Immunoglobulin A Nephropathy
Conditions
Brief summary
To determine the long-term (approximately 2 years) nephroprotective potential of treatment with sparsentan as compared to an angiotensin receptor blocker in patients with immunoglobulin A nephropathy (IgAN).
Detailed description
This is a 114-week,randomized, multicenter, double-blind, parallel-group, active-control study with an open-label extension period of up to 156 weeks, for a total duration of up to 270 weeks in patients with IgAN who have persistent overt proteinuria and remain at high risk of disease progression despite being on a stable dose (or doses) of an angiotensin-converting enzyme inhibitor (ACEI) and/or angiotensin receptor blocker (ARB) that is (are) a maximum tolerated dose that is at least one half of the maximum labeled dose (MLD) (according to approved labeling. Approximately 380 patients aged ≥18 years will be enrolled in the study globally. The investigational drug (sparsentan) is a dual acting angiotensin receptor blocker and endothelin receptor antagonist. The active control is irbesartan. The purpose of the study is to evaluate the potential benefit of sparsentan on kidney function by analyzing change in proteinuria (protein in urine) and estimated glomerular filtration rate (eGFR) as compared to current standard treatment. Patients enrolled in the PROTECT study (Protocol 021IGAN17001) will be those at high risk of progressing to renal failure. They will be randomly assigned in a 1:1 ratio to either sparsentan or irbesartan, as the active control (current standard treatment) at the Day 1 (Randomization) visit. Study medication (sparsentan and irbesartan) will be administered as a single oral morning dose. The primary analysis is change in proteinuria (urine protein/creatinine ratio) from baseline at Week 36 in sparsentan-treated patients as compared to irbesartan-treated patients. 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 participating in the open-label extension period may be evaluated for eligibility to participate in a randomized, open-label, controlled Sub study evaluating the safety and efficacy of an SGLT2 inhibitor in addition to stable sparsentan treatment (OLE Sub study). The SGLT2 inhibitor, dapagliflozin will be provided as "study medication" for the OLE Sub study. Following completion of the visit 12 weeks after the OLE baseline visit, eligible patients may receive open-label dapagliflozin for at least 12 weeks but up to 24 additional weeks, or through the end of the open-label extension period, whichever is shortest. Approximately 60 patients from the open-label extension period will be enrolled into the OLE Sub study.
Interventions
DRUGsparsentan
Target dose of 400 mg daily
DRUGirbesartan
Target dose of 300 mg daily
DRUGDapagliflozin
Target dose of 10 mg daily
Sponsors
Travere Therapeutics, Inc.
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 No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria for the Double-Blind Period: * Age 18 years or older at screening * Biopsy-proven primary IgAN * Proteinuria of ≥1 g/day at screening * eGFR ≥30 mL/min/1.73 m2 at screening * Currently on stable dose of ACEI and/or ARB therapy, for at least 12 weeks prior to screening (maximum tolerated dose and at least one-half of the maximum labeled dose) * Systolic BP ≤150 mmHg and diastolic BP ≤100 mmHg at screening * Willing to undergo change in ACEI and/or ARB and anti-hypertensive medications * Agree to contraception Key
Exclusion criteria
for the Double-Blind Period: * IgAN secondary to another condition * Presence of cellular glomerular crescents in \>25% of glomeruli on renal biopsy (if biopsy available within 6 months of screening) * Chronic kidney disease (CKD) in addition to IgAN * History of organ transplantation, with exception of corneal transplants * Require any prohibited medications * Treatment of systemic immunosuppressive medications (including corticosteroids) for \>2 weeks within 3 months of screening * History of heart failure or previous hospitalization for heart failure or unexplained dyspnea, orthopnea, paroxysmal nocturnal dyspnea, ascites, and/or peripheral edema * Clinically significant cerebrovascular disease or coronary artery disease within 6 months of screening * Jaundice, hepatitis, or known hepatobiliary disease or elevations of transaminases (ALT/AST) \>2 times upper limit of normal at screening * History of malignancy other