p)(MWp/MWm), where Cmax,m and MWm are Cmax and molecular weight of WAY-141624, respectively, and Cmax,p and MWp are Cmax and molecular weight of parent lixivaptan, respectively. The following molecular weights are to be used in all MRCmax calculations: lixivaptan: 473.93 g/mol WAY-141624: 505.95 g/mol Results will be summarized by cohort.
The pharmacokinetic parameter MRCmax for WAY-138451 will be calculated and corrected for molecular weight of WAY-138451 and parent lixivaptan as: (Cmax,m/Cmax,p)(MWp/MWm), where Cmax,m and MWm are Cmax and molecular weight of WAY-138451, respectively, and Cmax,p and MWp are Cmax and molecular weight of parent lixivaptan, respectively. The following molecular weights are to be used in all MRCmax calculations: lixivaptan: 473.93 g/mol WAY-138451: 488.92 g/mol Results will be summarized by cohort.
The pharmacokinetic parameter MRCmax for WAY-138758 will be calculated and corrected for molecular weight of WAY-138758 and parent lixivaptan as: (Cmax,m/Cmax,p)(MWp/MWm), where Cmax,m and MWm are Cmax and molecular weight of WAY-138758, respectively, and Cmax,p and MWp are Cmax and molecular weight of parent lixivaptan, respectively. The following molecular weights are to be used in all MRCmax calculations: lixivaptan: 473.93 g/mol WAY-138758: 426.82 g/mol Results will be summarized by cohort.
The pharmacokinetic parameter MRAUC(0-14) for WAY-141624 will be calculated and corrected for molecular weight of WAY-141624 and parent lixivaptan as: (AUC(0-14),m/AUC(0-14),p)(MWp/MWm), where AUC(0-14),m and MWm are AUC(0-14) and molecular weight of WAY-141624, respectively, and AUC(0-14),p and MWp are AUC(0-14) and molecular weight of parent lixivaptan, respectively. The following molecular weights are to be used in all MRAUC(0-14) calculations: lixivaptan: 473.93 g/mol WAY-141624: 505.95 g/mol Results will be summarized by cohort.
The pharmacokinetic parameter MRAUC(0-14) for WAY-138451 will be calculated and corrected for molecular weight of WAY-138451 and parent lixivaptan as: (AUC(0-14),m/AUC(0-14),p)(MWp/MWm), where AUC(0-14),m and MWm are AUC(0-14) and molecular weight of WAY-138451, respectively, and AUC(0-14),p and MWp are AUC(0-14) and molecular weight of parent lixivaptan, respectively. The following molecular weights are to be used in all MRAUC(0-14) calculations: lixivaptan: 473.93 g/mol WAY-138451: 488.92 g/mol Results will be summarized by cohort.
The pharmacokinetic parameter MRAUC(0-14) for WAY-138758 will be calculated and corrected for molecular weight of WAY-138758 and parent lixivaptan as: (AUC(0-14),m/AUC(0-14),p)(MWp/MWm), where AUC(0-14),m and MWm are AUC(0-14) and molecular weight of WAY-138758, respectively, and AUC(0-14),p and MWp are AUC(0-14) and molecular weight of parent lixivaptan, respectively. The following molecular weights are to be used in all MRAUC(0-14) calculations: lixivaptan: 473.93 g/mol WAY-138758: 426.82 g/mol Results will be summarized by cohort.
The number of study participants who experience treatment-emergent adverse events during the study will be counted and summarized by dose level.
The number of study participants who experience clinically significant physical examination findings during the study will be counted and summarized by cohort.
The number of study participants who experience vital signs (systolic blood pressure, diastolic blood pressure, pulse rate, respiratory rate, and body temperature) meeting the predefined markedly abnormal criteria during the study will be counted and summarized by cohort.
The number of study participants who experience 12-lead electrocardiograms meeting the predefined markedly abnormal criteria during the study will be counted and summarized by cohort.
The pharmacokinetic parameter Cmax, the highest concentration of lixivaptan measured in plasma after multiple doses of drug, will be calculated from the observed concentration of lixivaptan and summarized by cohort.
The number of study participants who answered "yes" to the following questions at Day 7 will be counted and summarized by dose level: Could you tolerate taking this dose of study drug for the next 12 months? Did the study drug make you feel thirsty more often than usual? Did the study drug make you go to the bathroom (urinate) more often than usual during the night? Would you be comfortable recommending the study drug to another patient with your kidney condition?
The number of study participants who answered "not at all" and "slightly" to the following question at Day 7 will be measured: • If the study drug made you feel thirsty more often than usual, were you bothered by it?
The number of study participants who answered "not at all" and "slightly" to the following question at Day 7 will be measured: • If the study drug made you go to the bathroom (urinate) more often than usual during the night, did it bother you?
Changes from baseline in spot urine measurements for samples taken at 0, 1, 2, 4, 6, 9, 10, 11, 12, 14, and 24 hours after the Day 1 and Day 7 doses will be summarized by cohort. The baseline value for each time point after first administration of study drug is the value observed at the corresponding time point on Day -1 (or Day 1 for the AM predose assessment only).
Changes from baseline of eGFR derived from the serum creatinine concentrations for samples taken at Day 1 (postdose), Day 2, Day 7, Day 8, and Day 35 will summarized by cohort
Changes from baseline (Day -1) in total kidney volume, measured by abdominal MRI on Day 7 and Day 35, will be summarized by cohort.
Changes from baseline (Day -1) in liver volume, measured by abdominal MRI on Day 7 and Day 35, will be summarized by cohort.
Changes from baseline (Day -1) in plasma copeptin, a marker for circulating vasopressin, at Day 2, Day 7, and Day 35 will be summarized by cohort.
Changes from baseline in serum creatinine for samples taken at Day 2, Day 7, Day 8, and Day 35 will be summarized by cohort.
Changes from baseline in BUN for samples taken at Day 2, Day 7, Day 8, and Day 35 will be summarized by cohort.
Changes from baseline in 24-hour urine output for samples taken on Day 1 and Day 7 will be summarized by cohort. The baseline value was the last value observed prior to first administration of study drug on Day -1.
The pharmacokinetic parameter VZ/F24H for lixivaptan, calculated as CL/F24H divided by Day 7 PM λZ, will be summarized by cohort. VZ/F24H was not specified in the statistical analysis plan and was calculated for the combined 24-hour period including AM and PM dosing intervals on Day 7. This parameter replaces VZ/F initially planned for the Day 7 AM dose.
