| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| FOCAL SEGMENTAL GLOMERULOSCLEROSIS (FSGS) |
|
| E.1.1.1 | Medical condition in easily understood language |
| FOCAL SEGMENTAL GLOMERULOSCLEROSIS (FSGS) |
|
| 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 |
|
| 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 |
| To determine the change in urine protein/creatinine ratio (Up/C) after 8 weeks of treatment in FSGS patients receiving Sparsentan, a novel dual endothelin receptor and angiotensin receptor blocker, over a range of dose levels (200 mg, 400 mg, and 800 mg) compared to treatment with Irbesartan as the active control. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate
* The proportion of patients that achieve the target of 30% or 50% reduction in Up/C at Week 8
* The time to and durability of achieving target improvement for Up/C by comparing the change from baseline in groups receiving fixed doses (200, 400, 800 mg) of Sparsentan versus the Irbesartan active control after 8 weeks
* Changes from baseline in serum albumin in each dose group
* Changes from baseline in lipid profile: total cholesterol and triglycerides, low density lipoprotein cholesterol (LDL-C),, very low density lipoprotein cholesterol, very low density lipoprotein triglyceride, low density lipoprotein cholesterol (VLDL-C) and triglycerides (VLDL-TG) and high density lipoprotein cholesterol (HDL) in each dose group
* Changes from baseline in plasma renin, serum endothelin, and serum aldosterone in each dose group
* Changes from baseline in quality of life for FSGS patients receiving Sparsentan versus Irbesartan active control |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Biopsy-proven primary FSGS (Primary FSGS confirmed by renal biopsy report) OR documentation of a genetic mutation in a podocyte protein associated with the disease.
2. Urine protein/creatinine ratio (Up/C) at or above 1.0 g/g.
3. Estimated glomerular filtration rate (eGFR) >30 mL/min.
4. Mean seated blood pressure (BP) >100/60 mmHg and <145/95 mmHg in patients >18 years of age. Mean seated BP for patients <18 should be >90/60 mmHg and <95th percentile for age, gender, and height.
5. If a patient is taking immunosuppressive medications (except for Rituximamb or cyclophosphamide), the dose and/or levels must be stable for 1 month prior to randomization and the Investigator should not have plans to alter the regimen during the first 8 weeks of treatment, except to stabilize levels. Patients on Rituximab or cyclophosphamide will be eligible provided they have not been taking these medications for 3 months prior to randomization.
6. US Sites: Males or females 8 to 75 years of age willing and able to provide written informed consent and/or assent, with informed consent signed by patient or parent/legal guardian.
7. EU Sites: Males or females 18 to 75 years of age willing and able to provide written informed consent, with informed consent, signed by patient or legal guardian. |
|
| E.4 | Principal exclusion criteria |
1. Patients with FSGS secondary to another condition.
2. Patients with history of type 1 diabetes mellitus, uncontrolled type 2 diabetes mellitus (HBA1c>8%), or non-fasting blood glucose >180 mg/dL at screening.
3. Patients who have had any organ transplant.
4. Pat. with a requirement for any of the medications indicated on the list of Excluded Medications, with the exception of ACE and ARBs (see Appendix A; Excluded Medications).
5. Patients with a documented history of heart failure (NYHA Class II-IV), and / or previous hospitalization for heart failure or unexplained dyspnea, orthopnea, paroxysmal nocturnal dyspnea, ascites and peripheral edema. Subjects with 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 or coronary angiogram revealing stenosis, coronary revascularization procedure) within 6 months before the screening.
6. Patients with clinically significant cardiac conduction defects, including second or third degree atrioventricular (AV) block, left bundle branch block, sick sinus syndrome, atrial fibrillation, atrial flutter, an accessory bypass tract, or any arrhythmia requiring medication.
7. Patients with jaundice, hepatitis, or known hepatobiliary disease (includes asymptomatic cholelithiasis); alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) >2 times the upper limit of normal (ULN) at Screening.
8. Pat. positive for HIV, and markers indicating acute (positivity of at least one of the following: Hepatitis B surface antigen [HBsAg], Hepatitis B "e" antigen [HBeAg], Hepatitis B virus [HBV] DNA in blood or liver, Immunoglobulin M Hepatitis B core antibody) or chronic (HBsAg and/or HBeAg and/or Hepatitis B virus [HBV] DNA positivity) HBV infection, or HCV infection (reactive anti-HCV antibody and/or HCV RNA). Testing at screening is only required for Pat. >18 years of age.
