Focal Segmental Glomerulosclerosis
Conditions
Brief summary
To determine the long-term nephroprotective potential of treatment with sparsentan as compared to an angiotensin receptor blocker in patients with primary and genetic focal segmental glomerulosclerosis (FSGS).
Detailed description
This is a randomized, multicenter, double-blind, parallel, active-control study. Approximately 300 patients aged 8 to 75 years (inclusive) will be enrolled in the study. The study will be conducted in approximately 300 study centers, globally. The investigational drug (sparsentan) is a dual-acting angiotensin receptor blocker and endothelin receptor antagonist. The active control is irbesartan. Patients who meet eligibility criteria will require washout from renin-angiotensin-aldosterone system (RAAS) blockers, if applicable prior to their first dose of study drug. Patients will be randomly assigned in a 1:1 ratio to receive either sparsentan or active control (irbesartan). After completing the double-blind portion of the study, patients may participate in the open-label extension for treatment with sparsentan if they meet eligibility criteria. Primary completion date represents the anticipated completion date of the double-blind portion of the study. Study completion date represents the anticipated completion date of the open-label extension portion of the study.
Interventions
DRUGsparsentan
Double-blind period: target dose of 800 mg daily; Open-label extension: target dose based on dosage from week 114 daily
DRUGIrbesartan
target dose of 300 mg daily
Sponsors
Travere Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
8 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria for the Double-blind Period: * Sites within the US and UK: The patient is male or female aged 8 to 75 years, inclusive, weighing ≥20 kg at screening * Sites outside the US and UK: The patient is male or female aged 18 to 75 years, inclusive, weighing ≥20 kg at screening * Biopsy-proven focal segmental glomerulosclerosis (FSGS) lesion(s) or documentation of a genetic mutation in a podocyte protein associated with FSGS. * Urine protein/creatinine (UP/C) ≥1.5 g/g (170 mg/mmol) at screening * eGFR ≥30 mL/min/1.73 m2 at screening. * Women of childbearing potential must agree to the use of one highly reliable method of contraception from 7 days prior to the first dose of study medication until 90 days after the last dose of study medication, plus one additional barrier method during sexual activity Key
Exclusion criteria
for the Double-blind Period: * FSGS secondary to another condition * Positive serological tests of another primary or secondary glomerular disease not consistent with a diagnosis of primary or genetic FSGS * History of type 1 diabetes mellitus, uncontrolled type 2 diabetes mellitus, or nonfasting blood glucose \>180 mg/dL (10.0 mmol/L) * Treated with rituximab, cyclophosphamide, or abatacept within ≤3 months prior to screening; if taking other chronic immunosuppressive medications, the dosage must be stable prior to screening * Documented history of heart failure, coronary artery disease, or cerebrovascular disease * Significant liver disease * Positive at screening for the human immunodeficiency virus or markers indicating acute or chronic hepatitis B virus infection or hepatitis C infection * History of malignancy other than adequately treated basal cell or squamous cell skin cancer or cervical carcinoma within the past 2 years * Screening hematocrit value \<27% (0.27 L/L) or hemoglobin value \<9 g/dL (90 g/L) * Screening potassium value of \>5.5 mEq/L (5.5 mmol/L) * Extreme obesity (ie, ≥18 years of age with a body mass index (BMI) \>40, or is \<18 years of age with a BMI in the 99th percentile plus 5 units at screening, in whom there is a causal relationship between obesity and the development of FSGS * History of alcohol or illicit drug use disorder * History of serious side effect or allergic response to any angiotensin II antagonist or endothelin receptor antagonist * Female patient is pregnant, plans to become pregnant during the course of the study, or is breastfeeding. Key Inclusion Criteria for the Open-label Extension Based on assessments at the Week 108 visit: * Complete participation in the double-blind period, including the Week 112 visit. * Patient received blinded study medication through the duration of the double-blind period (ie, did not permanently discontinue study medication) Key
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Slope of Estimated Glomerular Filtration Rate (eGFR) | From Day 1 to Week 108 | The total eGFR slope over 2 years, defined as the slope of eGFR following initiation of randomized treatment (ie, Day 1 to Week 108). Estimates are calculated from a mixed-effects model with treatment, Baseline eGFR, analysis visit, treatment-by-analysis visit, randomization stratification factors as fixed effects, and intercept and slope for each participant as a random effect. |
| Percentage of Participants Achieving FSGS Partial Remission Endpoint (FPRE) | Week 36 | Percentage of participants achieving FPRE, defined as urine protein-to-creatinine ratio (UP/C) ≤1.5 grams/gram (g/g) (170 milligrams per millimoles \[mg/mmol\]) and a \>40% reduction from Baseline was analyzed using a generalized linear model to model probability of achieving FPRE. Missing responses were imputed prior to analysis using multiple imputation. A generalized linear model with appropriate link function was implemented with Baseline log (UP/C), treatment, analysis visit, treatment by analysis visit interaction, and randomization strata as fixed effects. For estimates of probability of achieving FPRE, risk difference, and odds ratio, binomial distribution with logit link was used. For relative risk, Poisson distribution with log link was used. Using Rubin's approach, estimated treatment effects are combined across all imputations to obtain overall estimates for probabilities. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Slope of eGFR Following the Initial Acute Effect of Randomized Treatment | From Week 6 to Week 108 | The chronic eGFR slope over 2 years, defined as the slope of eGFR following the initial acute effect of randomized treatment (ie, Week 6 to Week 108). Estimates were calculated from a mixed-effects model with linear spline (ie, change point at Week 6), which included treatment, Baseline eGFR, time from Baseline (TFB) (weeks), time from change point (TFCP) (weeks), treatment-by-TFB and treatment-by-TFCP interactions, and randomization stratification factors as fixed effects, intercept and slopes as random effects. The slope difference was tested by the null hypothesis that the sum of the treatment-by-TFB and treatment-by-TFCP interactions = 0. |
| Change From Baseline in eGFR to 4 Weeks Post-cessation of Randomized Treatment | Baseline (Day 1) to Week 112 | The change from Baseline to 4 weeks post-cessation of randomized treatment (Week 112) was analyzed via an analysis of covariance (ANCOVA) model on the natural log(eGFR) with treatment, Baseline eGFR, and randomization strata as fixed effects. Only participants who completed the 108-week treatment period were included. Estimated LS Mean and 95% CI are converted to percentages as follows: \[exponential (LS mean change from baseline in natural log(eGFR)) minus 1\] multiplied by 100. Baseline (Day 1) was defined as the last non-missing assessment prior to and including the first administration of study medication in the study including unscheduled assessments. Percent change from Baseline was calculated as "\[(Post Baseline minus Baseline value)/ Baseline value\] multiplied by 100. |
Countries
Argentina, Australia, Belgium, Brazil, Canada, Croatia, Czechia, Denmark, Estonia, France, Germany, Hong Kong, Italy, New Zealand, Poland, Portugal, South Korea, Spain, Sweden, Taiwan, United Kingdom, United States
Contacts
STUDY_DIRECTORRadko Komers, MD, PhD
Travere Therapeutics, Inc.
Participant flow
Recruitment details
The DUPLEX study is a 112-week, Phase 3, randomized, multicenter, double-blind (DB), parallel, active-control study that evaluated the safety, tolerability, and long-term nephroprotective potential of treatment with sparsentan as compared to irbesartan in participants with focal segmental glomerulosclerosis (FSGS).
Pre-assignment details
The study included participants 8 to 75 years of age from the United States (US) and United Kingdom (UK), and participants 18 to 75 years of age from countries other than the US and UK. The results presented are based on the primary analysis.
Participants by arm
| Arm | Count |
|---|---|
| Sparsentan Participants were randomized to receive initial dose of Sparsentan as 400 milligrams (mg) over-encapsulated (blinded) with size 00 capsules orally once daily. A dose adjustment was made for participants whose body weight was ≤50 kilograms (kg) at screening; these participants received one-half of the specified dose of Sparsentan. The dose was then titrated to achieve the maximum daily target dose of 800 mg. | 184 |
| Irbesartan Participants were randomized to receive active control doses of Irbesartan 150 mg over-encapsulated (blinded) with size 00 capsules orally once daily. A dose adjustment was made for participants whose body weight was ≤50 kg at screening; these participants received one-half of the specified dose of Irbesartan. The dose was then titrated to achieve the maximum daily target dose of 300 mg. | 187 |
| Total | 371 |
Baseline characteristics
| Characteristic | Irbesartan | Total | Sparsentan |
|---|---|---|---|
| Age, Continuous | 41.5 Years STANDARD_DEVIATION 17.25 | 41.6 Years STANDARD_DEVIATION 16.87 | 41.7 Years STANDARD_DEVIATION 16.53 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 44 Participants | 78 Participants | 34 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 135 Participants | 282 Participants | 147 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 8 Participants | 11 Participants | 3 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 27 Participants | 50 Participants | 23 Participants |
| Race/Ethnicity, Customized Black or African American | 9 Participants | 25 Participants | 16 Participants |
| Race/Ethnicity, Customized Multiple | 4 Participants | 7 Participants | 3 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Other | 12 Participants | 17 Participants | 5 Participants |
| Race/Ethnicity, Customized White | 135 Participants | 269 Participants | 134 Participants |
| Sex: Female, Male Female | 88 Participants | 171 Participants | 83 Participants |
| Sex: Female, Male Male | 99 Participants | 200 Participants | 101 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 4 / 184 | 3 / 187 |
| other Total, other adverse events | 172 / 184 | 174 / 187 |
| serious Total, serious adverse events | 68 / 184 | 82 / 187 |
Outcome results
Primary
Percentage of Participants Achieving FSGS Partial Remission Endpoint (FPRE)
Percentage of participants achieving FPRE, defined as urine protein-to-creatinine ratio (UP/C) ≤1.5 grams/gram (g/g) (170 milligrams per millimoles \[mg/mmol\]) and a \>40% reduction from Baseline was analyzed using a generalized linear model to model probability of achieving FPRE. Missing responses were imputed prior to analysis using multiple imputation. A generalized linear model with appropriate link function was implemented with Baseline log (UP/C), treatment, analysis visit, treatment by analysis visit interaction, and randomization strata as fixed effects. For estimates of probability of achieving FPRE, risk difference, and odds ratio, binomial distribution with logit link was used. For relative risk, Poisson distribution with log link was used. Using Rubin's approach, estimated treatment effects are combined across all imputations to obtain overall estimates for probabilities.
Time frame: Week 36
Population: Full Analysis Set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sparsentan | Percentage of Participants Achieving FSGS Partial Remission Endpoint (FPRE) | 42.0 Percentage of participants |
| Irbesartan | Percentage of Participants Achieving FSGS Partial Remission Endpoint (FPRE) | 26.0 Percentage of participants |
p-value: 0.009495% CI: [3.96, 28.04]Mixed Models Analysis
Primary
Slope of Estimated Glomerular Filtration Rate (eGFR)
The total eGFR slope over 2 years, defined as the slope of eGFR following initiation of randomized treatment (ie, Day 1 to Week 108). Estimates are calculated from a mixed-effects model with treatment, Baseline eGFR, analysis visit, treatment-by-analysis visit, randomization stratification factors as fixed effects, and intercept and slope for each participant as a random effect.
Time frame: From Day 1 to Week 108
Population: Full Analysis Set.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sparsentan | Slope of Estimated Glomerular Filtration Rate (eGFR) | -5.4 milliliters/minute/1.73square meter/year |
| Irbesartan | Slope of Estimated Glomerular Filtration Rate (eGFR) | -5.7 milliliters/minute/1.73square meter/year |
p-value: 0.749195% CI: [-1.74, 2.41]Mixed Models Analysis
Secondary
Change From Baseline in eGFR to 4 Weeks Post-cessation of Randomized Treatment
The change from Baseline to 4 weeks post-cessation of randomized treatment (Week 112) was analyzed via an analysis of covariance (ANCOVA) model on the natural log(eGFR) with treatment, Baseline eGFR, and randomization strata as fixed effects. Only participants who completed the 108-week treatment period were included. Estimated LS Mean and 95% CI are converted to percentages as follows: \[exponential (LS mean change from baseline in natural log(eGFR)) minus 1\] multiplied by 100. Baseline (Day 1) was defined as the last non-missing assessment prior to and including the first administration of study medication in the study including unscheduled assessments. Percent change from Baseline was calculated as \[(Post Baseline minus Baseline value)/ Baseline value\] multiplied by 100.
Time frame: Baseline (Day 1) to Week 112
Population: Full Analysis Set (Patients who Completed Blinded Treatment). Only those participants with data available at specified time points have been presented.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Sparsentan | Change From Baseline in eGFR to 4 Weeks Post-cessation of Randomized Treatment | -10.4 milliliters/minute/1.73square meter |
| Irbesartan | Change From Baseline in eGFR to 4 Weeks Post-cessation of Randomized Treatment | -12.1 milliliters/minute/1.73square meter |
p-value: 0.270895% CI: [-1.39, 4.93]ANCOVA
Secondary
Slope of eGFR Following the Initial Acute Effect of Randomized Treatment
The chronic eGFR slope over 2 years, defined as the slope of eGFR following the initial acute effect of randomized treatment (ie, Week 6 to Week 108). Estimates were calculated from a mixed-effects model with linear spline (ie, change point at Week 6), which included treatment, Baseline eGFR, time from Baseline (TFB) (weeks), time from change point (TFCP) (weeks), treatment-by-TFB and treatment-by-TFCP interactions, and randomization stratification factors as fixed effects, intercept and slopes as random effects. The slope difference was tested by the null hypothesis that the sum of the treatment-by-TFB and treatment-by-TFCP interactions = 0.
Time frame: From Week 6 to Week 108
Population: Full Analysis Set.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sparsentan | Slope of eGFR Following the Initial Acute Effect of Randomized Treatment | -4.8 milliliters/minute/1.73square meter/year |
| Irbesartan | Slope of eGFR Following the Initial Acute Effect of Randomized Treatment | -5.7 milliliters/minute/1.73square meter/year |
p-value: 0.420395% CI: [-1.27, 3.04]Mixed Models Analysis