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: 22 April 2024
• Main ID: EUCTR2014-002358-38-BE
• Date of registration: 25/11/2014
• Prospective Registration: Yes
• Primary sponsor: Retrophin, 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: 05/02/2015
• Target sample size: 100
• Recruitment status: Not Recruiting
• 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, 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.
4. Mean seated blood pressure (BP) >100/60 and <140/90 in adults. Mean seated BP for children should be >90/60 and <95th percentile for age, gender, and height.
5. Patients who are on immunosuppressive medications (except for Rituximab or cyclophosphamide) at the time of screening are eligible for the study. However, the doses of the medications must be stable for at least 1 month- prior to randomization and cannot be changed during the 8-Week treatment period. Patients on Rituximab or cyclophosphamide will be eligible provided they have not been taking these medications in the prior 3 months from screening.
6. US Sites: Males or females 8 to 65 years of age able to provide written informed consent and/or assent at the time of consenting, with informed consent signed by patient or legal guardian.
7. EU Sites: Males or females 18 to 65 years of age able to provide written informed consent at the time of consenting, 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. Patients with a requirement for any of the medications indicated on the list of Excluded Medications (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. Patients positive for human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) positive.
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 (HCT) <27 or hemoglobin (Hgb) <9.
12. K+ >5.5.
13. N-terminal prohormone of brain natriuretic peptide (NT-proBNP) =200 pg/mL (57.8 pmol/L) in adults.
14. Adult Patients with body mass index (BMI) >40. Pediatrics 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 Investigator as clinically significant.
16. Patients with a history of drug or alcohol abuse within the past two 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. Female patients of child-bearing potential, defined as all women physiologically capable of becoming pregnant who are unwilling or unable to use two acceptable methods of contraception, with at least one being a barrier method, in order to avoid pregnancy for the entire study period and for 90 days post study participation. Female patients of child-bearing potential must have a negative serum pregnancy test.
20. Male patient and female spouse/partners who are of childbearing potential must be using highly effective contraception consisting of two forms of birth control (one of which must be a barrier method) to avoid pregnancy for the entire study period and for 90 days post study participation.
21. Patients who have participated in another investigational drug study within 28 days prior to signing the informed consent form, or who will participate in another drug study during the course of this study.
22. Prior exposure to Sparsentan, dual acting receptor antagonist (DARA), or PS433540.
23. Patients who are un

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

Health Condition(s) or Problem(s) studied

FOCAL SEGMENTAL GLOMERULOSCLEROSIS (FSGS)
MedDRA version: 17.1 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

Primary Outcome(s)

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 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 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 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) 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 treatment

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 (Up/C) 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 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 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) 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 treatment

Timepoint(s) of evaluation of this end point: after the Week 8 visit and after open label phase week 48

Secondary ID(s)

RET-D-001

2014-002358-38-CZ

Source(s) of Monetary Support

Retrophin, Inc.

Ethics review

Status: Approved
Approval date: 05/02/2015
Contact: