Clinical trial NCT03487913: The ELiSA Study - Evaluation of Lixivaptan in Subjects With Autosomal Dominant Polycystic Kidney Disease
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Autosomal Dominant Polycystic Kidney Disease
Lead sponsor: Palladio Biosciences
Sponsor class: INDUSTRY
First posted: 2018-04-04
Enrollment: 31
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Detailed description: 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).

Eligibility criteria: 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

Primary outcomes:
measure: Maximum Observed Plasma Concentration (Cmax) of Lixivaptan in ADPKD Patients
timeFrame: Day 1 (am and pm) and Day 7 (am and pm)
measure: Maximum Observed Plasma Concentration (Cmax) of WAY-141624 in ADPKD Patients
timeFrame: Day 1 (am and pm) and Day 7 (am and pm)
measure: Maximum Observed Plasma Concentration (Cmax) of WAY-138451 in ADPKD Patients
timeFrame: Day 1 (am and pm) and Day 7 (am and pm)
measure: Maximum Observed Plasma Concentration (Cmax) of WAY-138758 in ADPKD Patients
timeFrame: Day 1 (am and pm) and Day 7 (am and pm)
measure: Time to Reach Maximum Plasma Concentration (Tmax) of Lixivaptan in ADPKD Patients
timeFrame: Day 1 (am and pm) and Day 7 (am and pm)
measure: Time to Reach Maximum Plasma Concentration (Tmax) of WAY-141624 in ADPKD Patients
timeFrame: Day 1 (am and pm) and Day 7 (am and pm)
measure: Time to Reach Maximum Plasma Concentration (Tmax) of WAY-138451 in ADPKD Patients
timeFrame: Day 1 (am and pm) and Day 7 (am and pm)
measure: Time to Reach Maximum Plasma Concentration (Tmax) of WAY-138758 in ADPKD Patients
timeFrame: Day 1 (am and pm) and Day 7 (am and pm)
measure: Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of Lixivaptan in ADPKD Patients
timeFrame: Day 1 (am and pm) and Day 7 (am and pm)
measure: Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-141624 in ADPKD Patients
timeFrame: Day 1 (am and pm) and Day 7 (am and pm)
measure: Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-138451 in ADPKD Patients
timeFrame: Day 1 (am and pm) and Day 7 (am and pm)
measure: Area Under the Concentration-time Curve From Time 0 Until the Last Quantifiable Concentration (AUC[0-last]) of WAY-138758 in ADPKD Patients
timeFrame: Day 1 (am and pm) and Day 7 (am and pm)
measure: Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC[0-inf]) of Lixivaptan in ADPKD Patients
timeFrame: Day 1 (am)
measure: Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC[0-inf]) of WAY-141624 in ADPKD Patients
timeFrame: Day 1 (am)
measure: Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC[0-inf]) of WAY-138451 in ADPKD Patients
timeFrame: Day 1 (am)
measure: Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC[0-inf]) of WAY-138758 in ADPKD Patients
timeFrame: Day 1 (am)
measure: Terminal Elimination Phase Half-life (t1/2) of Lixivaptan in ADPKD Patients
timeFrame: Day 1 (am) and Day 7 (pm)
measure: Terminal Elimination Phase Half-life (t1/2) of WAY-141624 in ADPKD Patients
timeFrame: Day 1 (am) and Day 7 (pm)
measure: Terminal Elimination Phase Half-life (t1/2) of WAY-138451 in ADPKD Patients
timeFrame: Day 1 (am) and Day 7 (pm)
measure: Terminal Elimination Phase Half-life (t1/2) of WAY-138758 in ADPKD Patients
timeFrame: Day 1 (am) and Day 7 (pm)
measure: Apparent Terminal Elimination Rate Constant (λZ) of Lixivaptan in ADPKD Patients
timeFrame: Day 1 (am) and Day 7 (pm)
measure: Apparent Terminal Elimination Rate Constant (λZ) of WAY-141624 in ADPKD Patients
timeFrame: Day 1 (am) and Day 7 (pm)
measure: Apparent Terminal Elimination Rate Constant (λZ) of WAY-138451 in ADPKD Patients
timeFrame: Day 1 (am) and Day 7 (pm)
measure: Apparent Terminal Elimination Rate Constant (λZ) of WAY-138758 in ADPKD Patients
timeFrame: Day 1 (am) and Day 7 (pm)
measure: Apparent Systemic Clearance After Extravascular Dosing (CL/F) of Lixivaptan in ADPKD Patients
timeFrame: Day 1 (am) and Day 7 (am)
measure: Volume of Distribution After Extravascular Dosing (VZ/F) of Lixivaptan in ADPKD Patients
timeFrame: Day 1 (am) and Day 7 (am)
measure: Accumulation Ratio for Cmax (RCmax) of Lixivaptan in ADPKD Patients
timeFrame: Day 7 (am)
measure: Accumulation Ratio for AUC(0-last) (RAUC[0-last]) of Lixivaptan in ADPKD Patients
timeFrame: Day 7 (am)
measure: Area Under the Concentration-time Curve From Time 0 Until 14 Hours Postdose (AUC[0-14]) of Lixivaptan in ADPKD Patients
timeFrame: Day 7 (pm)
measure: Area Under the Concentration-time Curve From Time 0 Until 14 Hours Postdose (AUC[0-14]) of WAY-141624 in ADPKD Patients
timeFrame: Day 7 (pm)
measure: Area Under the Concentration-time Curve From Time 0 Until 14 Hours Postdose (AUC[0-14]) of WAY-138451 in ADPKD Patients
timeFrame: Day 7 (pm)
