Clinical trial NCT04064346: Efficacy and Safety of Lixivaptan in the Treatment of Autosomal Dominant Polycystic Kidney Disease
Official title: A Phase 3 Study of the Efficacy and Safety of Lixivaptan in Participants With Autosomal Dominant Polycystic Kidney Disease Consisting of a 1-year Double-blind, Placebo-controlled, Randomized Phase and a 1-year Open-label Phase: The ACTION Study
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Autosomal Dominant Polycystic Kidney
ADPKD
Lead sponsor: Palladio Biosciences
Sponsor class: INDUSTRY
Collaborators: name: Centessa Pharmaceuticals plc
First posted: 2019-08-21
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Part 1: 1-week, single-blind, Placebo Run-in Period, followed by a 5- to 6-week single-blind Lixivaptan Titration Period, followed by a 52-week Double-blind, Randomized Treatment Period, with 2/3 participants randomized to receive lixivaptan, and 1/3 participants randomized to receive placebo (the parallel assignment part of the study). There will be a 28-day off-treatment period during which final assessments will be obtained over 3 visits starting on the 8th day after the last dose of double-blind study drug through the 28th day after the last dose of double-blind study drug.

Part 2: 2- to 4-week Lixivaptan Re-titration Period, followed by a 52-week Maintenance Treatment Period. There will be a 28-day off-treatment period during which final assessments will be obtained over 3 visits starting on the 8th day after the last dose of study drug through the 28th day after the last dose of study drug.
Primary purpose: TREATMENT

Brief summary: This is a Phase 3 trial consisting of a 2-arm, double-blind, placebo-controlled, randomized phase (Part 1) followed by a single-arm open-label phase (Part 2) to demonstrate the efficacy and safety of lixivaptan in participants with autosomal dominant polycystic kidney disease (ADPKD). Part 1 of the trial is designed to demonstrate the efficacy of lixivaptan in slowing the decline in kidney function as measured by the difference in estimated glomerular filtration rate (eGFR) between the lixivaptan-treated and placebo-treated participants. Part 2 of the study is designed to provide confirmation of the durability of this effect. Additionally, both parts of the study will contribute to understanding the safety of lixivaptan, particularly any effects on liver chemistry tests.

Detailed description: Part 1: Approximately 2250 participants with ADPKD will be screened in order to qualify the 1350 individuals who will proceed through the Placebo Run-in Period, the Lixivaptan Titration Period, and then be randomized to receive lixivaptan or placebo in the Double-blind, Randomized Treatment Period. Throughout Part 1 the study drug will look identical regardless of whether it is placebo or lixivaptan.

After meeting entry criteria during screening, participants will enter a 1-week single-blind, Placebo Run-in Period to obtain select baseline measurements. This will be followed by a 5- to 6-week single-blind dose titration period during which lixivaptan administered twice daily (BID) will be titrated to the highest tolerated dose (the Lixivaptan Titration Period). The starting dose (Level 1) will be 50 mg BID) and this will be increased weekly through Levels 2 (100 mg BID), 3 (150mg BID), and 4 (200 mg BID). The minimum dose to enter the next period, the Double-blind, Randomized Treatment Period, is Level 2 (100 mg BID). Those participants successfully titrated and tolerating the drug will then be randomized (each participant has a 2/3 chance of receiving lixivaptan and a 1/3 chance of receiving placebo) to either continue receiving lixivaptan or switch immediately to matching placebo in a double-blind manner. All dosing throughout the study will be 4 capsules BID. Depending on the study period, treatment arm to which the participant is randomized, and current dose level, the set of 4 capsules may be all placebo, all active or a combination of active and placebo. Double-blind treatment will continue for 52 weeks after which study drug will be held, and final assessments obtained off-treatment over 3 visits starting on the 8th day after the last dose of double-blind study drug through the 28th day after the last dose of study drug.

For Part 1 summaries after randomization, the analysis results will be presented by 2 treatment groups: lixivaptan and placebo.

Part 2: All participants entering Part 1, who have not discontinued due to an adverse event or withdrawn consent, will continue into Part 2 of the study, and will proceed through the Lixivaptan Re-titration Period and a Maintenance Treatment Period.

The Lixivaptan Re-titration Period will be a 2- to 4-week period during which dosing with lixivaptan will start at Level 1 (50 mg BID) for all participants and will be increased weekly until the dose level of lixivaptan, or the inferred lixivaptan dose level for participants randomized to placebo treatment, taken at the end of the Double-blind, Randomized Treatment Period in Part 1 is achieved. Lixivaptan treatment will continue for 52 weeks during the Maintenance Treatment Period after which study drug will be held, and final assessments obtained off-treatment over 3 visits starting on the 8th day after the last dose of lixivaptan through the 28th day after the last dose of lixivaptan.

Since all participants in Part 2 are treated with lixivaptan, the summaries for Part 2 will be presented in the following treatment cohorts and overall (treatment cohorts combined):

* Part1/Part2 - placebo/lixivaptan: all participants in Part 2 who were randomized into the placebo treatment group in Part 1.
* Part1/Part2 - lixivaptan/lixivaptan: all participants in Part 2 who were randomized into the lixivaptan treatment group in Part 1.

Eligibility criteria: Inclusion Criteria:

* Diagnosis of ADPKD by appropriate imaging or genetic testing.
* Mayo Clinic MRI imaging classification of 1C, 1D or 1E.
* eGFR ≥25 mL/min/1.73 m2 and ≤90 mL/min/1.73 m\^2.
* Body mass index between 18 and 40 kg/m\^2.
* Control of hypertension consistent with the 2021 Kidney Disease: Improving Global Outcomes guidelines without a diuretic and with an angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) unless not considered medically appropriate.
* 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:

* Known sensitivity or idiosyncratic reaction to lixivaptan and/or its excipients.
* Hypovolemia.
* Abnormal serum sodium concentration at Screening.
* Subjects who have taken any investigational drug or used an investigational device within 30 days, or 5 half-lives, whichever is longer, prior to Screening.
* Subjects who are taking, have taken within the past 2 weeks, or are expected to be taking, strong or moderate CYP3A4 or CYP2C8 inhibitors or inducers including regular use of grapefruit juice or Seville oranges.
* Prior use of tolvaptan or lixivaptan within the past 2 months.
* Prior use of conivaptan, somatostatin analogs (e.g., lanreotide, pasireotide, octreotide, etc.), metformin, nicotinamide, bardoxolone, demeclocycline, or mammalian target of rapamycin kinase inhibitors (e.g., everolimus, sirolimus, etc.), or KetoCitra™ or any beta-hydroxybutyrate containing supplements to treat ADPKD within the past 2 months.
* Prior use of a sodium-glucose cotransporter 2 (SGLT2) inhibitor (e.g., canagliflozin, dapagliflozin, empagliflozin, etc.) within the past 2 months or expected need for initiation of treatment with a SGLT2 inhibitor during the study.
* Prior use of a hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor within the past 2 months or expected need for initiation of treatment with a HIF-PH inhibitor during the study.
* Requirement for ongoing diuretic use.
* Advanced diabetes (e.g., glycosylated hemoglobin \>7.5%, and/or glycosuria by dipstick, significant proteinuria \[\>300 mcg albumin/mg creatinine\]), other significant kidney disease, kidney cancer, transplanted kidney, single kidney, recent kidney surgery within the past 6 months (including cyst drainage or fenestration) or acute kidney injury within past 6 months.
* 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 ECG findings that could pose a safety risk to the subject.
* Positive test results for hepatitis B surface antigen or hepatitis C antibody.
* History of infection with human immunodeficiency virus unless the participant is clinically stable and doing well on a non-CYP interacting anti-retroviral therapy (ART) regimen and who has not required more than 2 changes in their ART regimen since treatment inception.
* History of clinically significant drug or alcohol abuse in the past 2 years.
* Contraindications to or interference with MRI assessments.
* Malignancy within the past 5 years except for those not considered to affect participant survival.
* Medical history or findings that preclude safe participation in the trial or participants who are likely to be non-compliant with trial procedures in the opinion of the Investigator or medical monitor.
* Clinically significant liver disease or impairment or alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin values \>1.2 x ULN during Screening. Note: This criterion will preliminarily be reviewed at Visit 2 based on Visit 1a and Visit 1b results (if Visit 1b is required). The criterion must be re-evaluated no later than Visit 3 when results for Visit 2 are available.
* Simvastatin at a total daily dose \>10 mg or amlodipine at a total daily dose \>5 mg.

