PROTOCOL RET-D-001: EFFICACY AND SAFETY OF SPARSENTAN (RE-021), A DUAL ENDOTHELIN RECEPTOR AND ANGIOTENSIN RECEPTOR BLOCKER, IN PATIENTS WITH FOCAL SEGMENTAL GLOMERULOSCLEROSIS (FSGS): A RANDOMIZED, DOUBLE-BLIND, ACTIVE-CONTROL, DOSE-ESCALATION STUDY

• Register: EUCTR
• Last refreshed on: 9 May 2022
• Main ID: EUCTR2014-002358-38-CZ
• Date of registration: 14/10/2014
• Prospective Registration: Yes
• Primary sponsor: Travere Therapeutics, Inc.
• Public title: PROTOCOL RET-D-001: EFFICACY AND SAFETY OF SPARSENTAN (RE-021), A DUAL ENDOTHELIN RECEPTOR AND ANGIOTENSIN RECEPTOR BLOCKER, IN PATIENTS WITH FOCAL SEGMENTAL GLOMERULOSCLEROSIS (FSGS): A RANDOMIZED, DOUBLE-BLIND, ACTIVE-CONTROL, DOSE-ESCALATION STUDY
• Scientific title: PROTOCOL RET-D-001: EFFICACY AND SAFETY OF SPARSENTAN (RE-021), A DUAL ENDOTHELIN RECEPTOR AND ANGIOTENSIN RECEPTOR BLOCKER, IN PATIENTS WITH FOCAL SEGMENTAL GLOMERULOSCLEROSIS (FSGS): A RANDOMIZED, DOUBLE-BLIND, ACTIVE-CONTROL, DOSE-ESCALATION STUDY
• Date of first enrolment: 28/04/2015
• Target sample size: 100
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2014-002358-38
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: yes Placebo: no Other: yes Other specify the comparator: Ibesartan Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Belgium, Czech Republic, Czechia, Italy

Contacts

• Name: CTI EU Office
• Affiliation: CTI Clincal Trial and Consulting Services Europe GmbH

• Name: CTI EU Office
• Affiliation: CTI Clincal Trial and Consulting Services Europe GmbH

Key inclusion & exclusion criteria

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.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 100
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

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 endothel

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

FOCAL SEGMENTAL GLOMERULOSCLEROSIS (FSGS)
MedDRA version: 21.1 Level: PT Classification code 10067757 Term: Focal segmental glomerulosclerosis System Organ Class: 10038359 - Renal and urinary disorders

Therapeutic area: Diseases [C] - Symptoms and general pathology [C23]

Intervention(s)

Product Name: Sparsentan
Product Code: RE-021
Pharmaceutical Form: Capsule
INN or Proposed INN: Sparsentan
CAS Number: 254740-64-2
Current Sponsor code: RE-021
Other descriptive name: SPARSENTAN
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-

Trade Name: Aprovel (150 mg)
Product Name: Aprovel 150 mg Tablets
Pharmaceutical Form: Tablet
INN or Proposed INN: Irbesartan
CAS Number: 138402-11-6
Other descriptive name: IRBESARTAN
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 150-
Pharmaceutical form of the placebo: Capsule
Route of administration of the placebo: Oral use

Product Name: Sparsentan
Product Code: RE-021
Pharmaceutical Form: Tablet
INN or Proposed INN: Sparsentan
CAS Number: 254740-64-2
Current Sponsor code: RE-021
Other descriptive name: SPARSENTAN
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 400-

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: from baseline to the Week 8 visit

Main Objective: 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.

Secondary Objective: 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

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

Secondary Outcome(s)

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

Timepoint(s) of evaluation of this end point: after the Week 8 visit and after open label phase week 312

Secondary ID(s)

RET-D-001

Source(s) of Monetary Support

Travere Therapeutics, Inc.

Ethics review

Status: Approved
Approval date: 14/01/2015
Contact: