ADPKD, Autosomal Dominant Polycystic Kidney
Conditions
Keywords
ADPKD, Autosomal Dominant Polycystic Kidney Disease, Polycystic Kidney, Tesevatinib, Polycystic Kidney Disease, PKD
Brief summary
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).
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.
Interventions
DRUGTesevatinib
Pharmaceutical form: Tablet; Route of administration: orally
DRUGPlacebo
Pharmaceutical form: Tablet (identical to tesevatinib); Route of administration: orally
Sponsors
Kadmon, a Sanofi Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Height Adjusted Total Kidney Volume (htTKV) at Month 12 | Baseline (Day 1), 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. |
| Change From Baseline in Height Adjusted Total Kidney Volume at Month 18 | Baseline (Day 1), 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. |
| Change From Baseline in Height Adjusted Total Kidney Volume at Month 24 | Baseline (Day 1), 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. |
| Change From Baseline in Height Adjusted Total Kidney Volume at End of Study | Baseline (Day 1), End of study (anytime up to 26 months) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | From Baseline (Day 1) up to 30 days post last dose of study drug (i.e., up to 26 months) | 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. |
| Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Months 12, 18, 24 and End of Study | Baseline (Day 1), Months 12, 18, 24 and at end of study (i.e., anytime up to 26 months) | 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. |
Countries
United States
Participant flow
Recruitment details
The study was conducted at 20 active sites in the United States. A total of 191 participants were screened between 12 October 2017 and 29 January 2020, of which 80 participants were enrolled.
Pre-assignment details
Participants were randomized in a 1:1 ratio to receive tesevatinib or placebo.
Participants by arm
| Arm | Count |
|---|---|
| Tesevatinib Participants received tesevatinib 50 mg tablet orally once daily (QD) for up to 25.3 months. | 38 |
| Placebo Participants received placebo matched to tesevatinib tablet orally QD for up to 25.3 months. | 40 |
| Total | 78 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 1 |
| Overall Study | Investigator's decision | 3 | 0 |
| Overall Study | Lost to Follow-up | 2 | 1 |
| Overall Study | Other than above specified | 0 | 1 |
| Overall Study | Participant moved | 0 | 1 |
| Overall Study | Termination of the study by sponsor | 1 | 1 |
| Overall Study | Withdrawal by Subject | 6 | 6 |
Baseline characteristics
| Characteristic | Placebo | Total | Tesevatinib |
|---|---|---|---|
| Age, Continuous | 45.6 years STANDARD_DEVIATION 10 | 46.3 years STANDARD_DEVIATION 9.7 | 47.0 years STANDARD_DEVIATION 9.6 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 6 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) White | 33 Participants | 65 Participants | 32 Participants |
| Sex: Female, Male Female | 18 Participants | 42 Participants | 24 Participants |
| Sex: Female, Male Male | 22 Participants | 36 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 38 | 0 / 40 |
| other Total, other adverse events | 37 / 38 | 40 / 40 |
| serious Total, serious adverse events | 6 / 38 | 2 / 40 |
Outcome results
Primary
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.
Time frame: Baseline (Day 1), End of study (anytime up to 26 months)
Population: Analysis was performed on efficacy population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Tesevatinib | Change From Baseline in Height Adjusted Total Kidney Volume at End of Study | 0.0604 milliliters per meter | Standard Error 0.009 |
| Placebo | Change From Baseline in Height Adjusted Total Kidney Volume at End of Study | 0.0589 milliliters per meter | Standard Error 0.0094 |
Comparison: An ANCOVA model included treatment group as a factor and the Baseline htTKV (log10 transformed) as a covariate for the analysis. The outcome measure was tested at 2-sided 0.05 level to control Type I error rate.p-value: 0.9093ANCOVA
Primary
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.
Time frame: Baseline (Day 1), Month 18
Population: Analysis was performed on efficacy population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Tesevatinib | Change From Baseline in Height Adjusted Total Kidney Volume at Month 18 | 0.0383 milliliters per meter | Standard Error 0.0081 |
| Placebo | Change From Baseline in Height Adjusted Total Kidney Volume at Month 18 | 0.0425 milliliters per meter | Standard Error 0.0075 |
Comparison: An ANCOVA model included treatment group as a factor and the Baseline htTKV (log10 transformed) as a covariate for the analysis. The outcome measure was tested at 2-sided 0.05 level to control Type I error rate.p-value: 0.7076ANCOVA
Primary
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.
Time frame: Baseline (Day 1), Month 24
Population: Analysis was performed on efficacy population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Tesevatinib | Change From Baseline in Height Adjusted Total Kidney Volume at Month 24 | 0.0485 milliliters per meter | Standard Error 0.0103 |
| Placebo | Change From Baseline in Height Adjusted Total Kidney Volume at Month 24 | 0.0607 milliliters per meter | Standard Error 0.0095 |
Comparison: An ANCOVA model included treatment group as a factor and the Baseline htTKV (log10 transformed) as a covariate for the analysis. The outcome measure was tested at 2-sided 0.05 level to control Type I error rate.p-value: 0.3895ANCOVA
Primary
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.
Time frame: Baseline (Day 1), Month 12
Population: Analysis was performed on efficacy population which included all randomized participants who received at least 1 dose of study drug and completed at least 12 months of tesevatinib or placebo treatment and had a centrally read MRI at Baseline and after 12 months of treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Tesevatinib | Change From Baseline in Height Adjusted Total Kidney Volume (htTKV) at Month 12 | 0.0236 milliliters per meter | Standard Error 0.0059 |
| Placebo | Change From Baseline in Height Adjusted Total Kidney Volume (htTKV) at Month 12 | 0.0288 milliliters per meter | Standard Error 0.0057 |
Comparison: An ANCOVA model included treatment group as a factor and the Baseline htTKV (log10 transformed) as a covariate for the analysis. The outcome measure was tested at 2-sided 0.05 level to control Type I error rate.p-value: 0.5265ANCOVA
Secondary
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.
Time frame: Baseline (Day 1), Months 12, 18, 24 and at end of study (i.e., anytime up to 26 months)
Population: Analysis was performed on efficacy population.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Tesevatinib | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Months 12, 18, 24 and End of Study | Month 12 | -6.8032 mL/min/1.73m^2 | Standard Error 1.2293 |
| Tesevatinib | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Months 12, 18, 24 and End of Study | Month 18 | -7.3626 mL/min/1.73m^2 | Standard Error 1.6645 |
| Tesevatinib | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Months 12, 18, 24 and End of Study | Month 24 | -9.7307 mL/min/1.73m^2 | Standard Error 1.4708 |
| Tesevatinib | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Months 12, 18, 24 and End of Study | End of study | -3.2757 mL/min/1.73m^2 | Standard Error 0.599 |
| Placebo | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Months 12, 18, 24 and End of Study | End of study | -3.7497 mL/min/1.73m^2 | Standard Error 0.6323 |
| Placebo | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Months 12, 18, 24 and End of Study | Month 12 | -2.1780 mL/min/1.73m^2 | Standard Error 1.1709 |
| Placebo | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Months 12, 18, 24 and End of Study | Month 24 | -6.4070 mL/min/1.73m^2 | Standard Error 1.4138 |
| Placebo | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Months 12, 18, 24 and End of Study | Month 18 | -3.8950 mL/min/1.73m^2 | Standard Error 1.6971 |
Secondary
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.
Time frame: From Baseline (Day 1) up to 30 days post last dose of study drug (i.e., up to 26 months)
Population: Analysis was performed on safety population which included all participants who received at least 1 dose of study drug and were analyzed according to the study drug they actually received.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tesevatinib | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 37 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 40 Participants |