NCT03487913|CompletedPhase 2ResultsFDA Drug

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

Palladio Biosciences ClinicalTrials.gov

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1 other identifier

PA-102

Study Type

interventional

Target

Locations

1 country

Sites

Timeline

RegisteredApr 2018

StartedSep 2018

CompletionFeb 2020

Brief Summary

This 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.

Trial Health

On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment

participants targeted

Target at P25-P50 for phase_2

Timeline

Completed

Started Sep 2018

Shorter than P25 for phase_2

Geographic Reach

1 country

13 active sites

Status

completed

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

1.4 years study duration

First Submitted

Initial submission to the registry

March 16, 2018

Completed

19 days until next milestone

First Posted

Study publicly available on registry

April 4, 2018

Completed

5 months until next milestone

Study Start

First participant enrolled

September 14, 2018

Completed

1.2 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

December 2, 2019

Completed

2 months until next milestone

Study Completion

Last participant's last visit for all outcomes

February 11, 2020

Completed

2.8 years until next milestone

Results Posted

Study results publicly available

December 5, 2022

Completed

Last Updated

December 5, 2022

Status Verified

November 1, 2022

Enrollment Period

1.2 years

First QC Date

March 16, 2018

Results QC Date

September 28, 2022

Last Update Submit

November 8, 2022

Conditions

Autosomal Dominant Polycystic Kidney Disease

Outcome Measures

Primary Outcomes (46)

Maximum Observed Plasma Concentration (Cmax) of Lixivaptan in ADPKD Patients
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.
Day 1 (am and pm) and Day 7 (am and pm)
Maximum Observed Plasma Concentration (Cmax) of WAY-141624 in ADPKD Patients
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.
Day 1 (am and pm) and Day 7 (am and pm)
Maximum Observed Plasma Concentration (Cmax) of WAY-138451 in ADPKD Patients
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.
Day 1 (am and pm) and Day 7 (am and pm)
Maximum Observed Plasma Concentration (Cmax) of WAY-138758 in ADPKD Patients
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.
Day 1 (am and pm) and Day 7 (am and pm)
Time to Reach Maximum Plasma Concentration (Tmax) of Lixivaptan in ADPKD Patients
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.
Day 1 (am and pm) and Day 7 (am and pm)
Time to Reach Maximum Plasma Concentration (Tmax) of WAY-141624 in ADPKD Patients
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.
Day 1 (am and pm) and Day 7 (am and pm)
Time to Reach Maximum Plasma Concentration (Tmax) of WAY-138451 in ADPKD Patients
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.
Day 1 (am and pm) and Day 7 (am and pm)
Time to Reach Maximum Plasma Concentration (Tmax) of WAY-138758 in ADPKD Patients
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.
Day 1 (am and pm) and Day 7 (am and pm)
Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of Lixivaptan in ADPKD Patients
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.
Day 1 (am and pm) and Day 7 (am and pm)
Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-141624 in ADPKD Patients
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.
Day 1 (am and pm) and Day 7 (am and pm)
Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-138451 in ADPKD Patients
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.
Day 1 (am and pm) and Day 7 (am and pm)
Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-138758 in ADPKD Patients
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.
Day 1 (am and pm) and Day 7 (am and pm)
Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC[0-inf]) of Lixivaptan in ADPKD Patients
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.
Day 1 (am)
Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC[0-inf]) of WAY-141624 in ADPKD Patients
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.
Day 1 (am)
Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC[0-inf]) of WAY-138451 in ADPKD Patients
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.
Day 1 (am)
Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC[0-inf]) of WAY-138758 in ADPKD Patients
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.
Day 1 (am)
Terminal Elimination Phase Half-life (t1/2) of Lixivaptan in ADPKD Patients
The pharmacokinetic parameter t1/2 for lixivaptan, determined as ln2/apparent terminal elimination rate constant, will be calculated and summarized by cohort.
Day 1 (am) and Day 7 (pm)
Terminal Elimination Phase Half-life (t1/2) of WAY-141624 in ADPKD Patients
The pharmacokinetic parameter t1/2 for WAY-141624, determined as ln2/apparent terminal elimination rate constant, will be calculated and summarized by cohort.
Day 1 (am) and Day 7 (pm)
Terminal Elimination Phase Half-life (t1/2) of WAY-138451 in ADPKD Patients
The pharmacokinetic parameter t1/2 for WAY-138451, determined as ln2/apparent terminal elimination rate constant, will be calculated and summarized by cohort.
Day 1 (am) and Day 7 (pm)
Terminal Elimination Phase Half-life (t1/2) of WAY-138758 in ADPKD Patients
The pharmacokinetic parameter t1/2 for WAY-138758, determined as ln2/apparent terminal elimination rate constant, will be calculated and summarized by cohort.
Day 1 (am) and Day 7 (pm)
Apparent Terminal Elimination Rate Constant (λZ) of Lixivaptan in ADPKD Patients
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.
Day 1 (am) and Day 7 (pm)
Apparent Terminal Elimination Rate Constant (λZ) of WAY-141624 in ADPKD Patients
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.
Day 1 (am) and Day 7 (pm)
Apparent Terminal Elimination Rate Constant (λZ) of WAY-138451 in ADPKD Patients
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.
Day 1 (am) and Day 7 (pm)
Apparent Terminal Elimination Rate Constant (λZ) of WAY-138758 in ADPKD Patients
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.
Day 1 (am) and Day 7 (pm)
Apparent Systemic Clearance After Extravascular Dosing (CL/F) of Lixivaptan in ADPKD Patients
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.
Day 1 (am) and Day 7 (am)
Volume of Distribution After Extravascular Dosing (VZ/F) of Lixivaptan in ADPKD Patients
The pharmacokinetic parameter VZ/F for lixivaptan, calculated as CL/F divided by λZ, will be summarized by cohort.
Day 1 (am) and Day 7 (am)
Accumulation Ratio for Cmax (RCmax) of Lixivaptan in ADPKD Patients
The pharmacokinetic parameter RCmax for lixivaptan, calculated as \[Cmax on Day 7\]/\[Cmax on Day 1\], will be summarized by cohort.
Day 7 (am)
Accumulation Ratio for AUC(0-last) (RAUC[0-last]) of Lixivaptan in ADPKD Patients
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.
Day 7 (am)
Area Under the Concentration-time Curve From Time 0 Until 14 Hours Postdose (AUC[0-14]) of Lixivaptan in ADPKD Patients
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.
Day 7 (pm)
Area Under the Concentration-time Curve From Time 0 Until 14 Hours Postdose (AUC[0-14]) of WAY-141624 in ADPKD Patients
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.
Day 7 (pm)
Area Under the Concentration-time Curve From Time 0 Until 14 Hours Postdose (AUC[0-14]) of WAY-138451 in ADPKD Patients
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.
Day 7 (pm)
Area Under the Concentration-time Curve From Time 0 Until 14 Hours Postdose (AUC[0-14]) of WAY-138758 in ADPKD Patients
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.
Day 7 (pm)
Ratio of WAY-141624 Cmax to Parent Lixivaptan Cmax (MRCmax) in ADPKD Patients
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.
Day 7 (pm)
Ratio of WAY-138451 Cmax to Parent Lixivaptan Cmax (MRCmax) in ADPKD Patients
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.
Day 7 (pm)
Ratio of WAY-138758 Cmax to Parent Lixivaptan Cmax (MRCmax) in ADPKD Patients
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.
Day 7 (pm)
Ratio of Metabolite AUC(0-14) to Parent Lixivaptan AUC(0-14) (MRAUC[0-14]) of WAY-141624 in ADPKD Patients
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.
Day 7 (pm)
Ratio of Metabolite AUC(0-14) to Parent Lixivaptan AUC(0-14) (MRAUC[0-14]) of WAY-138451 in ADPKD Patients
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.
Day 7 (pm)
Ratio of Metabolite AUC(0-14) to Parent Lixivaptan AUC(0-14) (MRAUC[0-14]) of WAY-138758 in ADPKD Patients
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.
Day 7 (pm)
Number of Study Participants With Treatment-emergent Adverse Events
The number of study participants who experience treatment-emergent adverse events during the study will be counted and summarized by dose level.
35 days
Number of Study Participants With Clinically Significant Physical Examination Findings
The number of study participants who experience clinically significant physical examination findings during the study will be counted and summarized by cohort.
35 days
Number of Study Participants With Clinically Significant Vital Signs
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.
35 days
Number of Study Participants With Clinically Significant Changes in 12-lead Electrocardiograms
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.
Baseline (Day 1) to Day 8 (8 days)
Number of Study Participants With Abnormal Clinical Laboratory Findings (Including Clinical Chemistry, Hematology, and Urinalysis)
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.
35 days
Aquaretic Tolerability of Lixivaptan Measured by a Tolerability Questionnaire Relating to the Symptom Burden of Nocturia, Urgency, and Frequency at Day 7: Questions 1, 2, 6, and 10
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?
Day 7
Aquaretic Tolerability of Lixivaptan Measured by a Tolerability Questionnaire Relating to the Symptom Burden of Nocturia, Urgency, and Frequency at Day 7: Question 3
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?
Day 7
Aquaretic Tolerability of Lixivaptan Measured by a Tolerability Questionnaire Relating to the Symptom Burden of Nocturia, Urgency, and Frequency at Day 7: Question 7
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?
Day 7

Secondary Outcomes (8)

Change From Baseline in Spot Urine Osmolality
At time of dose, and at 1, 2, 4, 6, 9, 10, 11, 12, 14, and 24 hours after the Day 1 and Day 7 doses
Change From Baseline in 24-hour Urine Output
Baseline (Day -1), Day 1, and Day 7
Change From Baseline of the Estimated Glomerular Filtration Rate (eGFR)
Baseline (Day 1) to end of study (35 days)
Change From Baseline in Total Kidney Volume
Baseline (Day -1) to end of study (36 days)
Change From Baseline in Liver Volume
Baseline (Day -1) to end of study (36 days)
+3 more secondary outcomes

Other Outcomes (1)

Volume of Distribution Over 24 Hours After Extravascular Dosing (VZ/F24H) of Lixivaptan in ADPKD Patients
Day 7 (am)

Study Arms (4)

High dose lixivaptan / CKD1 or CKD2

EXPERIMENTAL

Oral high dose lixivaptan in participants with CKD1 or CKD2

Drug: Lixivaptan

Low dose lixivaptan / CKD1 or CKD2

EXPERIMENTAL

Oral low dose lixivaptan in participants with CKD1 or CKD2

Drug: Lixivaptan

High dose lixivaptan / CKD3

EXPERIMENTAL

Oral high dose lixivaptan in participants with CKD3

Drug: Lixivaptan

Low dose lixivaptan / CKD3

EXPERIMENTAL

Oral low dose lixivaptan in participants with CKD3

Drug: Lixivaptan

Interventions

LixivaptanDRUG

Oral vasopressin V2 receptor antagonist

Also known as: VPA-985

High dose lixivaptan / CKD1 or CKD2High dose lixivaptan / CKD3Low dose lixivaptan / CKD1 or CKD2Low dose lixivaptan / CKD3

Eligibility Criteria

Age18 Years - 65 Years

Sexall

Healthy VolunteersNo

Age GroupsAdult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

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

Contact the study team to confirm eligibility.