Immunoglobulin A Nephropathy
Conditions
Keywords
IgAN
Brief summary
This was a 28-week, open-label, multicenter, single-group Phase 2 exploratory study to determine the safety and effect of sparsentan in participants with IgAN who are at risk of disease progression to kidney failure despite being on both stable RAASi and SGLT2 inhibitor treatment for at least 12 weeks prior to study entry
Detailed description
This was a 28-week, open-label, multicenter, single-group Phase 2 exploratory study to determine the safety and effect of sparsentan in participants with Immunoglobulin A Nephropathy (IgAN) who are at risk of disease progression to kidney failure (KF) despite being on both stable renin angiotensin aldosterone system inhibitor (RAASi) and sodium glucose cotransporter-2 (SGLT2) inhibitor treatment for at least 12 weeks prior to study entry. Participants who provided written informed consent were assessed for eligibility and underwent baseline evaluations including clinical laboratory tests. Per the eligibility criteria, all participants were required to be on a stable dose(s) of angiotensin converting enzyme inhibitor (ACEI) and/or angiotensin receptor blocker (ARB) and on a stable dose of a SGLT2 inhibitor at screening and continued their stable treatments through the screening period. Eligible participants discontinued ACEI and/or ARB therapy the day before the Day 1 visit and remained on stable SGLT2 inhibitor dosing for the duration of the study. Study intervention was administered daily for a treatment period of 24 weeks with study visits conducted at weeks 2-, 4-, 12-, and 24- following Day 1. Following the 24-week treatment period, study intervention was discontinued for 4 weeks and standard of care RAASi treatment resumed, with a safety visit at Week 28.
Interventions
DRUGSparsentan
Target dose of 400 mg daily
Sponsors
Travere Therapeutics, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Aged ≥18 years at the time of signing the informed consent. * Biopsy-proven IgAN. The biopsy may have been performed at any time in the past. * UA/C ≥0.3 g/g at screening * An eGFR value of ≥25 mL/min/1.73m\^2 at screening. * On a stable dose of an SGLT2 inhibitor for at least 12 weeks prior to screening. * On a stable dose of ACEI and/or ARB therapy for at least 12 weeks prior to screening that is: * The participant's maximum tolerated dose (MTD), and * at least one half of the maximum labeled dose (MLD) * Systolic BP must be ≤160 mmHg, and diastolic BP must be ≤110 mmHg at screening. * For participants receiving chronic low dose systemic corticosteroids (defined as ≤10 mg/day prednisone or equivalent), or an enteric formulation of budesonide and/or a mineralocorticoid receptor antagonist (MRA), the dosage must be stable for ≥12 weeks prior to screening.
Exclusion criteria
* IgAN secondary to another condition or immunoglobulin A (IgA) vasculitis. * Undergone any organ transplant, with the exception of corneal transplants. * Documented history of heart failure. * Taking high dose (defined as \>10 mg/day prednisone) or other any systemic immunosuppressive medications within 12 weeks of prior to screening. * Has clinically significant cerebrovascular disease (transient ischemic attack or stroke) and/or coronary artery disease (hospitalization for myocardial infarction unstable angina, new onset of angina with positive functional tests, coronary angiogram revealing stenosis, or a coronary revascularization procedure) within 3 months prior to screening. * Has jaundice, hepatitis, or known hepatobiliary disease (excluding asymptomatic cholelithiasis), or ALT and/or AST \>2 times the ULN range at screening. * Has a history of malignancy other than adequately treated basal cell or squamous cell skin cancer or cervical carcinoma within the past 2 years. * Has a history of serious side effect or allergic response to any AngII antagonist, ERA or sparsentan, or has a hypersensitivity to any of the excipients in the study intervention. * Requires any of the prohibited concomitant medications. * Treatment with sparsentan within 12 weeks prior to screening * Has participated in a study of another investigational product within 28 days prior to screening or plans to participate in such a study during the course of this study. * Has a screening hematocrit value \<27% (0.27 Volume/Volume) or hemoglobin value \<9 g/dL (90 g/L). * Has a screening potassium value of \>5.5 mEq/L (5.5 mmol/L). * Is pregnant, plans to become pregnant during the course of the study, or is breastfeeding. * The participant, in the opinion of the Investigator, is unable to adhere to the requirements of the study, including the ability to swallow the study intervention capsules whole.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Urine Albumin-creatinine Ratio (UA/C) at Week 24 | Week 24 | The change from baseline in UA/C at Week 24 based on first morning void (FMV) samples |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 30% Reduction From Baseline in UA/C at Week 24 | Week 24 | Achievement of 30% reduction from baseline in UA/C at Week 24 based on FMV samples |
| 50% Reduction From Baseline in UA/C at Week 24 | Week 24 | Achievement of 50% reduction from baseline in UA/C at Week 24 based on FMV samples |
| Change in Urine Protein-to-creatinine Ratio (UP/C) at Week 24 | Week 24 | The change from baseline in UP/C at Week 24 based on FMV samples |
| UA/C <0.2 g/g at Week 24 | Week 24 | Achievement of UA/C of \<0.2 g/g at Week 24 based on FMV samples |
| Systolic Blood Pressure (BP) at Week 24 | Week 24 | The change from baseline in systolic BP at Week 24 |
| Change in Diastolic Blood Pressure (BP) | Week 24 | The change from baseline in diastolic BP at Week 24 |
| Estimated Glomerular Filtration Rate (eGFR) | Week 24 | Change from baseline estimated glomerular filtration rate at 24 weeks |
Countries
Hong Kong, United States
Participant flow
Recruitment details
Forty-eight participants were enrolled in the study and all 48 (100%) received at least 1 dose of sparsentan. Sparsentan was prematurely discontinued in 9 participants (19%). Forty-one participants (85%) completed the study, and 7 participants (15%) discontinued the study. The most common reasons for discontinuation from the study were withdrawal by participant (3 participants \[6%\]) and AEs (2 participants \[4%\]).
Pre-assignment details
93 participants were screened; 45 participants were screen failures. * 29 participants did not meet the inclusion criteria of UA/C ≥0.3 g/g * 7 participants did not meet the inclusion criteria of being on a stable dose of ACEI and/or ARB * 5 participants did not meet the inclusion criteria of being on a stable dose of an SGLT2 inhibitor * 4 participants were excluded for other reasons
Participants by arm
| Arm | Count |
|---|---|
| Sparsentan Sparsentan will be administered daily as a 200-mg oral tablet. The goal is to titrate from the initial dose of 200 mg (Day 1) to the target dose of 400 mg at Week 2.
Sparsentan: Target dose of 400 mg daily | 48 |
| Total | 48 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 2 |
| Overall Study | Physician Decision | 1 |
| Overall Study | Protocol Violation | 1 |
| Overall Study | Withdrawal by Subject | 3 |
Baseline characteristics
| Characteristic | Sparsentan |
|---|---|
| Age, Continuous | 48 years |
| BMI | 30.02 kg/m^2 STANDARD_DEVIATION 5.619 |
| Estimated Glomerular Filtration Rate (eGFR) <25 mL/min/1.73m^2 | 0 participants |
| Estimated Glomerular Filtration Rate (eGFR) >/=25 to <60 mL/min/173m^2 | 33 participants |
| Estimated Glomerular Filtration Rate (eGFR) >/=60 mL/min/1.73m^2 | 15 participants |
| Height | 168.2 centimeters STANDARD_DEVIATION 11.16 |
| Race/Ethnicity, Customized Ethnicity Hispanic or Latino | 5 Participants |
| Race/Ethnicity, Customized Ethnicity Not Hispanic or Latino | 42 Participants |
| Race/Ethnicity, Customized Ethnicity Not Reported | 1 Participants |
| Race/Ethnicity, Customized Race Asian | 19 Participants |
| Race/Ethnicity, Customized Race Black or African American | 1 Participants |
| Race/Ethnicity, Customized Race White | 28 Participants |
| Region of Enrollment Hong Kong | 11 participants |
| Region of Enrollment United States | 37 participants |
| Sex: Female, Male Female | 20 Participants |
| Sex: Female, Male Male | 28 Participants |
| Urine albumin/creatinine ratio (UA/C) | 0.75 g/g |
| Urine protein/creatinine ratio (UP/C) | 1.29 g/g |
| Weight | 85.9 Kilograms STANDARD_DEVIATION 22.25 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 48 |
| other Total, other adverse events | 26 / 48 |
| serious Total, serious adverse events | 4 / 48 |
Outcome results
Primary
Change in Urine Albumin-creatinine Ratio (UA/C) at Week 24
The change from baseline in UA/C at Week 24 based on first morning void (FMV) samples
Time frame: Week 24
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sparsentan | Change in Urine Albumin-creatinine Ratio (UA/C) at Week 24 | -55.78 percent change |
Secondary
30% Reduction From Baseline in UA/C at Week 24
Achievement of 30% reduction from baseline in UA/C at Week 24 based on FMV samples
Time frame: Week 24
Population: UA/C Responder Endpoints While on Treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sparsentan | 30% Reduction From Baseline in UA/C at Week 24 | 77 percentage of participants |
Secondary
50% Reduction From Baseline in UA/C at Week 24
Achievement of 50% reduction from baseline in UA/C at Week 24 based on FMV samples
Time frame: Week 24
Population: Full Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sparsentan | 50% Reduction From Baseline in UA/C at Week 24 | 51 percentage of participants |
Secondary
Change in Diastolic Blood Pressure (BP)
The change from baseline in diastolic BP at Week 24
Time frame: Week 24
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sparsentan | Change in Diastolic Blood Pressure (BP) | -4.6 mmHg |
Secondary
Change in Urine Protein-to-creatinine Ratio (UP/C) at Week 24
The change from baseline in UP/C at Week 24 based on FMV samples
Time frame: Week 24
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sparsentan | Change in Urine Protein-to-creatinine Ratio (UP/C) at Week 24 | -45.20 percentage change |
Secondary
Estimated Glomerular Filtration Rate (eGFR)
Change from baseline estimated glomerular filtration rate at 24 weeks
Time frame: Week 24
Population: Full Analysis Set
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Sparsentan | Estimated Glomerular Filtration Rate (eGFR) | -2.0 mL/min/1.73 square meter |
Secondary
Systolic Blood Pressure (BP) at Week 24
The change from baseline in systolic BP at Week 24
Time frame: Week 24
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sparsentan | Systolic Blood Pressure (BP) at Week 24 | -3.4 mmHg |
Secondary
UA/C <0.2 g/g at Week 24
Achievement of UA/C of \<0.2 g/g at Week 24 based on FMV samples
Time frame: Week 24
Population: Full Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sparsentan | UA/C <0.2 g/g at Week 24 | 31 percentage of participants |