Primary outcomes:
measure: Annualized Change in Estimated Glomerular Filtration Rate (eGFR) - Part 1
timeFrame: Baseline to the end of Follow-up Period I (up to 71 weeks)
measure: Annualized Change in Estimated Glomerular Filtration Rate (eGFR) - Part 2
timeFrame: Baseline to the end of Follow-up Period II (up to 64 weeks)
Secondary outcomes:
measure: Number of Participants With Serum Alanine Aminotransferase (ALT) Levels >3 × the Upper Limit of Normal (ULN) - Part 1
timeFrame: From the end of the Single-blind Lixivaptan Titration Period to the end of Follow-up Period I (maximum of 102 days)
measure: Number of Participants With Serum ALT Levels >3 × the ULN - Part 2
timeFrame: Duration of the Lixivaptan Re-titration Period and the Maintenance Treatment Period (56 weeks) and Follow-up Period II (4 weeks)
measure: eGFR Slope - Part 1
timeFrame: Baseline to the end of Double-blind Randomized Treatment Period (up to 67 weeks), with changes from baseline calculated every 4 weeks during the Double-blind Randomized Treatment Period
measure: eGFR Slope - Part 2
timeFrame: Baseline to the end of the Maintenance Treatment Period (up to 60 weeks), with changes from baseline calculated every 4 weeks during the Maintenance Treatment Period
measure: Height-adjusted Total Kidney Volume (htTKV) - Part 1
timeFrame: Baseline to the end of Follow-up Period I (up to 71 weeks)
measure: Height-adjusted Total Kidney Volume (htTKV) - Part 2
timeFrame: Baseline to the end of Follow-up Period II (up to 60 weeks)
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs) During the Lixivaptan Titration Period in Part 1
timeFrame: Up to 6 weeks
measure: Number of Participants With TEAEs After Randomization in Part 1
timeFrame: From Randomization to study completion (up to 102 days)
measure: Number of Participants With TEAEs in Part 2
timeFrame: Up to 60 weeks
measure: Number of Participants With Potentially Clinically Important Clinical Laboratory Findings During the Lixivaptan Titration Period in Part 1
timeFrame: Up to 6 weeks
measure: Number of Participants With Potentially Clinically Important Clinical Laboratory Findings After Randomization in Part 1
timeFrame: From Randomization to last clinical laboratory evaluation (up to 102 days)
measure: Number of Participants With Potentially Clinically Important Clinical Laboratory Findings in Part 2
timeFrame: Up to 60 weeks
measure: Number of Participants With Potentially Clinically Important Vital Signs Findings During the Lixivaptan Titration Period in Part 1
timeFrame: Up to 6 weeks
measure: Number of Participants With Potentially Clinically Important Vital Signs Findings After Randomization in Part 1
timeFrame: From Randomization to last measurement of vital signs (up to 102 days)
measure: Number of Participants With Potentially Clinically Important Vital Signs Findings in Part 2
timeFrame: Up to 60 weeks
measure: Number of Participants With Potentially Clinically Significant 12-lead Electrocardiogram (ECG) Findings During the Lixivaptan Titration Period in Part 1
timeFrame: Up to 6 weeks
measure: Number of Participants With Potentially Clinically Significant 12-lead ECG Findings After Randomization in Part 1
timeFrame: From Randomization to last ECG (up to 102 days)
measure: Number of Participants With Potentially Clinically Significant 12-lead ECG Findings in Part 2
timeFrame: Up to 60 weeks
Other outcomes:
Locations:
city: Hoover
country: United States
facility: Nephrology Associates, PC - Greystone
state: Alabama
city: Huntsville
country: United States
facility: Nephrology Consultants, LLC
state: Alabama
city: Scottsdale
country: United States
facility: Arizona Kidney Disease & Hypertension Center - Scottsdale / Pima
state: Arizona
city: Atlantis
country: United States
facility: JEM Research Institute
state: Florida
city: Fort Lauderdale
country: United States
facility: Elixia at Florida Kidney Physicians - Southeast
state: Florida
city: Hialeah
country: United States
facility: Qway Research
state: Florida
city: Lauderdale Lakes
country: United States
facility: South Florida Nephrology Associates PA
state: Florida
city: Miami
country: United States
facility: Total Research Group, LLC
state: Florida
city: Palmetto Bay
country: United States
facility: Innovation Medical Research Center, Inc
state: Florida
city: Tampa
country: United States
facility: Florida Kidney Physicians - Tampa
state: Florida
city: Winter Park
country: United States
facility: Clinical Site Partners, LLC
state: Florida
city: Boston
country: United States
facility: Tufts Medical Center, Inc,
state: Massachusetts
city: Roseville
country: United States
facility: St Clair Nephrology Research, LLC
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Kansas City
country: United States
facility: Clinical Research Consultants, LLC
state: Missouri
city: Morrisville
country: United States
facility: Angel City Research, Inc
state: North Carolina
city: Bethlehem
country: United States
facility: Northeast Clinical Research Center, LLC
state: Pennsylvania
city: Riverside
country: United States
facility: Brown Medicine - Brown Physicians Patient Center
state: Rhode Island
city: Knoxville
country: United States
facility: Knoxville Kidney Center LLC
state: Tennessee
city: Houston
country: United States
facility: Prolato Clinical Research Center (PCRC)
state: Texas
city: San Antonio
country: United States
facility: Clinical Advancement Center, PLLC
state: Texas
city: Salt Lake City
country: United States
facility: Utah Kidney Research Institute
state: Utah
city: Fairfax
country: United States
facility: Nephrology Associates of Northern Virginia, Inc
state: Virginia
city: Gosford
country: Australia
facility: Renal Research - Gosford
state: New South Wales
city: Pleven
country: Bulgaria
facility: University Multiprofile Hospital for Active Treatment
city: Plovdiv
country: Bulgaria
facility: University Multiprofile Hospital for Active Treatment - Kaspela
city: Plovdiv
country: Bulgaria
facility: Medical Center "Hipokrat - N"
city: Varna
country: Bulgaria
facility: Kidney Center - Medical Center
city: Varna
country: Bulgaria
facility: Multi-Profile Hospital for Active Treatment Sveta Anna - Varna
city: Baja
country: Hungary
facility: Bajai Szent Rokus Korhaz
city: Budapest
country: Hungary
facility: Semmelweis Egyetem
city: Debrecen
country: Hungary
facility: Debreceni Egyetem
city: Gyöngyös
country: Hungary
facility: Bugat Pal Korhaz
city: Pécs
country: Hungary
facility: University of Pecs
city: Kraków
country: Poland
facility: SCM Spolka z o.o
city: Warsaw
country: Poland
facility: Provita Centrum Medyczne sp. z o.o.
city: Barcelona
country: Spain
facility: Hospital Universitari de Bellvitge (HUB)
city: Madrid
country: Spain
facility: Hospital Universitario Fundacion Jimenez Diaz
city: Ankara
country: Turkey
facility: T.R. Ministry of Health Ankara Training and Research Hospital (Internal Disease, Division of Nephrology)
city: Fatih
country: Turkey
facility: Bezmialem Vakif Universitesi Tip Fakultesi Hastanesi
city: Fatih
country: Turkey
facility: Istanbul Universitesi - Cerrahpasa Tip Fakultesi Hastanesi (IUCTFH)
city: Kayseri
country: Turkey
facility: Erciyes Universitesi Tip Fakultesi (Erciyes University Faculty of Medicine) (Internal Medicine; Nephrology)
city: Salford
country: United Kingdom
facility: Salford Royal NHS Foundation Trust
Study officials:
affiliation: Mayo Clinic
name: Vicente Torres, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: