| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Focal segmental glomerulosclerosis (FSGS) |
| Fokális szegmentális glomeruloszklerózisban (FSGS) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Scarring of the tissue in the filtering unit of the kidney (glomerulus). |
|
| 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 | 10067757 |
| E.1.2 | Term | Focal segmental glomerulosclerosis |
| 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 long-term nephroprotective potential of treatment with sparsentan as compared to an angiotensin receptor blocker in patients with primary FSGS.
The safety objective of the study is to assess the safety and tolerability of sparsentan by double-blind monitoring of safety endpoints. |
|
| 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 or parent/legal guardian (as appropriate) is willing and able to provide signed informed consent, and where required, the patient is willing to provide assent, prior to any screening procedures.
2. The patient has biopsy-proven primary FSGS or documentation of a genetic mutation in a podocyte protein associated with FSGS. The biopsy may have been performed at any time in the past, but will preferably include electron microscopy (EM) and immunofluorescence (IF) characteristics consistent with primary FSGS. The patient may be enrolled based on light microscopy diagnosis of FSGS in the absence of EM and/or IF analysis, provided the history (nephrotic syndrome with hypoalbuminemia, treatment with immunosuppression) and the course of the disease are indicative of primary FSGS, and potential secondary causes captured by the exclusion criteria have been carefully ruled out.
3. Sites within the US: The patient is male or female aged 8 to 75 years, inclusive.
Sites outside the US: The patient is male or female aged 18 to 75 years, inclusive.
4. The patient has a UP/C ≥1.5 g/g at screening.
5. The patient has an eGFR ≥30 mL/min/1.73 m2 at screening.
6. The patient has a mean seated blood pressure ≥100/60 mmHg (on a maximum of 2 antihypertensive treatments at screening, including RAAS inhibitors) and ≤160/100 mmHg (patients >18 years of age) or ≥90/60 mmHg and ≤ the 95th percentile for age, sex, and height (patients ≤18 years of age).
7. Sexually active women of childbearing potential (WOCBP) must agree to the simultaneous use of 2 medically accepted methods of contraception from Day 1/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 Visits 1 and 3 (Screening and Day 1/Randomization).
NOTE: Prior to menarche, pregnancy testing and contraceptive use is not required. However, the patient and their parent/guardian must be advised that, immediately upon menarche, the patient will be required to begin pregnancy testing and, if deemed necessary by the Investigator, initiate contraceptive use. This requirement cannot be avoided.
8. 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 Day 1/Randomization until 90 days after the last dose of study medication. |
|
| E.4 | Principal exclusion criteria |
1. The patient has FSGS secondary to another condition.
2. The patient has positive findings on any of the following serological tests of primary or secondary glomerular injury: anti-nuclear antibody, anti-double stranded deoxyribonucleic acid (DNA) antibodies, anti-neutrophil cytoplasmic antibody, rheumatoid factor, anti-glomerular basement membrane antibodies, polyclonal antibodies identified by serum and urine protein electrophoresis, cryoglobulins, or kappa and lambda chains.
3. The patient has an indicator of relapse from complete remission (ie, recurrence or new occurrence of proteinuria >3.5 g/24 hours or UP/C >3.5 g/g within 30 days prior to or during screening).
4. 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.
5. The patient has undergone any organ transplantation, with the exception of corneal transplants.
6. The patient requires any of the prohibited concomitant medications.
7. The patient has been treated with rituximab, cyclophosphamide, or abatacept within ≤3 months prior to screening. If a patient is taking other chronic immunosuppressive medications, the dosage must be stable for ≥1 month prior to randomization.
8. 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.
9. 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.
10. The patient has hemodynamically significant valvular disease.
11. 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.
12. The patient is positive at screening for the human immunodeficiency virus (HIV) or markers indicating acute or chronic hepatitis B (HBV) infection (acute HBV is defined as a positive hepatitis B surface antigen [HBsAg], hepatitis B “e” antigen [HBeAg], HBV DNA in blood or liver, or immunoglobulin M [IgM] hepatitis B core antibody; chronic HBV is defined as a positive HBsAg and/or HBeAg and/or HBV DNA) or hepatitis C virus (HCV) infection (defined as reactive anti-HCV antibody and/or HCV RNA).
13. 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.
14. The patient has a screening hematocrit value <27% or hemoglobin value <9 g/dL.
15. The patient has a screening potassium value of >5.5 mEq/L.
16. The patient is >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.
17. 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), or a reported habitual alcohol intake greater than 21 units/week within 2 years prior to screening.
18. 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 medication.
19. The female patient is pregnant, plans to become pregnant during the course of the study, or is breastfeeding.
20. The male patient plans to father a child during the course of the study.
21. 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.
22. The patient has had prior exposure to sparsentan.
23. 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 slope of eGFR assessed at the final analysis.
The surrogate efficacy endpoint is the proportion of patients achieving a Up/C ≤1.5 g/g and a >40% reduction from baseline in Up/C at Week 36.
Safety End points:
• Changes from baseline in body weight, vital signs, physical examinations, peripheral edema, 12-lead electrocardiogram (ECG), and clinical laboratory parameters
• Changes from baseline in lipid profile (total cholesterol and triglycerides, low density lipoprotein cholesterol [LDL-C], very low-density lipoprotein cholesterol [VLDL-C] and triglycerides [VLDL-TG], and high-density lipoprotein cholesterol [HDL])
• Changes from baseline in serum albumin and serum potassium at each visit
• The incidence of treatment-emergent adverse events (TEAEs)
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Primary efficacy and safety endpoints will be evaluated at the final analysis (Week 108)
Surrogate efficacy analysis at Week 36 |
|
| E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints include:
• The percent change from Week 6 in eGFR at Week 108
• The percent change from baseline in Up/C at Week 36 assessed at the final analysis
Other Efficacy Endpoints:
• The absolute and percent change from baseline in eGFR at each visit
• The percent change from Week 6 in eGFR at each visit
• The proportion of patients achieving a Up/C ≤1.5 g/g and a >40% reduction from baseline in Up/C at each visit
• The percent change from baseline in Up/C at each visit
• The time to achieve the target reduction in Up/C (ie, ≤1.5 g/g and a >40% reduction)
• 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 during the study
• New occurrence of, or relapse back to, nephrotic-range proteinuria (ie, Up/C >3.5 g/g) in patients who have achieved the target reduction in Up/C (ie, ≤1.5 g/g and a >40% reduction) at any time during the study
• Changes from baseline in blood pressure at each visit
• The proportion of patients requiring intensification in immunosuppressive medication during the study
• The proportion of patients undergoing reduction in immunosuppressive medication during the study
• Changes from baseline in quality of life (QOL), measured via patient-reported outcome (PRO) at each visit beginning with Week 12 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Secondary endpoints will be assessed at the final analysis (Week 108) |
|
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 60 |
| 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 |
| Canada |
| Czech Republic |
| Denmark |
| France |
| Germany |
| Hungary |
| Italy |
| Korea, Republic of |
| Poland |
| South Africa |
| Spain |
| Taiwan |
| 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 | 4 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 14 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 14 |
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