Autosomal Dominant Polycystic KidneyPhase 3ACTIONNCT04064346
Efficacy and Safety of Lixivaptan in the Treatment of Autosomal Dominant Polycystic Kidney Disease
A Phase 3 study testing Lixivaptan in people with Autosomal Dominant Polycystic Kidney and ADPKD, run by Palladio Biosciences at 43 sites in 8 countries.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 to 60 years
- Conditions the study is for
- Autosomal Dominant Polycystic Kidney, ADPKD
- What is being tested?
- Lixivaptan
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 12 participants
- Where
- 43 sitesin 8 countries
- Study dates
- 28 Oct 2021to 3 Aug 2022
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 60 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- 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.
Who cannot join
- 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.
Show all 21Show fewer
- 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.
Trial locations and contacts
43 sites in 8 countries.
43 sites in 8 countries
United States23 sites
JEM Research Institute
Atlantis, Florida, 33462
Northeast Clinical Research Center, LLC
Bethlehem, Pennsylvania, 18107
Tufts Medical Center, Inc,
Boston, Massachusetts, 02111
Nephrology Associates of Northern Virginia, Inc
Fairfax, Virginia, 22033
Elixia at Florida Kidney Physicians - Southeast
Fort Lauderdale, Florida, 33308
Qway Research
Hialeah, Florida, 33010
Nephrology Associates, PC - Greystone
Hoover, Alabama, 35242
Prolato Clinical Research Center (PCRC)
Houston, Texas, 77054-2854
Nephrology Consultants, LLC
Huntsville, Alabama, 35805-4104
Clinical Research Consultants, LLC
Kansas City, Missouri, 64111
Knoxville Kidney Center LLC
Knoxville, Tennessee, 37923
South Florida Nephrology Associates PA
Lauderdale Lakes, Florida, 33313-1600
Total Research Group, LLC
Miami, Florida, 33126
Angel City Research, Inc
Morrisville, North Carolina, 27560
Innovation Medical Research Center, Inc
Palmetto Bay, Florida, 33157
Brown Medicine - Brown Physicians Patient Center
Riverside, Rhode Island, 02915-2235
Mayo Clinic
Rochester, Minnesota, 55905
St Clair Nephrology Research, LLC
Roseville, Michigan, 48066
Utah Kidney Research Institute
Salt Lake City, Utah, 84115
Clinical Advancement Center, PLLC
San Antonio, Texas, 78212
Arizona Kidney Disease & Hypertension Center - Scottsdale / Pima
Scottsdale, Arizona, 85258
Florida Kidney Physicians - Tampa
Tampa, Florida, 33615
Clinical Site Partners, LLC
Winter Park, Florida, 32789
Bulgaria5 sites
University Multiprofile Hospital for Active Treatment
Pleven, 5809
University Multiprofile Hospital for Active Treatment - Kaspela
Plovdiv, 4001
Medical Center "Hipokrat - N"
Plovdiv, 4003
Kidney Center - Medical Center
Varna, 9000
Multi-Profile Hospital for Active Treatment Sveta Anna - Varna
Varna, 9002
Hungary5 sites
Bajai Szent Rokus Korhaz
Baja, 6500
Semmelweis Egyetem
Budapest, 1083
Debreceni Egyetem
Debrecen, 4032
Bugat Pal Korhaz
Gyöngyös, 3200
University of Pecs
Pécs, 7622
Turkey (Türkiye)4 sites
T.R. Ministry of Health Ankara Training and Research Hospital (Internal Disease, Division of Nephrology)
Ankara, 6340
Bezmialem Vakif Universitesi Tip Fakultesi Hastanesi
Fatih, 34093
Istanbul Universitesi - Cerrahpasa Tip Fakultesi Hastanesi (IUCTFH)
Fatih, 34098
Erciyes Universitesi Tip Fakultesi (Erciyes University Faculty of Medicine) (Internal Medicine; Nephrology)
Kayseri, 38039
Poland2 sites
SCM Spolka z o.o
Krakow, 31-559
Provita Centrum Medyczne sp. z o.o.
Warsaw, 02-647
Spain2 sites
Hospital Universitari de Bellvitge (HUB)
Barcelona, 8097
Hospital Universitario Fundacion Jimenez Diaz
Madrid, 28040
United Kingdom1 site
Salford Royal NHS Foundation Trust
Salford, M6 8HD
About this study
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
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.
