Efficacy and Safety of Lixivaptan in the Treatment of Autosomal Dominant Polycystic Kidney Disease (ACTION)

• ClinicalTrials.gov Identifier: NCT04064346
• Recruitment Status: Terminated
• First Posted: August 21, 2019
• Results First Posted: February 6, 2023
• Last Update Posted: February 6, 2023
• Sponsor: Palladio Biosciences
• Collaborator: Centessa Pharmaceuticals plc
• Information provided by (Responsible Party): Palladio Biosciences

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Autosomal Dominant Polycystic Kidney; ADPKD	Drug: Lixivaptan; Drug: Placebo	Phase 3

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 12 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment

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.

• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Sponsor - identical appearing active and placebo capsules in Part 1; all active capsules in Part 2
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: October 28, 2021
• Actual Primary Completion Date: August 3, 2022
• Actual Study Completion Date: August 3, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Lixivaptan; Lixivaptan capsules, 100-200 mg twice a day (BID)	Drug: Lixivaptan; Oral vasopressin V2 receptor antagonist
Placebo Comparator: Placebo; Matching placebo capsules BID	Drug: Placebo; Matching placebo

Outcome Measures

Primary Outcome Measures :

1. Annualized Change in Estimated Glomerular Filtration Rate (eGFR) - Part 1 [ Time Frame: Baseline to the end of Follow-up Period I (up to 71 weeks) ]
   The annualized change in eGFR will be calculated from the Chronic Kidney Disease Epidemiology Collaboration eGFR creatinine equation refit without the race variable (CKD-EPIcr_R) equation for serum creatinine from baseline (mean of 3 eGFR determinations obtained during Screening and Placebo Run-in Periods [Visits 1a/1b (if required), Visit 2, and Visit 3]) to final assessment (mean of 3 eGFR determinations obtained during Follow-up Period I or, for participants who discontinue treatment prior to Visit 22, during the Follow-up Period 8 to 28 days following study drug treatment discontinuation).
2. Annualized Change in Estimated Glomerular Filtration Rate (eGFR) - Part 2 [ Time Frame: Baseline to the end of Follow-up Period II (up to 64 weeks) ]
   The annualized change in eGFR will be calculated from the CKD-EPIcr_R equation for serum creatinine from baseline (mean of 3 eGFR determinations obtained during obtained during Follow-up Period I) to final assessment (mean of 3 eGFR determinations obtained during Follow-up Period II or, for participants who discontinue treatment prior to Visit 43, during the Follow-up Period 8 to 28 days following study drug treatment discontinuation).

Secondary Outcome Measures :

1. Number of Participants With Serum Alanine Aminotransferase (ALT) Levels >3 × the Upper Limit of Normal (ULN) - Part 1 [ Time Frame: From the end of the Single-blind Lixivaptan Titration Period to the end of Follow-up Period I (maximum of 102 days) ]
   Number of participants randomized to lixivaptan with serum ALT levels >3 × the ULN compared to those randomized to placebo. The normal range of ALT was defined as 0-33 or 0-44 U/L, depending on the lab used.
2. Number of Participants With Serum ALT Levels >3 × the ULN - Part 2 [ Time Frame: Duration of the Lixivaptan Re-titration Period and the Maintenance Treatment Period (56 weeks) and Follow-up Period II (4 weeks) ]
   Number of participants randomized to lixivaptan with serum ALT levels >3 × ULN compared to those randomized to placebo. The normal range of ALT was defined as 0-33 or 0-44 U/L, depending on the lab used.
3. eGFR Slope - Part 1 [ Time Frame: 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 ]
   Annualized rate of change (slope) in eGFR for serum creatinine, based on all eGFR determinations from baseline to all visits with on-treatment eGFR values during the Double-blind, Randomized Treatment Period. The baseline value will be calculated as the mean of 3 eGFR determinations obtained during Screening and Placebo Run-in Periods (Visits 1a/1b [if required], Visit 2, and Visit 3).
4. eGFR Slope - Part 2 [ Time Frame: 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 ]
   Annualized rate of change (slope) in eGFR for serum creatinine, based on all eGFR determinations from baseline to all visits with on-treatment eGFR values during the Maintenance Treatment Period. The baseline value will be calculated as the mean of 3 eGFR determinations obtained during obtained during Follow-up Period I.
5. Height-adjusted Total Kidney Volume (htTKV) - Part 1 [ Time Frame: Baseline to the end of Follow-up Period I (up to 71 weeks) ]
   Annualized percent change in htTKV, determined by magnetic resonance imaging (MRI), from baseline (obtained at Screening [Visit 1a]) to the end of Follow-up Period I.
6. Height-adjusted Total Kidney Volume (htTKV) - Part 2 [ Time Frame: Baseline to the end of Follow-up Period II (up to 60 weeks) ]
   Annualized percent change in htTKV, determined by MRI from baseline (obtained at Visit 25/Week 56) to the end of Follow-up Period II.
7. Number of Participants With Treatment-emergent Adverse Events (TEAEs) During the Lixivaptan Titration Period in Part 1 [ Time Frame: Up to 6 weeks ]
   Number of participants with TEAEs during the Lixivaptan Titration Period.
8. Number of Participants With TEAEs After Randomization in Part 1 [ Time Frame: From Randomization to study completion (up to 102 days) ]
   Number of participants with TEAEs by treatment group after Randomization (Double-blind Randomized Treatment Period and Follow-up Period I)
9. Number of Participants With TEAEs in Part 2 [ Time Frame: Up to 60 weeks ]
   Number of participants with TEAEs by treatment cohort during Part 2 (Lixivaptan Re-titration Period, Maintenance Treatment Period, and Follow-up Period II).
10. Number of Participants With Potentially Clinically Important Clinical Laboratory Findings During the Lixivaptan Titration Period in Part 1 [ Time Frame: Up to 6 weeks ]
    Number of participants with clinical laboratory findings (clinical chemistry, hematology and urinalysis) recorded during the Lixivaptan Titration Period and considered to be potentially clinically important.
11. Number of Participants With Potentially Clinically Important Clinical Laboratory Findings After Randomization in Part 1 [ Time Frame: From Randomization to last clinical laboratory evaluation (up to 102 days) ]
    Number of participants with clinical laboratory findings (clinical chemistry, hematology and urinalysis) recorded after Randomization (Double-blind Randomized Treatment Period and Follow-up Period I) and considered to be potentially clinically important, by treatment group.
12. Number of Participants With Potentially Clinically Important Clinical Laboratory Findings in Part 2 [ Time Frame: Up to 60 weeks ]
    Number of participants with clinical laboratory findings (clinical chemistry, hematology and urinalysis) recorded during Part 2 (Lixivaptan Re-titration Period, Maintenance Treatment Period, and Follow-up Period II) and considered to be potentially clinically important, by treatment cohort.
13. Number of Participants With Potentially Clinically Important Vital Signs Findings During the Lixivaptan Titration Period in Part 1 [ Time Frame: Up to 6 weeks ]
    Number of participants with vital signs findings (heart rate, diastolic and systolic blood pressure, weight) recorded during the Lixivaptan Titration Period and considered to be potentially clinically important.
14. Number of Participants With Potentially Clinically Important Vital Signs Findings After Randomization in Part 1 [ Time Frame: From Randomization to last measurement of vital signs (up to 102 days) ]
    Number of participants with vital signs findings (heart rate, diastolic and systolic blood pressure, weight) recorded after Randomization (Double-blind Randomized Treatment Period and Follow-up Period I) and considered to be potentially clinically important, by treatment group.
15. Number of Participants With Potentially Clinically Important Vital Signs Findings in Part 2 [ Time Frame: Up to 60 weeks ]
    Number of participants with vital signs findings (heart rate, diastolic and systolic blood pressure, weight) recorded during Part 2 (Lixivaptan Re-titration Period, Maintenance Treatment Period, and Follow-up Period II) and considered to be potentially clinically important, by treatment cohort.
16. Number of Participants With Potentially Clinically Significant 12-lead Electrocardiogram (ECG) Findings During the Lixivaptan Titration Period in Part 1 [ Time Frame: Up to 6 weeks ]
    Number of participants with ECG findings recorded during the Lixivaptan Titration 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).
17. Number of Participants With Potentially Clinically Significant 12-lead ECG Findings After Randomization in Part 1 [ Time Frame: From Randomization to last ECG (up to 102 days) ]
    Number of participants with ECG findings recorded after Randomization (Double-blind Randomized Treatment Period and Follow-up Period I) and considered to be potentially clinically important (defined as a QTcF ≥ 450 msec), by treatment group.
18. Number of Participants With Potentially Clinically Significant 12-lead ECG Findings in Part 2 [ Time Frame: Up to 60 weeks ]
    Number of participants with ECG findings recorded during Part 2 (Lixivaptan Re-titration Period, Maintenance Treatment Period, and Follow-up Period II) and considered to be potentially clinically important (defined as a QTcF ≥ 450 msec), by treatment cohort.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 60 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

United States, Alabama

Nephrology Associates, PC - Greystone

Hoover, Alabama, United States, 35242

Nephrology Consultants, LLC

Huntsville, Alabama, United States, 35805-4104

United States, Arizona

Arizona Kidney Disease & Hypertension Center - Scottsdale / Pima

Scottsdale, Arizona, United States, 85258

United States, Florida

JEM Research Institute

Atlantis, Florida, United States, 33462

Elixia at Florida Kidney Physicians - Southeast

Fort Lauderdale, Florida, United States, 33308

Qway Research

Hialeah, Florida, United States, 33010

South Florida Nephrology Associates PA

Lauderdale Lakes, Florida, United States, 33313-1600

Total Research Group, LLC

Miami, Florida, United States, 33126

Innovation Medical Research Center, Inc

Palmetto Bay, Florida, United States, 33157

Florida Kidney Physicians - Tampa

Tampa, Florida, United States, 33615

Clinical Site Partners, LLC

Winter Park, Florida, United States, 32789

United States, Massachusetts

Tufts Medical Center, Inc,

Boston, Massachusetts, United States, 02111

United States, Michigan

St Clair Nephrology Research, LLC

Roseville, Michigan, United States, 48066

United States, Minnesota

Mayo Clinic

Rochester, Minnesota, United States, 55905

United States, Missouri

Clinical Research Consultants, LLC

Kansas City, Missouri, United States, 64111

United States, North Carolina

Angel City Research, Inc

Morrisville, North Carolina, United States, 27560

United States, Pennsylvania

Northeast Clinical Research Center, LLC

Bethlehem, Pennsylvania, United States, 18107

United States, Rhode Island

Brown Medicine - Brown Physicians Patient Center

Riverside, Rhode Island, United States, 02915-2235

United States, Tennessee

Knoxville Kidney Center LLC

Knoxville, Tennessee, United States, 37923

United States, Texas

Prolato Clinical Research Center (PCRC)

Houston, Texas, United States, 77054-2854

Clinical Advancement Center, PLLC

San Antonio, Texas, United States, 78212

United States, Utah

Utah Kidney Research Institute

Salt Lake City, Utah, United States, 84115

United States, Virginia

Nephrology Associates of Northern Virginia, Inc

Fairfax, Virginia, United States, 22033

Australia, New South Wales

Renal Research - Gosford

Gosford, New South Wales, Australia, 2250

Bulgaria

University Multiprofile Hospital for Active Treatment

Pleven, Bulgaria, 5809

University Multiprofile Hospital for Active Treatment - Kaspela

Plovdiv, Bulgaria, 4001

Medical Center "Hipokrat - N"

Plovdiv, Bulgaria, 4003

Kidney Center - Medical Center

Varna, Bulgaria, 9000

Multi-Profile Hospital for Active Treatment Sveta Anna - Varna

Varna, Bulgaria, 9002

Hungary

Bajai Szent Rokus Korhaz

Baja, Hungary, 6500

Semmelweis Egyetem

Budapest, Hungary, 1083

Debreceni Egyetem

Debrecen, Hungary, 4032

Bugat Pal Korhaz

Gyöngyös, Hungary, 3200

University of Pecs

Pécs, Hungary, 7622

Poland

SCM Spolka z o.o

Kraków, Poland, 31-559

Provita Centrum Medyczne sp. z o.o.

Warsaw, Poland, 02-647

Spain

Hospital Universitari de Bellvitge (HUB)

Barcelona, Spain, 8097

Hospital Universitario Fundacion Jimenez Diaz

Madrid, Spain, 28040

Turkey

T.R. Ministry of Health Ankara Training and Research Hospital (Internal Disease, Division of Nephrology)

Ankara, Turkey, 6340

Bezmialem Vakif Universitesi Tip Fakultesi Hastanesi

Fatih, Turkey, 34093

Istanbul Universitesi - Cerrahpasa Tip Fakultesi Hastanesi (IUCTFH)

Fatih, Turkey, 34098

Erciyes Universitesi Tip Fakultesi (Erciyes University Faculty of Medicine) (Internal Medicine; Nephrology)

Kayseri, Turkey, 38039

United Kingdom

Salford Royal NHS Foundation Trust

Salford, United Kingdom, M6 8HD

Sponsors and Collaborators

Palladio Biosciences

Centessa Pharmaceuticals plc

Investigators

• Principal Investigator: Vicente Torres, MD, PhD; Mayo Clinic

  Study Documents (Full-Text)

Documents provided by Palladio Biosciences:

Study Protocol  [PDF] February 14, 2022

Statistical Analysis Plan  [PDF] August 24, 2022

More Information

• Responsible Party: Palladio Biosciences
• ClinicalTrials.gov Identifier: NCT04064346
• Other Study ID Numbers: PA-ADPKD-301
• First Posted: August 21, 2019
• Results First Posted: February 6, 2023
• Last Update Posted: February 6, 2023
• Last Verified: January 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Arthrogryposis; Kidney Diseases; Polycystic Kidney Diseases; Polycystic Kidney, Autosomal Dominant; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Joint Diseases; Musculoskeletal Diseases; Muscular Diseases; Musculoskeletal Abnormalities; Congenital Abnormalities; Kidney Diseases, Cystic; Abnormalities, Multiple; Ciliopathies; Genetic Diseases, Inborn