| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Immunoglobulin A Nephropathy (IgAN) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Also known as Berger’s disease; a form of glomerulonephritis or an inflammation of the glomeruli of the kidney. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Symptoms and general pathology [C23] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10021263 |
| E.1.2 | Term | IgA nephropathy |
| E.1.2 | System Organ Class | 10038359 - Renal and urinary disorders |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The efficacy objective of the study is to determine the effect of sparsentan on proteinuria and renal function, as compared to an angiotensin receptor blocker, in patients with Immunoglobulin A Nephropathy (IgAN).
The safety objective of the study is to assess the safety and tolerability of sparsentan by double-blind monitoring of safety endpoints. |
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| E.2.2 | Secondary objectives of the trial |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. The patient is willing and able to provide signed informed consent.
2. The patient is male or female, aged ≥18 years.
3. The patient has biopsy-proven primary IgAN. The biopsy may have been performed at any time in the past.
4. The patient has a urine total protein value ≥1.0 g/day at screening.
5. The patient has an eGFR ≥30 mL/min/1.73 m2 at screening.
6. The patient has been on a stable dose of ACEI and/or ARB therapy for at least 12 weeks prior to screening that is:
A. the patient’s maximum tolerated dose, AND
B. at least one-half of the maximum labeled dose (according to approved labeling).
7. In the Investigator’s opinion, the patient’s blood pressure has been managed in accordance with standard of care using ACEI and/or ARB therapy as described in Inclusion Criterion #6 and additional antihypertensive agents if needed. At screening, the patient’s systolic blood pressure must be ≤150 mmHg and diastolic blood pressure must be ≤100 mmHg.
8. The patient is willing to undergo a change in ACEI and/or ARB and antihypertensive medications.
9. Women of childbearing potential (WOCBP) must agree to the simultaneous use of 2 medically accepted methods of contraception from randomization until 90 days after the last dose of study medication. At least one method of contraception must be highly reliable (ie, can achieve a failure rate of <1% per year), such as stable oral, implanted, transdermal, or injected contraceptive hormones associated with inhibition of ovulation, or an intrauterine device (IUD) in place for at least 3 months. The other method of contraception must be a barrier method, such as a diaphragm with spermicide or male partner’s use of male condom with spermicide. WOCBP are defined as those who are fertile, following menarche and until becoming postmenopausal unless permanently sterile; permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as amenorrhea for more than 24 consecutive months without an alternative medical cause; women on hormone replacement therapy must have a documented plasma follicle-stimulating hormone level >40 mIU/mL. All WOCBP must have a negative pregnancy test (urine, with positive results confirmed by serum) at screening and randomization.
10. Males must be surgically sterile (more than 3 months post-vasectomy) or must agree to the use of medically accepted methods of contraception that are considered highly reliable from randomization until 90 days after the last dose of study medication. |
|
| E.4 | Principal exclusion criteria |
1. The patient has IgAN secondary to another condition (eg, systemic lupus erythematosus, liver cirrhosis) or Henoch-Schonlein purpura.
2. The patient has cellular glomerular crescents present in >25% of glomeruli on renal biopsy within 6 months prior to screening.
3. The patient has a history of type 1 diabetes mellitus, uncontrolled type 2 diabetes mellitus (hemoglobin A1c [HbA1c] >8%), or nonfasting blood glucose >180 mg/dL at screening.
4. The patient has undergone any organ transplantation, with the exception of corneal transplants.
5. The patient requires any of the prohibited concomitant medications.
6. The patient has been taking any systemic immunosuppressive medications (including corticosteroids) for >2 weeks within 3 months prior to screening.
7. The patient has a documented history of heart failure (New York Heart Association Class II-IV) and/or previous hospitalization for heart failure or unexplained dyspnea, orthopnea, paroxysmal nocturnal dyspnea, ascites, and/or peripheral edema.