Read the 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.
- Conditions
- Autosomal Dominant Polycystic Kidney, ADPKD
- Being tested
- Lixivaptan, Placebo
- Medical subject headings
- Polycystic Kidney, Autosomal Dominant
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
LixivaptanDrug
Oral vasopressin V2 receptor antagonist
PlaceboDrug
Matching placebo
| Study group | Role | What they receive |
|---|---|---|
| Lixivaptan | Experimental | Lixivaptan capsules, 100-200 mg twice a day (BID) Receives: Drug: Lixivaptan |
| Placebo | Placebo comparator | Matching placebo capsules BID Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Annualized Change in Estimated Glomerular Filtration Rate (eGFR) - Part 1
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).
Measured: Baseline to the end of Follow-up Period I (up to 71 weeks)
Annualized Change in Estimated Glomerular Filtration Rate (eGFR) - Part 2
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).
Measured: Baseline to the end of Follow-up Period II (up to 64 weeks)
Secondary outcomes (18)
Number of Participants With Serum Alanine Aminotransferase (ALT) Levels >3 × the Upper Limit of Normal (ULN) - Part 1
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.
Measured: 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 With Serum ALT Levels >3 × the ULN - Part 2
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.
Measured: Duration of the Lixivaptan Re-titration Period and the Maintenance Treatment Period (56 weeks) and Follow-up Period II (4 weeks)
eGFR Slope - Part 1
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).
Measured: 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
eGFR Slope - Part 2
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.
Measured: 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
Height-adjusted Total Kidney Volume (htTKV) - Part 1
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.
Measured: Baseline to the end of Follow-up Period I (up to 71 weeks)
Height-adjusted Total Kidney Volume (htTKV) - Part 2
Annualized percent change in htTKV, determined by MRI from baseline (obtained at Visit 25/Week 56) to the end of Follow-up Period II.
Measured: Baseline to the end of Follow-up Period II (up to 60 weeks)
Number of Participants With Treatment-emergent Adverse Events (TEAEs) During the Lixivaptan Titration Period in Part 1
Number of participants with TEAEs during the Lixivaptan Titration Period.
Measured: Up to 6 weeks
Number of Participants With TEAEs After Randomization in Part 1
Number of participants with TEAEs by treatment group after Randomization (Double-blind Randomized Treatment Period and Follow-up Period I)
Measured: From Randomization to study completion (up to 102 days)
Number of Participants With TEAEs in Part 2
Number of participants with TEAEs by treatment cohort during Part 2 (Lixivaptan Re-titration Period, Maintenance Treatment Period, and Follow-up Period II).
Measured: Up to 60 weeks
Number of Participants With Potentially Clinically Important Clinical Laboratory Findings During the Lixivaptan Titration Period in Part 1
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.
Measured: Up to 6 weeks
Number of Participants With Potentially Clinically Important Clinical Laboratory Findings After Randomization in Part 1
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.
Measured: From Randomization to last clinical laboratory evaluation (up to 102 days)
Number of Participants With Potentially Clinically Important Clinical Laboratory Findings in Part 2
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.
Measured: Up to 60 weeks
Number of Participants With Potentially Clinically Important Vital Signs Findings During the Lixivaptan Titration Period in Part 1
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.
Measured: Up to 6 weeks
Number of Participants With Potentially Clinically Important Vital Signs Findings After Randomization in Part 1
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.
Measured: From Randomization to last measurement of vital signs (up to 102 days)
Number of Participants With Potentially Clinically Important Vital Signs Findings in Part 2
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.
Measured: Up to 60 weeks
Number of Participants With Potentially Clinically Significant 12-lead Electrocardiogram (ECG) Findings During the Lixivaptan Titration Period in Part 1
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).
Measured: Up to 6 weeks
Number of Participants With Potentially Clinically Significant 12-lead ECG Findings After Randomization in Part 1
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.
Measured: From Randomization to last ECG (up to 102 days)
Number of Participants With Potentially Clinically Significant 12-lead ECG Findings in Part 2
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.
Measured: Up to 60 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Aug 2019
- Study start28 Oct 2021
- Primary completion3 Aug 2022
- Study completion3 Aug 2022
Why it stopped: The decision is based on a thorough reassessment of the commercial potential of lixivaptan as a potential best-in-class therapy for patients with autosomal dominant polycystic kidney disease (ADPKD).
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Autosomal Dominant Polycystic KidneyStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- 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 blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 12 participants (actual)
Sponsor and investigators
- Lead sponsor
- Palladio Biosciences
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Centessa Pharmaceuticals plc
- Responsible party
- Sponsor
- Investigators
- Vicente Torres, MD, PhD, Principal investigator, Mayo Clinic
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04064346
- Sponsor's protocol ID
- PA-ADPKD-301
- Acronym
- ACTION
- Status last verified
- Jan 2023
- First submitted
- 19 Aug 2019
- Last updated
- 6 Feb 2023
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 6 Feb 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT04064346
- Acronym / sponsor ID
- ACTION / PA-ADPKD-301
- Conditions
- Autosomal Dominant Polycystic Kidney, ADPKD
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: The decision is based on a thorough reassessment of the commercial potential of lixivaptan as a potential best-in-class therapy for patients with autosomal dominant polycystic kidney disease (ADPKD).
- Enrolment
- 12 participants (actual)
- Lead sponsor
- Palladio BiosciencesIndustry (pharma, biotech, devices)
- Collaborators
- Centessa Pharmaceuticals plc
- Study start
- 28 Oct 2021 (actual)
- Primary completion
- 3 Aug 2022 (actual)
- Study completion
- 3 Aug 2022 (actual)
- First posted
- 21 Aug 2019 (actual)
- Results
- Posted 6 Feb 2023
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- 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.
| Arm | Type | Receives |
|---|---|---|
| Lixivaptan | Experimental | Drug: LixivaptanLixivaptan capsules, 100-200 mg twice a day (BID) |
| Placebo | Placebo comparator | Drug: PlaceboMatching placebo capsules BID |
Who may qualify
- Ages
- 18 to 60 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (7 listed)
- 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.
Key exclusion criteria (21 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| LixivaptanOral vasopressin V2 receptor antagonist | Drug | Lixivaptan |
| PlaceboMatching placebo | Drug | Placebo |
Primary outcome
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).
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).
18 secondary outcomes
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 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)
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
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
Height-adjusted Total Kidney Volume (htTKV) - Part 1
Time frame: Baseline to the end of Follow-up Period I (up to 71 weeks)
Height-adjusted Total Kidney Volume (htTKV) - Part 2
Time frame: Baseline to the end of Follow-up Period II (up to 60 weeks)
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 After Randomization in Part 1
Time frame: From Randomization to study completion (up to 102 days)
Number of Participants With TEAEs in Part 2
Time frame: Up to 60 weeks
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 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 Potentially Clinically Important Clinical Laboratory Findings in Part 2
Time frame: Up to 60 weeks
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 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 Potentially Clinically Important Vital Signs Findings in Part 2
Time frame: Up to 60 weeks
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 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 Potentially Clinically Significant 12-lead ECG Findings in Part 2
Time frame: Up to 60 weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Feb 2023.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
Related trials for Autosomal Dominant Polycystic Kidney
RecruitingObservational study
Hypertension in Children and Young People at Risk of Autosomal Dominant Polycystic Kidney Disease
Autosomal Dominant Polycystic Kidney Disease (ADPKD
Active, not recruitingObservational study
Role of ROS and cAMP-PKA Biomarkers in ADPKD
Autosomal Dominant Polycystic Kidney Disease
Not yet recruitingPhase 1
A Study to Investigate the Pharmacokinetics of JMKX003142 in Healthy Participants and Participants With Hepatic Impairment
ADPKD (Autosomal Dominant Polycystic Kidney Disease), Renal Edema
RecruitingPhase 1
Absorption, Distribution, Metabolism, and Excretion of 14C-VX-407 After a Single Oral Dose
Autosomal Dominant Polycystic Kidney Disease (ADPKD)
RecruitingObservational study
Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
Rare Disorders, Undiagnosed Disorders
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Vicente Torres, MD, PhD principal investigator
Mayo Clinic
43 sites in 8 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Lixivaptan in people with Autosomal Dominant Polycystic Kidney and ADPKD, run by Palladio Biosciences at 43 sites in 8 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 21 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 6 Feb 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 43 sites in United States, Bulgaria, Hungary, Turkey (Türkiye), Poland and 3 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 6 Feb 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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 study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Feb 2023.