Trial Review

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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT04064346




Registration number
NCT04064346
Ethics application status
Date submitted
19/08/2019
Date registered
21/08/2019
Date last updated
6/02/2023

Titles & IDs
Public title
Efficacy and Safety of Lixivaptan in the Treatment of Autosomal Dominant Polycystic Kidney Disease
Scientific 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
Secondary ID [1] 0 0
PA-ADPKD-301
Universal Trial Number (UTN)
Trial acronym
ACTION
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Autosomal Dominant Polycystic Kidney 0 0
ADPKD 0 0
Condition category
Condition code
Musculoskeletal 0 0 0 0
Other muscular and skeletal disorders
Renal and Urogenital 0 0 0 0
Kidney disease
Renal and Urogenital 0 0 0 0
Other renal and urogenital disorders
Human Genetics and Inherited Disorders 0 0 0 0
Other human genetics and inherited disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Lixivaptan
Treatment: Drugs - Placebo

Experimental: Lixivaptan - Lixivaptan capsules, 100-200 mg twice a day (BID)

Placebo Comparator: Placebo - Matching placebo capsules BID


Treatment: Drugs: Lixivaptan
Oral vasopressin V2 receptor antagonist

Treatment: Drugs: Placebo
Matching placebo
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Annualized Change in Estimated Glomerular Filtration Rate (eGFR) - Part 1
Timepoint [1] 0 0
Baseline to the end of Follow-up Period I (up to 71 weeks)
Primary outcome [2] 0 0
Annualized Change in Estimated Glomerular Filtration Rate (eGFR) - Part 2
Timepoint [2] 0 0
Baseline to the end of Follow-up Period II (up to 64 weeks)
Secondary outcome [1] 0 0
Number of Participants With Serum Alanine Aminotransferase (ALT) Levels >3 × the Upper Limit of Normal (ULN) - Part 1
Timepoint [1] 0 0
From the end of the Single-blind Lixivaptan Titration Period to the end of Follow-up Period I (maximum of 102 days)
Secondary outcome [2] 0 0
Number of Participants With Serum ALT Levels >3 × the ULN - Part 2
Timepoint [2] 0 0
Duration of the Lixivaptan Re-titration Period and the Maintenance Treatment Period (56 weeks) and Follow-up Period II (4 weeks)
Secondary outcome [3] 0 0
eGFR Slope - Part 1
Timepoint [3] 0 0
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
Secondary outcome [4] 0 0
eGFR Slope - Part 2
Timepoint [4] 0 0
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
Secondary outcome [5] 0 0
Height-adjusted Total Kidney Volume (htTKV) - Part 1
Timepoint [5] 0 0
Baseline to the end of Follow-up Period I (up to 71 weeks)
Secondary outcome [6] 0 0
Height-adjusted Total Kidney Volume (htTKV) - Part 2
Timepoint [6] 0 0
Baseline to the end of Follow-up Period II (up to 60 weeks)
Secondary outcome [7] 0 0
Number of Participants With Treatment-emergent Adverse Events (TEAEs) During the Lixivaptan Titration Period in Part 1
Timepoint [7] 0 0
Up to 6 weeks
Secondary outcome [8] 0 0
Number of Participants With TEAEs After Randomization in Part 1
Timepoint [8] 0 0
From Randomization to study completion (up to 102 days)
Secondary outcome [9] 0 0
Number of Participants With TEAEs in Part 2
Timepoint [9] 0 0
Up to 60 weeks
Secondary outcome [10] 0 0
Number of Participants With Potentially Clinically Important Clinical Laboratory Findings During the Lixivaptan Titration Period in Part 1
Timepoint [10] 0 0
Up to 6 weeks
Secondary outcome [11] 0 0
Number of Participants With Potentially Clinically Important Clinical Laboratory Findings After Randomization in Part 1
Timepoint [11] 0 0
From Randomization to last clinical laboratory evaluation (up to 102 days)
Secondary outcome [12] 0 0
Number of Participants With Potentially Clinically Important Clinical Laboratory Findings in Part 2
Timepoint [12] 0 0
Up to 60 weeks
Secondary outcome [13] 0 0
Number of Participants With Potentially Clinically Important Vital Signs Findings During the Lixivaptan Titration Period in Part 1
Timepoint [13] 0 0
Up to 6 weeks
Secondary outcome [14] 0 0
Number of Participants With Potentially Clinically Important Vital Signs Findings After Randomization in Part 1
Timepoint [14] 0 0
From Randomization to last measurement of vital signs (up to 102 days)
Secondary outcome [15] 0 0
Number of Participants With Potentially Clinically Important Vital Signs Findings in Part 2
Timepoint [15] 0 0
Up to 60 weeks
Secondary outcome [16] 0 0
Number of Participants With Potentially Clinically Significant 12-lead Electrocardiogram (ECG) Findings During the Lixivaptan Titration Period in Part 1
Timepoint [16] 0 0
Up to 6 weeks
Secondary outcome [17] 0 0
Number of Participants With Potentially Clinically Significant 12-lead ECG Findings After Randomization in Part 1
Timepoint [17] 0 0
From Randomization to last ECG (up to 102 days)
Secondary outcome [18] 0 0
Number of Participants With Potentially Clinically Significant 12-lead ECG Findings in Part 2
Timepoint [18] 0 0
Up to 60 weeks