than adequately treated basal cell or squamous cell skin cancer or cervical carcinoma within the past 2 years * Hematocrit value \<27% (0.27 V/V) or hemoglobin value \<9 g/dL (90 g/L) at Screening * Potassium \>5.5 mEq/L (5.5 mmol/L) at Screening * History of alcohol of illicit drug use disorder * History of serious side effect or allergic response to any angiotensin II antagonist or endothelin receptor antagonist, including sparsentan or irbesartan, or has a hypersensitivity to any of the excipients in the study medications * For female: Pregnancy, or planning to become pregnant during the course of the study, or breastfeeding * Participation in a study of another investigational product within 28 days of screening Key Inclusion Criteria for the Open-Label Extension Period based on assessments at the Week 110 visit: * Completed participation in the double-blind period, including the Week 114 visit * Did not permanently discontinue study medication during the double-blind period * Agree to contraception Key
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in the Urine Protein/Creatinine (UP/C) at Week 36 | Baseline (Day 1) and at Week 36 | 24-hour urine sample was collected for analysis of UP/C via a mixed-model repeated-measures (MMRM) analysis. Missing responses were imputed prior to analysis using multiple imputation. Change from Baseline during the double-blind period in UP/C on the log scale was the dependent variable. Log Baseline UP/C was included as a covariate along with fixed effects for randomized treatment, time (ie, nominal visit in weeks), randomized treatment-by-time interaction, and randomization strata with participants as random effect. Estimates in log scale were back transformed. Baseline was defined as the last non-missing observation on or prior to the start of the dosing. Using Rubin's approach, estimated treatment effects are combined across all imputations to obtain overall estimates. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Total Slope of Estimated Glomerular Filtration Rate (eGFR) Over a 110-week Period | From Day 1 to Week 110 | The rate of change in eGFR from Day 1 to Week 110 (ie, over 110 weeks) was analyzed via a mixed-model random coefficients analysis. Missing responses were imputed prior to analysis using multiple imputation. Fixed effects for randomized treatment, Baseline eGFR, time (in weeks), randomized treatment-by-time interaction, and randomization strata were included. In addition, the model also included a random intercept and random slope for each participant. Using Rubin's approach, the estimated treatment effects are combined across all imputations to obtain the overall estimates. |
| Annualized Slope of eGFR Following the Initial Acute Effect of Randomized Treatment (Chronic Slope) | From Week 6 to Week 110 post randomization | The rate of change in eGFR from Week 6 to Week 110 (ie, over 104 weeks following the initial acute effect of randomized therapy) was analyzed via a mixed-model random coefficients analysis. Missing responses were imputed prior to analysis using multiple imputation. Fixed effects for randomized treatment, Baseline eGFR, time (in weeks), randomized treatment-by-time interaction, and randomization strata were included. In addition, the model also included a random intercept and random slope for each participant. Using Rubin's approach, the estimated treatment effects are combined across all imputations to obtain the overall estimates. |
Countries
Australia, Belgium, Croatia, Czechia, Estonia, France, Germany, Hong Kong, Italy, Lithuania, New Zealand, Poland, Portugal, South Korea, Spain, Taiwan, United Kingdom, United States
Contacts
STUDY_DIRECTORRadko Komers, MD, PhD
Travere Therapeutics, Inc.
Participant flow
Recruitment details
The PROTECT study is a 114-week, randomized, multicenter, double-blind (DB), parallel-group, active control study, in participants with Immunoglobulin A nephropathy (IgAN) who had persistent overt proteinuria and remained at high risk of disease progression despite being on a stable dose (or doses) of an Angiotensin converting enzyme inhibitor (ACEI) and/or Angiotensin II receptor blocker (ARB) that was (were) a maximum tolerated dose
Pre-assignment details
The study was conducted across 3 regions (North America, Europe, and Asia Pacific), 18 countries, and 156 sites. The results presented are based on the double-blind period of the study.
Participants by arm
| Arm | Count |
|---|---|
| Sparsentan Participants randomized to Sparsentan received an initial dose of 200 mg (ie, one-half the target dose) tablets over-encapsulated (blinded) with size 00 capsules for the first 2 weeks after randomization. At the Week 2 visit, titration was done up to the target dose (400 mg) based on blood pressure and lack of AEs or after the Week 2 laboratory results were available (ie, between the Week 2 and Week 4 visits). | 202 |
| Irbesartan Participants randomized to Irbesartan received an initial dose of 150 mg (ie, one-half the target dose) tablets over-encapsulated (blinded) with size 00 capsules for the first 2 weeks after randomization. At the Week 2 visit, titration was done up to the target dose (300 mg) based on blood pressure and lack of AEs or after the Week 2 laboratory results were available (ie, between the Week 2 and Week 4 visits). | 202 |
| Total | 404 |
Baseline characteristics
| Characteristic | Total | Irbesartan | Sparsentan |
|---|---|---|---|
| Age, Continuous | 46.0 Years STANDARD_DEVIATION 12.44 | 45.4 Years STANDARD_DEVIATION 12.12 | 46.6 Years STANDARD_DEVIATION 12.76 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 33 Participants | 16 Participants | 17 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 368 Participants | 183 Participants | 185 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 3 Participants | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 115 Participants | 48 Participants | 67 Participants |
| Race/Ethnicity, Customized Black or African American | 4 Participants | 3 Participants | 1 Participants |
| Race/Ethnicity, Customized Multiple | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 12 Participants | 8 Participants | 4 Participants |
| Race/Ethnicity, Customized White | 272 Participants | 142 Participants | 130 Participants |
| Sex: Female, Male Female | 122 Participants | 59 Participants | 63 Participants |
| Sex: Female, Male Male | 282 Participants | 143 Participants | 139 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 202 | 1 / 202 |
| other Total, other adverse events | 187 / 202 | 177 / 202 |
| serious Total, serious adverse events | 75 / 202 | 71 / 202 |
Outcome results
Primary
Percent Change From Baseline in the Urine Protein/Creatinine (UP/C) at Week 36
24-hour urine sample was collected for analysis of UP/C via a mixed-model repeated-measures (MMRM) analysis. Missing responses were imputed prior to analysis using multiple imputation. Change from Baseline during the double-blind period in UP/C on the log scale was the dependent variable. Log Baseline UP/C was included as a covariate along with fixed effects for randomized treatment, time (ie, nominal visit in weeks), randomized treatment-by-time interaction, and randomization strata with participants as random effect. Estimates in log scale were back transformed. Baseline was defined as the last non-missing observation on or prior to the start of the dosing. Using Rubin's approach, estimated treatment effects are combined across all imputations to obtain overall estimates.
Time frame: Baseline (Day 1) and at Week 36
Population: The Primary Analysis Set (PAS) is the subset of the Full Analysis Set at the time of the data extraction for primary analysis. Participants in the PAS were analyzed according to randomized treatment assignment.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Sparsentan | Percent Change From Baseline in the Urine Protein/Creatinine (UP/C) at Week 36 | -49.77 Percent change |
| Irbesartan | Percent Change From Baseline in the Urine Protein/Creatinine (UP/C) at Week 36 | -15.05 Percent change |
p-value: <0.000195% CI: [0.51, 0.69]Mixed Models Analysis
Secondary
Annualized Slope of eGFR Following the Initial Acute Effect of Randomized Treatment (Chronic Slope)
The rate of change in eGFR from Week 6 to Week 110 (ie, over 104 weeks following the initial acute effect of randomized therapy) was analyzed via a mixed-model random coefficients analysis. Missing responses were imputed prior to analysis using multiple imputation. Fixed effects for randomized treatment, Baseline eGFR, time (in weeks), randomized treatment-by-time interaction, and randomization strata were included. In addition, the model also included a random intercept and random slope for each participant. Using Rubin's approach, the estimated treatment effects are combined across all imputations to obtain the overall estimates.
Time frame: From Week 6 to Week 110 post randomization
Population: Full Analysis Set.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sparsentan | Annualized Slope of eGFR Following the Initial Acute Effect of Randomized Treatment (Chronic Slope) | -2.7 milliliters/minute/1.73square meter/year |
| Irbesartan | Annualized Slope of eGFR Following the Initial Acute Effect of Randomized Treatment (Chronic Slope) | -3.8 milliliters/minute/1.73square meter/year |
p-value: 0.036995% CI: [0.07, 2.12]Mixed Models Analysis
Secondary
Total Slope of Estimated Glomerular Filtration Rate (eGFR) Over a 110-week Period
The rate of change in eGFR from Day 1 to Week 110 (ie, over 110 weeks) was analyzed via a mixed-model random coefficients analysis. Missing responses were imputed prior to analysis using multiple imputation. Fixed effects for randomized treatment, Baseline eGFR, time (in weeks), randomized treatment-by-time interaction, and randomization strata were included. In addition, the model also included a random intercept and random slope for each participant. Using Rubin's approach, the estimated treatment effects are combined across all imputations to obtain the overall estimates.
Time frame: From Day 1 to Week 110
Population: Full Analysis Set.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sparsentan | Total Slope of Estimated Glomerular Filtration Rate (eGFR) Over a 110-week Period | -2.9 milliliters/minute/1.73square meter/year |
| Irbesartan | Total Slope of Estimated Glomerular Filtration Rate (eGFR) Over a 110-week Period | -3.9 milliliters/minute/1.73square meter/year |
p-value: 0.058295% CI: [-0.03, 1.94]Mixed Models Analysis