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).
Brief Title
Study of Sparsentan in Patients With Primary 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.
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.
Completion Date
Completion Date Type
Estimated
Conditions
Focal Segmental Glomerulosclerosis
Eligibility 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 Exclusion Criteria for the Open-label Extension Based on Assessments at Week 108 and 112 visits:
* Progression to end-stage renal disease requiring replacement therapy
* The patient developed criteria for discontinuation between Week 108 and Week 112
* The patient was unable to initiate, or developed contraindications to, treatment with RAAS inhibitors between Week 108 and Week 112
* eGFR ≤20 mL/min/1.73 m2 at Week 108
* 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 Exclusion Criteria for the Open-label Extension Based on Assessments at Week 108 and 112 visits:
* Progression to end-stage renal disease requiring replacement therapy
* The patient developed criteria for discontinuation between Week 108 and Week 112
* The patient was unable to initiate, or developed contraindications to, treatment with RAAS inhibitors between Week 108 and Week 112
* eGFR ≤20 mL/min/1.73 m2 at Week 108
Inclusion Criteria
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
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)
* 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
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)
Gender
All
Gender Based
false
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Maximum Age
75 Years
Minimum Age
8 Years
NCT Id
NCT03493685
Org Class
Industry
Org Full Name
Travere Therapeutics, Inc.
Org Study Id
021FSGS16010
Overall Status
Active, not recruiting
Phases
Phase 3
Primary Completion Date
Primary Completion Date Type
Actual
Official Title
A Randomized, Multicenter, Double-blind, Parallel, Active-control Study of the Effects of Sparsentan, a Dual Endothelin Receptor and Angiotensin Receptor Blocker, on Renal Outcomes in Patients With Primary FSGS
Primary Outcomes
Outcome Description
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.
Outcome Measure
Slope of Estimated Glomerular Filtration Rate (eGFR)
Outcome Time Frame
From Day 1 to Week 108
Outcome Description
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.
Outcome Measure
Percentage of Participants Achieving FSGS Partial Remission Endpoint (FPRE)
Outcome Time Frame
Week 36
Secondary Outcomes
Outcome Description
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.
Outcome Time Frame
From Week 6 to Week 108
Outcome Measure
Slope of eGFR Following the Initial Acute Effect of Randomized Treatment
Outcome Description
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.
Outcome Time Frame
Baseline (Day 1) to Week 112
Outcome Measure
Change From Baseline in eGFR to 4 Weeks Post-cessation of Randomized Treatment
See Also Links
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Actual
First Submit Date
First Submit QC Date
Std Ages
Child
Adult
Older Adult
Locked Fields
Render the field
Maximum Age Number (converted to Years and rounded down)
75
Minimum Age Number (converted to Years and rounded down)
8
Investigators
Investigator Type
Principal Investigator
Investigator Name
Frederick Kaskel
Investigator Email
FKASKEL@montefiore.org
Investigator Phone
718-655-1120