8. The patient has clinically significant cerebrovascular disease (transient ischemic attack or stroke) and/or coronary artery disease (hospitalization for myocardial infarction or unstable angina, new onset of angina with positive functional tests, coronary angiogram revealing stenosis, or a coronary revascularization procedure) within 6 months prior to screening.
9. The patient has jaundice, hepatitis, or known hepatobiliary disease (including asymptomatic cholelithiasis), or alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) >2 times the upper limit of the normal range at screening.
10. The patient has a history of malignancy other than adequately treated basal cell or squamous cell skin cancer or cervical carcinoma within the past 2 years.
11. The patient has a screening hematocrit value <27% or hemoglobin value <9 g/dL.
12. The patient has a screening potassium value of >5.5 mEq/L.
13. The patient has a history of alcohol or illicit drug use disorder (as defined in the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition).
14. The patient has a 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.
15. The female patient is pregnant, plans to become pregnant during the course of the study, or is breastfeeding.
16. The male patient plans to father a child during the course of the study.
17. The patient 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.
18. The patient, in the opinion of the Investigator, is unable to adhere to the requirements of the study, including the ability to swallow the study medication capsules whole. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Efficacy End points:
The primary efficacy endpoint is the change from baseline in the urine protein/creatinine ratio (UP/C), based on a 24-hour urine sample, at Week 36, assessed on the log scale.
Safety End points:
• Changes from baseline in body weight, vital signs, physical examinations, peripheral edema, and clinical laboratory parameters
• The incidence of TEAEs |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Primary efficacy endpoints will be evaluated at Week 36. The primary safety endpoint will be evaluated from randomization to Week 114. |
|
| E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints:
The secondary efficacy endpoints with Type I error control are:
• The rate of change in eGFR over a 52-week (approximately 1-year) period following the initial acute effect of randomized therapy (the initial acute effect of randomized therapy is defined as the first 6 weeks of randomized treatment with study medication; thus, the analysis is from 6 weeks post randomization to 58 weeks post randomization)
• The rate of change in eGFR over a 104-week (approximately 2-year) period following the initial acute effect of randomized therapy (the initial acute effect of randomized therapy is defined as the first 6 weeks of randomized treatment with study medication; thus, the analysis is from 6 weeks post randomization to 110 weeks post randomization)
• Achievement of urinary protein excretion, based on a 24-hour urine sample, <0.3 g/day at Week 36
Other Efficacy Endpoints:
• The mean change from baseline over time in selected proteinuria variables, based on a 24-hour urine sample (eg, total urine protein, total urine albumin, urine albumin/creatinine ratio [UA/C]), up to Week 110
• The proportion of patients reaching a confirmed 40% change in eGFR, end-stage renal disease (ESRD), or death. (ESRD is defined as initiation of renal replacement therapy [RRT], kidney transplantation, or sustained eGFR <15 mL/min/1.73 m2.)
Exploratory endpoints are:
• The change from baseline in eGFR at 6 weeks post randomization (ie, the acute effect of randomized therapy)
• The change from end-of-treatment (EOT; ie, Week 110) in eGFR 4 weeks following cessation of treatment (ie, at Week 114)
• The proportion of patients with hematuria at each visit
• The proportion of patients requiring immunosuppressive medication during the study
• Mean changes from baseline in quality of life (QOL), measured via patient-reported outcome (PRO) at each visit beginning with Week 36
• Frequency and duration of hospitalizations (for any reason and for reasons related to the kidney)
• Trough plasma PK concentrations |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The subsequent key secondary endpoint analysis of 6- to 110-week eGFR rate of change will be assessed at the 4% two-sided alpha level if the 6- to 58-week eGFR rate of change analysis fails to achieve p<0.01; otherwise the 6- to 110-week eGFR rate of change will be assessed at the 5% two-sided alpha level. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 79 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Belgium |
| Croatia |
| Czech Republic |
| Estonia |
| France |
| Germany |
| Hong Kong |
| Hungary |
| Italy |
| Korea, Republic of |
| Lithuania |
| Malaysia |
| New Zealand |
| Poland |
| Portugal |
| Spain |
| Turkey |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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