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

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ClinicalTrials.gov Identifier: NCT04064346
Recruitment Status : Not yet recruiting
First Posted : August 21, 2019
Last Update Posted : May 10, 2021
Sponsor:
Information provided by (Responsible Party):
Palladio Biosciences

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 renal 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
Polycystic Kidney Disease, Adult Drug: Lixivaptan Drug: Placebo Phase 3

Detailed Description:

Part 1: Approximately 2000 participants with ADPKD will be screened in order to qualify the 1200 individuals who will then be randomized to receive lixivaptan or placebo. Each participant has a 2/3 chance of receiving lixivaptan and a 1/3 chance of receiving placebo. After meeting entry criteria during screening, participants will begin receiving treatment with study drug. At some point during Part 1, all participants will receive placebo and all participants will receive lixivaptan. The dose will be adjusted to the highest level that is tolerated and that dose will be continued for the rest of Part 1. Similarly, at some point participants will be randomized to lixivaptan or placebo. Throughout Part 1 the study drug will look identical regardless of whether it is placebo or lixivaptan. After 58-59 weeks, the administration of study drug will be paused, and final eGFR assessments for Part 1 will be obtained during 3 follow-up visits starting over a period of 28 days.

Part 2: All participants entering Part 1 will continue into Part 2 of the study and be treated with the active drug, lixivaptan, for an additional 54-56 weeks unless study drug was previously discontinued for a safety reason or a participant withdraws consent. At the end of that time, study drug will be discontinued, and final eGFR assessments for Part 2 will be obtained during 3 follow-up visits starting over a period of 28 days.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1200 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Double-blind, randomized, placebo-controlled in Part 1 Single-arm, active drug in Part 2
Masking: Triple (Participant, Care Provider, Investigator)
Masking Description: Sponsor - identical appearing active and placebo capsules in Part 1; all active capsules in Part 2
Primary Purpose: Treatment
Official Title: A 2-Year, 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
Estimated Study Start Date : December 2021
Estimated Primary Completion Date : February 2025
Estimated Study Completion Date : April 2026

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Kidney Diseases

Arm Intervention/treatment
Experimental: Lixivaptan - Part 1 and Part 2
Lixivaptan capsules, 100-200 mg twice a day (BID)
Drug: Lixivaptan
Oral vasopressin 2 receptor antagonist

Placebo Comparator: Placebo - Part 1
Matching placebo capsules BID
Drug: Placebo
Matching placebo




Primary Outcome Measures :
  1. Estimated Glomerular Filtration Rate (eGFR) - Part 1 [ Time Frame: 52 weeks ]
    Annualized change in eGFR from baseline to follow-up in Part 1


Secondary Outcome Measures :
  1. Serum alanine aminotransferase (ALT) levels [ Time Frame: 52 weeks ]
    Incidence of serum ALT levels >3 x ULN in participants randomized to lixivaptan compared to those randomized to placebo in Part 1

  2. Estimated Glomerular Filtration Rate (eGFR) - Part 2 [ Time Frame: 52 weeks ]
    Annualized change in eGFR from baseline to follow-up in Part 2

  3. eGFR Slope in Part 1 [ Time Frame: 52 weeks ]
    Annualized rate of change (slope) in eGFR, based on all eGFR determinations during the Double-Blind, Randomized Treatment Period in Part 1

  4. Total Kidney Volume (TKV) [ Time Frame: 52 weeks ]
    Annualized rate of change from baseline to follow-up in TKV, determined by MRI, in Part 1

  5. Liver Volume (LV) [ Time Frame: 52 Weeks ]
    Annualized rate of change from baseline to follow-up in LV, determined by MRI, stratified by baseline LV in Part 1.

  6. Non-hepatic safety in Part 1 [ Time Frame: 52 weeks ]
    Incidence of adverse events by treatment group in Part 1

  7. Non-hepatic safety in Part 2 [ Time Frame: 52 weeks ]
    Incidence of adverse events in Part 2



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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 m2
  • Body mass index (BMI) between 18 and 40 kg/m2
  • Control of hypertension consistent with KDIGO guidelines without a diuretic

Exclusion Criteria:

  • Known sensitivity or idiosyncratic reaction to any compound present in lixivaptan and related compounds.
  • Hypovolemia or inability to perceive thirst
  • 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, venglustat, demeclocycline, or mammalian target of rapamycin (mTOR) kinase inhibitors (e.g. everolimus, sirolimus, etc.) 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 chronic diuretic use
  • Advanced diabetes (e.g., glycosylated hemoglobin [HgbA1c] >7.5%, and/or glycosuria by dipstick, significant proteinuria [>300 mcg albumin/mg creatinine]), other significant renal disease, renal 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 electrocardiogram (ECG) findings that could pose a safety risk to the subject.
  • Positive test results for hepatitis B surface antigen (HBsAg) or hepatitis C (HCV).
  • History of infection with human immunodeficiency virus (HIV) unless the participant is 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.
  • Contraindication to or interference with MRI assessments.
  • Malignancy within the past 5 years except for those not considered to affect participant survival.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04064346


Contacts
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Contact: Robin Waymer 267-609-7553 ClinicalTrials@palladiobio.com
Contact: Neil Shusterman, MD 267-609-7553 ClinicalTrials@palladiobio.com

Sponsors and Collaborators
Palladio Biosciences
Investigators
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Principal Investigator: Vicente Torres, MD, PhD Mayo Clinic
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Responsible Party: Palladio Biosciences
ClinicalTrials.gov Identifier: NCT04064346    
Other Study ID Numbers: PA-ADPKD-301
First Posted: August 21, 2019    Key Record Dates
Last Update Posted: May 10, 2021
Last Verified: May 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Kidney Diseases
Polycystic Kidney Diseases
Polycystic Kidney, Autosomal Dominant
Urologic Diseases
Kidney Diseases, Cystic
Abnormalities, Multiple
Congenital Abnormalities
Ciliopathies
Genetic Diseases, Inborn