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

• Register: ClinicalTrials.gov
• Last refreshed on: 12 December 2022
• Main ID: NCT04064346
• Date of registration: 19/08/2019
• Prospective Registration: Yes
• Primary sponsor: Palladio Biosciences
• Public title: Efficacy and Safety of Lixivaptan in the Treatment of Autosomal Dominant Polycystic Kidney Disease ACTION
• 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
• Date of first enrolment: October 28, 2021
• Target sample size: 12
• Recruitment status: Terminated
• URL: https://clinicaltrials.gov/show/NCT04064346
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: Triple (Participant, Care Provider, Investigator).
• Phase: Phase 3

Countries of recruitment

Argentina, Australia, Bulgaria, Canada, Chile, Hungary, Israel, Italy, Mexico, Poland, Romania, Slovakia, Spain, Turkey, United Kingdom, United States

Contacts

• Name: Vicente Torres, MD, PhD
• Affiliation: Mayo Clinic

Key inclusion & exclusion 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 between 18 and 40 kg/m2.

- 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 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, 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.



Age minimum: 18 Years
Age maximum: 60 Years
Gender: All

Health Condition(s) or Problem(s) studied

Autosomal Dominant Polycystic Kidney

ADPKD

Intervention(s)

Drug: Lixivaptan

Drug: Placebo

Primary Outcome(s)

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)]

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)]

Secondary Outcome(s)

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 significant 12-lead electrocardiogram (ECG) findings during the Lixivaptan Titration Period in Part 1 [Time Frame: Up to 6 weeks]

Height-adjusted Total Kidney Volume (htTKV) - Part 1 [Time Frame: Baseline to the end of Follow-up Period I (up to 71 weeks)]

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 in Part 2 [Time Frame: Up to 60 weeks]

Number of participants with potentially clinically significant 12-lead ECG findings after Randomization in Part 1 [Time Frame: Up to 56 weeks]

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]

Number of participants with potentially clinically significant 12-lead ECG findings in Part 2 [Time Frame: Up to 60 weeks]

Serum alanine aminotransferase (ALT) levels - Part 1 [Time Frame: Duration of the Double-blind Randomized Treatment Period (52 weeks)]

Serum alanine aminotransferase (ALT) levels - Part 2 [Time Frame: Duration of the Lixivaptan Re-titration Period and the Maintenance Treatment Period (56 weeks)]

Number of participants with TEAEs after Randomization in Part 1 [Time Frame: Up to 56 weeks]

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]

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]

Number of participants with potentially clinically important vital signs findings after Randomization in Part 1 [Time Frame: Up to 56 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 potentially clinically important clinical laboratory findings after Randomization in Part 1 [Time Frame: Up to 56 weeks]

Number of participants with treatment-emergent adverse events (TEAEs) during the Lixivaptan Titration Period in Part 1 [Time Frame: Up to 6 weeks]

Secondary ID(s)

PA-ADPKD-301

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Secondary Sponsor(s)

Centessa Pharmaceuticals plc