measure: Area Under the Concentration-time Curve From Time 0 Until 14 Hours Postdose (AUC[0-14]) of WAY-138758 in ADPKD Patients
timeFrame: Day 7 (pm)
measure: Ratio of WAY-141624 Cmax to Parent Lixivaptan Cmax (MRCmax) in ADPKD Patients
timeFrame: Day 7 (pm)
measure: Ratio of WAY-138451 Cmax to Parent Lixivaptan Cmax (MRCmax) in ADPKD Patients
timeFrame: Day 7 (pm)
measure: Ratio of WAY-138758 Cmax to Parent Lixivaptan Cmax (MRCmax) in ADPKD Patients
timeFrame: Day 7 (pm)
measure: Ratio of Metabolite AUC(0-14) to Parent Lixivaptan AUC(0-14) (MRAUC[0-14]) of WAY-141624 in ADPKD Patients
timeFrame: Day 7 (pm)
measure: Ratio of Metabolite AUC(0-14) to Parent Lixivaptan AUC(0-14) (MRAUC[0-14]) of WAY-138451 in ADPKD Patients
timeFrame: Day 7 (pm)
measure: Ratio of Metabolite AUC(0-14) to Parent Lixivaptan AUC(0-14) (MRAUC[0-14]) of WAY-138758 in ADPKD Patients
timeFrame: Day 7 (pm)
measure: Number of Study Participants With Treatment-emergent Adverse Events
timeFrame: 35 days
measure: Number of Study Participants With Clinically Significant Physical Examination Findings
timeFrame: 35 days
measure: Number of Study Participants With Clinically Significant Vital Signs
timeFrame: 35 days
measure: Number of Study Participants With Clinically Significant Changes in 12-lead Electrocardiograms
timeFrame: Baseline (Day 1) to Day 8 (8 days)
measure: Number of Study Participants With Abnormal Clinical Laboratory Findings (Including Clinical Chemistry, Hematology, and Urinalysis)
timeFrame: 35 days
measure: 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
timeFrame: Day 7
measure: Aquaretic Tolerability of Lixivaptan Measured by a Tolerability Questionnaire Relating to the Symptom Burden of Nocturia, Urgency, and Frequency at Day 7: Question 3
timeFrame: Day 7
measure: Aquaretic Tolerability of Lixivaptan Measured by a Tolerability Questionnaire Relating to the Symptom Burden of Nocturia, Urgency, and Frequency at Day 7: Question 7
timeFrame: Day 7
Secondary outcomes:
measure: Change From Baseline in Spot Urine Osmolality
timeFrame: 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
measure: Change From Baseline in 24-hour Urine Output
timeFrame: Baseline (Day -1), Day 1, and Day 7
measure: Change From Baseline of the Estimated Glomerular Filtration Rate (eGFR)
timeFrame: Baseline (Day 1) to end of study (35 days)
measure: Change From Baseline in Total Kidney Volume
timeFrame: Baseline (Day -1) to end of study (36 days)
measure: Change From Baseline in Liver Volume
timeFrame: Baseline (Day -1) to end of study (36 days)
measure: Change From Baseline of Plasma Copeptin
timeFrame: Baseline (Day -1) to end of study (36 days)
measure: Change From Baseline in Serum Creatinine
timeFrame: Baseline (Day 1, predose) to end of study (35 days)
measure: Change From Baseline in Blood Urea Nitrogen (BUN)
timeFrame: Baseline (Day 1, predose) to end of study (35 days)
Other outcomes:
measure: Volume of Distribution Over 24 Hours After Extravascular Dosing (VZ/F24H) of Lixivaptan in ADPKD Patients
timeFrame: Day 7 (am)
Locations:
city: Los Angeles
country: United States
facility: Palladio Biosciences Clinical Site
state: California
city: Jacksonville
country: United States
facility: Palladio Biosciences Clinical Site
state: Florida
city: Miami
country: United States
facility: Palladio Biosciences Clinical Site
state: Florida
city: Miami
country: United States
facility: Palladio Biosciences Clinical Site
state: Florida
city: Palmetto Bay
country: United States
facility: Palladio Biosciences Clinical Site
state: Florida
city: Tampa
country: United States
facility: Palladio Biosciences Clinical Site
state: Florida
city: Baltimore
country: United States
facility: Palladio Biosciences Clinical Site
state: Maryland
city: Rochester
country: United States
facility: Palladio Biosciences Clinical Site
state: Minnesota
city: Kansas City
country: United States
facility: Palladio Biosciences Clinical Site
state: Missouri
city: Laurelton
country: United States
facility: Palladio Biosciences Clinical Site
state: New York
city: Indiana
country: United States
facility: Palladio Biosciences Clinical Site
state: Pennsylvania
city: Nashville
country: United States
facility: Palladio Biosciences Clinical Site
state: Tennessee
city: Salt Lake City
country: United States
facility: Palladio Biosciences Clinical Site
state: Utah
Study officials:
affiliation: Mayo Clinic
name: Vicente E Torres, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Shusterman NH, Hogan LC, Pellegrini L: Effect of lixivaptan on pharmacokinetic (PK) and pharmacodynamic (PD) end points in patients with autosomal dominant polycystic kidney disease (ADPKD) in the ELiSA Study (PA-102) [Abstract]. J Am Soc Nephrol 30, 2019 (abstract supplement issue): page 339.