Study of the Efficacy and Safety of Tesevatinib in Subjects With ADPKD

A Double-blind Randomized Parallel Group Study of the Efficacy and Safety of Tesevatinib in Subjects With Autosomal Dominant Polycystic Kidney Disease

The goal of the study was to compare and evaluate safety and efficacy of tesevatinib 50 milligrams (mg) versus placebo in participants with autosomal dominant polycystic kidney disease (ADPKD).

Study Overview

• Status: Completed
• Conditions: Autosomal Dominant Polycystic Kidney; ADPKD
• Intervention / Treatment: Drug: Tesevatinib; Drug: Placebo

Detailed Description

Safety and efficacy of 50 mg tesevatinib in comparison to placebo in participants with ADPKD was assessed.

The primary purpose of this study was focused on evaluating the change from Baseline in height-adjusted total kidney volume (htTKV) as measured by magnetic resonance imaging (MRI) at Months 12, 18, and 24, and 30 days post-dose in participants with ADPKD treated with tesevatinib or placebo.

If eligible for the study participation, participants were randomly assigned to either investigational treatment group or placebo group. Treatment group received 50 mg tesevatinib once daily for 24 months and control group received the placebo once daily for 24 months.

• Study Type: Interventional
• Enrollment (Actual): 80
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • La Jolla, California, United States, 92037
      • University of California San Diego
    • La Mesa, California, United States, 91942
      • California Institute for Renal Research
    • Los Angeles, California, United States, 90095
      • University of California Los Angeles
    • San Francisco, California, United States, 94143
      • University of California San Francisco
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Denver
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale Nephrology Clinical Research
  • Florida
    • Port Charlotte, Florida, United States, 33952
      • Coastal Nephrology Associates Research Center, LLC
    • Tampa, Florida, United States, 33614
      • Genesis Clinical Research
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University School of Medicine
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University
  • New York
    • New York, New York, United States, 10021
      • Rogosin Institute
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
  • Texas
    • Temple, Texas, United States, 10016
      • Baylor Scott & White Research Institute
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• ADPKD diagnosis based on Ravine's criteria.
• Cysts of at least 1 centimeter.
• Estimated glomerular filtration rate greater than or equal to (>=) 25 milliliter per minute per 1.73 square meter (mL/min/1.73 m^2) and less than or equal to (<=) 90 mL/min/1.73 m^2, using the Modification of Diet in Renal Disease-4 variable formula.
• htTKV must meet the following requirements: >= 500 milliliters (mL) for participants 18-35 years of age; >= 750 mL for participants 36-49 years of age; >= 900 mL for participants 50-60 years of age.
• The participant had the following laboratory values:

Platelets greater than (>) lower limit of normal (LLN); Hemoglobin > 9 grams per deciliter; Total bilirubin <= 1.5 milligrams per deciliter; Aspartate aminotransferase less than (<) 2.5*upper limit of normal (ULN); Alanine aminotransferase < 2.5*ULN; Prothrombin time/partial thromboplastin time <=1.5*ULN; Serum potassium levels within normal limits; Serum magnesium levels within normal limits; Albumin >= LLN; Amylase <=1.5*ULN; Lipase <=1.5*ULN; Prothrombin time and partial thromboplastin time <=1.5*ULN; International normalized ratio (INR) <=1.5, except those participants taking warfarin who must have INR <=3.

• Female participants of childbearing potential with negative pregnancy test at screening.
• If sexually active, the participant agreed to use 2 accepted methods of contraception during the course of the study and for 6 months after their last dose of study drug.

Exclusion Criteria:

• Previous nephrectomy.
• Kidney transplant.
• Tuberous sclerosis.
• Hippel-Lindau disease.
• Acquired cystic disease.
• Congenital absence of 1 kidney and/or need for dialysis or transplantation in the foreseeable future.
• Moderate hematuria.
• Uncontrolled hypertension.
• Presence of renal or hepatic calculi (stones) causing symptoms.
• Received any investigational therapy within 30 days prior to initiation of therapy (Day 1 visit).
• Received tolvaptan 30 days prior to initiation of therapy (Day 1 visit).
• Received active treatment for urinary tract infection 4 weeks prior to initiation of therapy (Day 1 visit).
• History of pancreatitis or known risk of pancreatitis.
• The participant met any of the following cardiac criteria:
• Mean QTc interval corrected for heart rate using Fridericia's formula (QTcF) of >450 milliseconds.
• History of torsade de pointes, ventricular tachycardia or fibrillation, pathologic sinus bradycardia (< 50 beats per minute), heart block (excluding first-degree block, being PR interval prolongation only), congenital long QT syndrome or new ST segment elevation or depression or new Q wave on electrocardiogram.
• Participants with a history of atrial arrhythmias were discussed with the Medical Monitor.
• Family history of congenital long QT syndrome or unexplained cardiac death.
• Symptomatic heart failure (per New York Heart Association guidelines), unstable angina, myocardial infarction, or cerebrovascular accident within 6 months prior to study entry.
• History of ventricular rhythm disturbances.
• History of cardiac arrhythmias, stroke, or myocardial infarction.
• Has a cardiac pacemaker.
• History of pericardial effusion or presence of pericardial effusion on screening echocardiogram.
• Taking any medication known to inhibit the cytochrome P450 (CYP)3A4 isozyme or any drugs that are CYP3A4 inducers, or any drugs associated with torsade de pointes or known to prolong the QTcF interval, including anti-arrhythmic medications within 2 weeks prior to screening.
• Uncontrolled intercurrent illness that would limit compliance with study requirements.
• Participant was pregnant, planed to become pregnant, or nursing.
• Human immunodeficiency virus positive.
• Hepatitis B or C positive.
• Immunocompromised.
• Documented renal vascular disease resulting in uncontrolled hypertension.
• Previously received an epithelial growth factor receptor (EGFR).
• Allergy or hypersensitivity to components of tesevatinib or placebo or their formulations.
• Been aphakic due to previous cataract surgery or congenital abnormality.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Tesevatinib; Participants received tesevatinib 50 mg tablet orally once daily (QD) for up to 25.3 months.	Drug: Tesevatinib; Pharmaceutical form: Tablet; Route of administration: orally; Other Names: KD019
PLACEBO_COMPARATOR: Placebo; Participants received placebo matched to tesevatinib tablet orally QD for up to 25.3 months.	Drug: Placebo; Pharmaceutical form: Tablet (identical to tesevatinib); Route of administration: orally

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Height Adjusted Total Kidney Volume (htTKV) at Month 12	htTKV was calculated using total kidney volume (in milliliters) obtained from magnetic resonance imaging (MRI) divided by height (in meters). Least square (LS) mean and standard error (SE) were estimated by using analysis of covariance (ANCOVA) model. Change from Baseline in htTKV at Month 12 was reported in this outcome measure.	Baseline (Day 1), Month 12
Change From Baseline in Height Adjusted Total Kidney Volume at Month 18	htTKV was calculated using total kidney volume (in milliliters) obtained from MRI divided by height (in meters). LS mean and SE were estimated by using ANCOVA model. Change from Baseline in htTKV at Month 18 was reported in this outcome measure.	Baseline (Day 1), Month 18
Change From Baseline in Height Adjusted Total Kidney Volume at Month 24	htTKV was calculated using total kidney volume (in milliliters) obtained from MRI divided by height (in meters). LS mean and SE were estimated by using ANCOVA model. Change from Baseline in htTKV at Month 24 was reported in this outcome measure.	Baseline (Day 1), Month 24
Change From Baseline in Height Adjusted Total Kidney Volume at End of Study	htTKV was calculated using total kidney volume (in milliliters) obtained from MRI divided by height (in meters). LS mean and SE were estimated by using ANCOVA model. Change from Baseline in htTKV at end of study (i.e., up to 26 months) was reported in this outcome measure.	Baseline (Day 1), End of study (anytime up to 26 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-emergent Adverse Events (TEAEs)	An adverse event (AE) was any untoward medical occurrence in a clinical study participant administered a medicinal product and which did not necessarily had to have a causal relationship with the treatment. TEAEs were AEs that developed or worsened or became serious from the first dose (Day 1) of the study drug until end of study.	From Baseline (Day 1) up to 30 days post last dose of study drug (i.e., up to 26 months)
Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Months 12, 18, 24 and End of Study	eGFR is a test for renal function. eGFR was calculated by using the 4-variable modification of diet in renal disease (MDRD-4) formula reported as milliliters per minute per 1.73 square meter (mL/min/1.73 m^2). LS mean and SE were estimated using ANCOVA model.	Baseline (Day 1), Months 12, 18, 24 and at end of study (i.e., anytime up to 26 months)

Collaborators and Investigators

• Sponsor: Kadmon, a Sanofi Company

Study record dates

Study Major Dates

• Study Start (ACTUAL): October 12, 2017
• Primary Completion (ACTUAL): January 25, 2022
• Study Completion (ACTUAL): January 25, 2022

Study Registration Dates

• First Submitted: June 26, 2017
• First Submitted That Met QC Criteria: June 28, 2017
• First Posted (ACTUAL): June 29, 2017

Study Record Updates

• Last Update Posted (ACTUAL): February 6, 2023
• Last Update Submitted That Met QC Criteria: January 10, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: ADPKD; PKD; Autosomal Dominant Polycystic Kidney Disease; Polycystic Kidney Disease; Polycystic Kidney; Tesevatinib
• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Congenital Abnormalities; Genetic Diseases, Inborn; Joint Diseases; Musculoskeletal Diseases; Muscular Diseases; Musculoskeletal Abnormalities; Abnormalities, Multiple; Kidney Diseases, Cystic; Ciliopathies; Polycystic Kidney Diseases; Polycystic Kidney, Autosomal Dominant; Arthrogryposis; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; XL647
• Other Study ID Numbers: ACT17675; KD019-211 (OTHER: Kadmon)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No