| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Focal segmental glomerulosclerosis (FSGS) |
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| E.1.1.1 | Medical condition in easily understood language |
| Scarring of the tissue in the filtering unit of the kidney (glomerulus). |
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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 | 21.1 |
| 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 |
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| 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 with an ARB in patients with primary and genetic FSGS.
The safety objective of the study is to assess the safety and tolerability of sparsentan by double-blind monitoring of safety endpoints.
The open-label objective of the study is to assess the long-term efficacy, safety, and tolerability of open label sparsentan in patients with FSGS.
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| E.2.2 | Secondary objectives of the trial |
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| 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/assent
2. Biopsy-proven FSGS lesion(s) 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. The patient will be enrolled based on light microscopy diagnosis of FSGS and supportive findings on either electron microscopy (EM) or immunofluorescence (IF) analysis (preferably both). In exceptional cases, the patient may be enrolled based on light microscopy diagnosis of FSGS lesion(s) in the absence of EM or IF analysis, provided the history and/or the course of the disease are indicative of primary FSGS and the case has been reviewed by the Medical Monitor and Investigator.
3. Male or female aged 18 to 75 years, inclusive weighing at least 20 kg at screening (Note: patients under 18 may be recruited only in the United States and United Kingdom).
4. UP/C ≥1.5 g/g (170 mg/mmol) at screening.
5. eGFR ≥30 mL/min/1.73 m2 at screening.
6. Mean seated blood pressure ≥100/60 mmHg and ≤160/100 mmHg.
7. WOCBP agree to the use of contraception and pregnancy testing as described in the protocol.
Inclusion Criteria for the Open-Label Extension:
Based on assessments at the Week 108 visit, a patient will meet all of the following criteria to be eligible for the open-label extension.
1.The patient completed participation in the double-blind period, including the Week 112 visit.
2.The patient or parent/legal guardian (as appropriate) is willing and able to provide signed informed consent for participation in the open-label extension.
3.The patient received blinded study medication throughout the duration of the double blind period (ie, did not permanently discontinue study medication).
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| E.4 | Principal exclusion criteria |
1. FSGS secondary to another condition.
2. Positive findings on serological tests of another primary or secondary glomerular disease.
3. History of type 1 diabetes mellitus, uncontrolled type 2 diabetes mellitus (hemoglobin A1c [HbA1c] >8%), or nonfasting blood glucose >180 mg/dL (10.0 mmol/L) at screening.
4. Any organ transplantation, with the exception of corneal transplants.
5. Treatment with any of the prohibited concomitant medications.
6. Treatment 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 screening.
7. Documented history of heart failure and/or previous hospitalization for heart failure or unexplained dyspnea, orthopnea, paroxysmal nocturnal dyspnea, ascites, and/or peripheral edema.
8. Clinically significant cerebrovascular disease and/or coronary artery disease.
9. Hemodynamically significant valvular disease.
10. Jaundice, hepatitis, or known hepatobiliary disease (excluding asymptomatic cholelithiasis), or transaminase levels >2 times the upper limit of the normal range at screening.
11. Positive at screening for the human immunodeficiency virus (HIV) or markers indicating acute or chronic hepatitis B virus (HBV) infection or hepatitis C virus (HCV) infection.
12. History of malignancy other than adequately treated basal cell or squamous cell skin cancer or cervical carcinoma within the past 2 years.
13. A screening hematocrit value <27% (0.27 L/L) or hemoglobin value <9 g/dL(90 g/L).
14. A screening potassium value of >5.5 mEq/L(5.5 mmol/L).
15. Body mass index (BMI) >40 and there is a causal relationship to the FSGS lesion.
16. History of alcohol or illicit drug use, or excessive alcohol intake (>21 units per week within 2 years of screening)
17. History of serious side effect or allergic response to any AngII antagonist or ERA or hypersensitivity to any of the excipients
18. Female patient is pregnant, breastfeeding, or planning to conceive during the study.
19. Participation in a study of another investigational product within 28 days prior to screening.
20. Prior exposure to sparsentan.
21. Unable to adhere to the requirements of the study, including swallowing the study medication capsules whole.
Exclusion Criteria for the Open-Label Extension:
Based on assessments at the Week 108 and Week 112 visits, a patient who meets any of the following criteria will be excluded from the open-label extension.
1.The patient has progressed to ESRD requiring RRT.
2.The patient developed criteria for discontinuation as defined in Section 6.4.2 or Section 6.5 between Week 108 and Week 112.
3.The patient was unable to initiate, or developed contraindications to, treatment with RAAS inhibitors between Week 108 and Week 112.
4.The patient has an eGFR ≤20 mL/min/1.73 m2 at Week 108. NOTE: If, in the Investigator’s opinion, the eGFR value at Week 108 is deemed unlikely to be representative of the patient’s true status, the Investigator may repeat the eGFR measurement prior to Week 112 through the central laboratory to assess patient eligibility. Patients with an eGFR <30 mL/min/1.73 m2 will require close monitoring of eGFR and serum potassium throughout the open-label extension.
5. The female patient is pregnant, plans to become pregnant during the course of the study, or is breastfeeding. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Efficacy End points:
The primary efficacy endpoint is the slope of eGFR over approximately 2 years of randomized treatment assessed at the final analysis.
The surrogate efficacy endpoint is the proportion of patients achieving a target reduction in proteinuria.
Safety End points:
• Descriptive statistics will be used to summarize the safety data.
Open-Label Endpoints:
Endpoints for the open-label extension include, but are not necessarily limited to:
•The absolute and percent change from Week 112 in eGFR at each visit
•The percent change from Week 112 in UP/C at each visit
•Changes from Week 112 in QOL at each visit
•Changes from Week 112 in body weight, vital signs, physical examinations, peripheral edema, and clinical laboratory parameters
•Changes from Week 112 in lipid profile (total cholesterol and triglycerides, LDL-C, and HDL C
•The incidence of TEAEs during the open-label extension
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Week 36 and Week 108 or as defined above
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| E.5.2 | Secondary end point(s) |
Secondary Efficacy Endpoints:
The secondary efficacy endpoints in non-US countries are:
• The percent change from Week 6 in eGFR at Week 108
• The percent change in eGFR from baseline of the double-blind period to 4 weeks post -cessation of randomized treatment at Week 112
• The slope of eGFR following the initiation of randomized treatment (ie, from Day 1 to Week 108; total slope over 2 years)
The secondary efficacy endpoints in the US are:
• The slope of eGFR following the initial acute effect of randomized treatment (ie, from Week 6 to Week 108; chronic slope over 2 years)
• The change in eGFR from baseline of the double-blind period to 4 weeks post-cessation of randomized treatment at Week 112 |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 128 |
| 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 |
| Argentina |
| Australia |
| Brazil |
| Canada |
| Hong Kong |
| Korea, Republic of |
| New Zealand |
| Taiwan |
| United States |
| Belgium |
| Croatia |
| Czechia |
| Denmark |
| Estonia |
| France |
| Germany |
| Italy |
| Poland |
| Portugal |
| Spain |
| Sweden |
| United Kingdom |
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| 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
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| 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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