Efficacy and Safety Evaluation of Sparsentan in Patients with Immunoglobulin A Nephropathy: A Randomized, Double-Blind, Active-Controlled Study
- Trial ID
- 2023-505495-30-00
- Protocol
- 021IGAN17001
- Sponsor
- Travere Therapeutics Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of sparsentan in reducing proteinuria and preserving renal function in patients with **Immunoglobulin A Nephropathy (IgAN)**, compared to an angiotensin receptor blocker (ARB). This is clinically relevant as proteinuria and renal function are critical indicators of disease progression in IgAN, and effective management can potentially slow the progression to end-stage renal disease.
The study also aims to assess the **safety** and tolerability of sparsentan through double-blind monitoring of safety endpoints. Additionally, the long-term efficacy, safety, and tolerability of open-label treatment with sparsentan in patients with IgAN will be evaluated. These objectives are crucial for understanding the overall risk-benefit profile of sparsentan in the treatment of IgAN.
Participants
The clinical trial involves a total of **241 participants** diagnosed with **Immunoglobulin A Nephropathy (IgAN)**. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on specific criteria, including a biopsy-proven diagnosis of IgAN and a stable dose of ACEI and/or ARB therapy for at least 12 weeks prior to screening. The trial population is characterized by a urine protein excretion value of at least 1.0 g/day and an estimated glomerular filtration rate (eGFR) of at least 30 mL/min/1.73 m² at screening. Participants are required to maintain a systolic blood pressure of 150 mmHg or lower and a diastolic blood pressure of 100 mmHg or lower. The study includes individuals who are part of a vulnerable population, and lifestyle considerations such as diet and physical activity are not specified. Women of childbearing potential must adhere to strict contraceptive measures throughout the study duration. The trial aims to evaluate the efficacy and safety of sparsentan in comparison to an angiotensin receptor blocker (ARB) in managing proteinuria and preserving renal function in patients with IgAN.
Plans and Procedures
The clinical trial is designed as a **randomized**, double-blind, parallel-group, active-control study to evaluate the efficacy and safety of **sparsentan** in the treatment of **Immunoglobulin A Nephropathy (IgAN)**. The trial involves multiple phases, including a double-blind period and an open-label extension period. The primary objective is to assess the effect of sparsentan on proteinuria and renal function preservation compared to an angiotensin receptor blocker (ARB). The trial also aims to evaluate the safety and tolerability of sparsentan through double-blind monitoring of safety endpoints. The study is expected to conclude by July 28, 2026, with recruitment having started on February 11, 2019.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, biopsy-proven IgAN, and stable blood pressure. The double-blind period will include regular follow-up visits to monitor efficacy and safety endpoints, with the primary efficacy endpoint being the change in urine protein/creatinine ratio at Week 36. The open-label extension period will allow for long-term assessment of sparsentan's efficacy and safety, with visits scheduled to evaluate changes in eGFR, quality of life, and other clinical parameters.
The expected duration of participant involvement varies, with the double-blind period lasting up to 114 weeks, followed by the open-label extension period. Participants may be withdrawn from the study early if they experience significant adverse events, fail to adhere to the study protocol, or choose to discontinue participation. The study also includes a sub-study involving the combination of sparsentan with an SGLT2 inhibitor, requiring additional eligibility criteria and assessments.
Treatment
The clinical trial involves the administration of **Sparsentan**, a chemical compound provided in tablet form. The pharmaceutical product, identified as Sparsentan_DF3, is manufactured by Travere Therapeutics, Inc. The maximum daily dose of Sparsentan is 400 mg, administered orally. The treatment period for Sparsentan is up to 270 days. Sparsentan is designated as an orphan drug, with the designation number EU/3/20/2345, indicating its use in rare conditions. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen.
Another experimental medication used in the trial is **Dapagliflozin**, also in the form of a film-coated tablet. The maximum daily dose for Dapagliflozin is 10 mg, administered orally. The treatment duration for Dapagliflozin is limited to 12 days. This medication serves as a comparator in the study, providing a basis for evaluating the efficacy and safety of Sparsentan. Participant compliance with Dapagliflozin administration is similarly monitored to maintain the integrity of the trial data.
**Irbesartan** is included as a non-experimental treatment in the study, provided in tablet form. The maximum daily dose of Irbesartan is 300 mg, administered orally. The treatment period for Irbesartan extends up to 156 days. Irbesartan tablets are over-encapsulated to maintain blinding in the study. This medication acts as an angiotensin receptor blocker (ARB) comparator, allowing for the assessment of Sparsentan's effect on proteinuria and renal function preservation in patients with immunoglobulin A nephropathy (IgAN).
Additionally, Sparsentan_DF2, another formulation of Sparsentan, is utilized in the trial. It is also provided in tablet form with a maximum daily dose of 400 mg, administered orally. The treatment period for Sparsentan_DF2 is up to 270 days, similar to Sparsentan_DF3. This formulation is also designated as an orphan drug, supporting its use in the treatment of rare diseases. Monitoring of participant compliance with Sparsentan_DF2 is conducted to ensure accurate assessment of its efficacy and safety.
Efficacy
The efficacy of the clinical trial will be assessed by evaluating the effect of **sparsentan** on proteinuria and the preservation of renal function in patients with Immunoglobulin A Nephropathy (IgAN). The primary efficacy endpoint is the change from baseline in the urine protein/creatinine ratio (UP/C) at Week 36. Additionally, the open-label extension period will assess the absolute and percent change from Week 114 in estimated glomerular filtration rate (eGFR) at each visit, as well as the percent change from Week 114 in UP/C at each visit.
For the Sparsentan + SGLT2 Inhibitor Sub-study, efficacy endpoints include the mean change from Sub-study baseline in UP/C and urinary albumin/creatinine ratio (UA/C) based on a 24-hour urine sample at the next scheduled visit, and the achievement of urinary protein excretion of less than 0.3 g/day at the next scheduled visit. The change in absolute and percent change from Sub-study baseline in eGFR at the next scheduled visit will also be evaluated. These assessments will be conducted using validated laboratory tests and patient-reported outcomes at specified timepoints throughout the study.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Double-Blind Period: Male or female, aged ≥18 years.
- Double-Blind Period: Biopsy-proven IgAN.
- Double-Blind Period: Urine protein excretion value ≥1.0 g/day at screening.
- Double-Blind Period: eGFR value of ≥30 mL/min/1.73 m2 at screening.
- Double-Blind Period: The patient has been on a stable dose of ACEI and/or ARB therapy for at least 12 weeks prior to screening.
- Double-Blind Period: At screening, systolic blood pressure ≤150 mmHg and diastolic blood pressure ≤100 mmHg.
- Double-Blind Period: Women of childbearing potential (WOCBP) must agree to the use of two forms of contraception.
- Open-Label Extension Period: Based on assessments at the Week 110 and Week 114 visit, a patient must meet all of the following criteria to be eligible for the open-label extension period. The patient completed participation in the double-blind period, including the Week 114 visit.
- Open-Label Extension Period: The patient is willing and able to provide signed informed consent for participation in the open-label extension period.
- Open-Label Extension Period: The patient did not permanently discontinue study medication during the double-blind period.
- Open-Label Extension Period: WOCBP, beginning at menarche, must agree to the use of 1 highly reliable (ie, can achieve a failure rate of <1% per year) method of contraception from 7 days prior to the first dose of study medication until 90 days after the last dose of study medication (including open-label sparsentan). One additional barrier method must also be used during sexual activity, such as a diaphragm or diaphragm with spermicide (preferred), or male partner's use of male condom or male condom with spermicide (preferred), from the Week 114 visit until 90 days after the last dose of study medication.
- Sparsentan + SGLT2 Inhibitor Sub-study: Based on assessments at a regularly scheduled open-label extension visit, a patient must meet all of the following criteria to be eligible for the Sub-study: The patient is participating in the open-label extension and is willing and able to provide signed informed consent for participation in the open-label extension period Sub-study.
- Sparsentan + SGLT2 Inhibitor Sub-study: The patient has a urine protein excretion value of ≥0.3 g/day.
- Sparsentan + SGLT2 Inhibitor Sub-study: The patient has an eGFR of ≥25 mL/min/1.73m2.
- Sparsentan + SGLT2 Inhibitor Sub-study: The patient is on a stable dose of sparsentan for ≥8 weeks in the open-label extension period that is the maximum tolerated dose.
- Sparsentan + SGLT2 Inhibitor Sub-study: The patient has ≥12 weeks of the study remaining.
- Sparsentan + SGLT2 Inhibitor Sub-study: The patient fulfils local requirements, recommendations and does not have contraindications for on-label prescription of dapagliflozin.
Exclusion Criteria
- Double-Blind Period: IgAN secondary to another condition.
- Double-Blind Period: Cellular glomerular crescents present in >25% of glomeruli on renal biopsy within 6 months prior to screening.
- Double-Blind Period: The patient has a chronic kidney disease in addition to IgAN.
- Double-Blind Period: Any organ transplantation, with the exception of corneal transplants.
- Double-Blind Period: Treatment with any of the prohibited concomitant medications.
- Double-Blind Period: Treatment with any systemic immunosuppressive medications (including corticosteroids) for >2 weeks within 3 months prior to screening
- Double-Blind Period: Documented history of heart failure and/or previous hospitalization for heart failure or unexplained dyspnea, orthopnea, paroxysmal nocturnal dyspnea, ascites, and/or peripheral edema.
- Double-Blind Period: Clinically significant cerebrovascular disease and/or coronary artery disease.
- Double-Blind Period: Jaundice, hepatitis, or known hepatobiliary disease (excluding asymptomatic cholelithiasis), or transaminase levels >2 times the upper limit of the normal range at screening.
- Double-Blind Period: History of malignancy other than adequately treated basal cell or squamous cell skin cancer or cervical carcinoma within the past 2 years.
- Double-Blind Period: A screening hematocrit value <27% (0.27 Volume/Volume) or hemoglobin value <9 g/dL (90 g/L).
- Double-Blind Period: A screening potassium value of >5.5 mEq/L (5.5 mmol/L).
- Double-Blind Period: Female patient is pregnant, breastfeeding or planning to conceive during the study.
- Double-Blind Period: Participation in a study of another investigational product within 28 days prior to screening.
- Open-Label Extension Period: Based on assessments at the Week 110 and Week 114 visits, a patient who meets any of the following criteria will be excluded from the open-label extension period: The patient has progressed to end-stage renal disease (ESRD) requiring renal replacement therapy (RRT).
- Open-Label Extension Period: The patient developed any criteria for discontinuation of study medication or discontinuation from the study, respectively, between Week 110 and Week 114.
- Open-Label Extension Period: The patient was unable to initiate, or developed contraindications to, treatment with RAAS inhibitors between Week 110 and Week 114.
- Open-Label Extension Period: The patient has an eGFR value of ≤20 mL/min/1.73 m2 at Week 110.
- Open-Label Extension Period: The patient has a potassium value of >5.5 mEq/L (5.5 mmol/L).
- Open-Label Extension Period: The female patient is pregnant or is breastfeeding.
- Sparsentan + SGLT2 inhibitor Sub-study: Based on assessments at an open-label extension visit, a patient who meets any of the following criteria will be excluded from participation in the open-label extension period Sub-study: The patient has progressed to ESRD requiring RRT.
- Sparsentan + SGLT2 inhibitor Sub-study: The patient has initiated or changed dose of a systemic immunosuppressive medication (including systemic steroids) within 12 weeks.
- Sparsentan + SGLT2 inhibitor Sub-study: The patient has been taking an SGLT2 inhibitor within 12 weeks.
- Sparsentan + SGLT2 inhibitor Sub-study: The patient, in the opinion of the Investigator, is unable to adhere to the requirements of the Sub-study.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 11 Feb 2019 | 12 |
 Croatia | Not Recruiting | 11 Feb 2019 | 11 |
 Czechia | Not Recruiting | 11 Feb 2019 | 13 |
 Estonia | Not Recruiting | 11 Feb 2019 | 7 |
 France | Not Recruiting | 11 Feb 2019 | 13 |
 Germany | Not Recruiting | 11 Feb 2019 | 16 |
 Italy | Not Recruiting | 11 Feb 2019 | 27 |
 Lithuania | Not Recruiting | 11 Feb 2019 | 11 |
 Poland | Not Recruiting | 11 Feb 2019 | 10 |
 Portugal | Not Recruiting | 11 Feb 2019 | 12 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
IRBESARTAN | Test | — | ORAL USE | 300 | 156 | SUB08293MIG |
DAPAGLIFLOZIN | Test | — | ORAL USE | 10 | 12 | SUB31650 |
Sparsentan_DF3 | Test | TABLET | ORAL USE | 400 | 270 | PRD11161698 |
Sparsentan_DF2 | Test | TABLET | ORAL USE | 400 | 270 | PRD11161697 |