Eligibility
Key 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.
Minimum age
18 Years
Maximum age
60 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Terminated
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
28/10/2021
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
3/08/2022
Sample size
Target
Accrual to date
Final
12
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 0 0
Renal Research - Gosford - Gosford
Recruitment postcode(s) [1] 0 0
2250 - Gosford
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Alabama
Country [2] 0 0
United States of America
State/province [2] 0 0
Arizona
Country [3] 0 0
United States of America
State/province [3] 0 0
Florida
Country [4] 0 0
United States of America
State/province [4] 0 0
Massachusetts
Country [5] 0 0
United States of America
State/province [5] 0 0
Michigan
Country [6] 0 0
United States of America
State/province [6] 0 0
Minnesota
Country [7] 0 0
United States of America
State/province [7] 0 0
Missouri
Country [8] 0 0
United States of America
State/province [8] 0 0
North Carolina
Country [9] 0 0
United States of America
State/province [9] 0 0
Pennsylvania
Country [10] 0 0
United States of America
State/province [10] 0 0
Rhode Island
Country [11] 0 0
United States of America
State/province [11] 0 0
Tennessee
Country [12] 0 0
United States of America
State/province [12] 0 0
Texas
Country [13] 0 0
United States of America
State/province [13] 0 0
Utah
Country [14] 0 0
United States of America
State/province [14] 0 0
Virginia
Country [15] 0 0
Bulgaria
State/province [15] 0 0
Pleven
Country [16] 0 0
Bulgaria
State/province [16] 0 0
Plovdiv
Country [17] 0 0
Bulgaria
State/province [17] 0 0
Varna
Country [18] 0 0
Hungary
State/province [18] 0 0
Baja
Country [19] 0 0
Hungary
State/province [19] 0 0
Budapest
Country [20] 0 0
Hungary
State/province [20] 0 0
Debrecen
Country [21] 0 0
Hungary
State/province [21] 0 0
Gyöngyös
Country [22] 0 0
Hungary
State/province [22] 0 0
Pécs
Country [23] 0 0
Poland
State/province [23] 0 0
Kraków
Country [24] 0 0
Poland
State/province [24] 0 0
Warsaw
Country [25] 0 0
Spain
State/province [25] 0 0
Barcelona
Country [26] 0 0
Spain
State/province [26] 0 0
Madrid
Country [27] 0 0
Turkey
State/province [27] 0 0
Ankara
Country [28] 0 0
Turkey
State/province [28] 0 0
Fatih
Country [29] 0 0
Turkey
State/province [29] 0 0
Kayseri
Country [30] 0 0
United Kingdom
State/province [30] 0 0
Salford

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Palladio Biosciences
Address
Country
Other collaborator category [1] 0 0
Commercial sector/Industry
Name [1] 0 0
Centessa Pharmaceuticals plc
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/ct2/show/NCT04064346
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Vicente Torres, MD, PhD
Address 0 0
Mayo Clinic
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT04064346