9. History of malignancy other than adequately treated basal cell or squamous cell skin cancer within the past 5 years.
10. Patients with hemodynamically significant valvular disease.
11. Hematocrit <27 g/dL or hemoglobin <9 %.
12. Potassium >5.5 mEq/L
13. Patients >18 years of age with eGFR ≥60 ml mL/min who have Nterminal prohormone of brain natriuretic peptide (NT-proBNP) ≥200 pg/mL (57.8 pmol/L). For patients >18 years of age with eGFR <60 mL/min, the following parameters requiring ECHO at screening should be used for exclusion:
a. NT-proBNP ≥300 pg/mL in patients >18 years of age with eGFR 45 59.9 mL/min
b. NT-proBNP = 200-299 pg/mL in patients >18 years of age with eGFR 45 59.9 mL/min, and abnormal ejection fraction (EF <55) and/or diastolic dysfunction on ECHO
c. NT-proBNP ≥400 pg/mL in patients >18 years of age with eGFR 30.0 44.9 mL/min
d. NT-proBNP = 200-399 pg/mL in patients >18 years of age with eGFR 30.0 44.9 mL/min, and abnormal ejection fraction (EF <55) and/or diastolic dysfunction on ECHO.
14) Patients >18 years of age with body mass index (BMI) >40. Patients <18 years of age with a BMI in the 99% percentile plus 5 units.
15) Patients who have abnormal clinical laboratory values at Screening, which are designated by the Principal Investigator as clinically significant.
16) Patients with a history of drug or alcohol abuse within the past 2 years.
17) Patients with a history of an allergic response to any angiotensin II antagonist or endothelin receptor antagonist.
18) Women who are pregnant or breastfeeding.
19) Women of child-bearing potential (WOCBP) who are unwilling or unable to use two reliable methods of contraception, with at least one being highly reliable and one being a barrier method, in order to avoid pregnancy for the entire study period and for 90 days post study participation.
20) Patients who have participated in another investigational drug study within 28 days prior to screening, or who will participate in another drug study during the course of this study.
21) Prior exposure to Sparsentan, dual-acting receptor antagonist (DARA), or PS433540.
22) Patients who are unable to comply with the study procedures and assessments, including the ability swallow the study drug or control capsules. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the change from baseline to the Week 8 visit of the natural log (ln) of the Up/C. Week 0/Randomization (baseline) and Week 8 values will be an average of two Up/C measurements at each time point.
Primary Safety Objectives
* To assess the safety and tolerability of Sparsentan over a range of doses by double-blind monitoring of body weight, peripheral edema, blood pressure, echocardiographic functional parameters, as well as related signs and symptoms
* To compare the occurrence of adverse events in the double-blind Sparsentan treated patients versus active control Irbesartan
* To compare medications required to control edema and blood pressure in the double-blind management of Sparsentan-treated patients versus Irbesartan active control |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| from baseline to the Week 8 visit |
|
| E.5.2 | Secondary end point(s) |
To evaluate
* The proportion of patients that achieve the target of 30% or 50% reduction in Up/C at Week 8
* The time to and durability of achieving target improvement for Up/C by comparing the change from baseline in groups receiving fixed doses (200 mg, 400 mg, 800 mg) of Sparsentan versus the Irbesartan control after 8 weeks
* changes from baseline in serum albumin in each dose group
* Changes from baseline in lipid profile: total cholesterol, very low density lipoprotein cholesterol, very low density lipoprotein triglyceride, low density lipoprotein cholesterol and high density lipoprotein cholesterol in each dose group
* Changes from baseline in plasma renin, serum endothelin, and serum aldosterone in each dose group
* Changes from baseline in quality of life for FSGS patients receiving Sparsentan versus Irbesartan active control |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| after the Week 8 visit and after open label phase week 312 |
|
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
|
| 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 | 6 |
| 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 |
|
| 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
|
| LVLS + 496 week Open-Label Extension Period |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 9 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 15 |
| E.8.9.2 | In all countries concerned by the trial years | 9 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 15 |
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