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    Summary
    EudraCT Number:2014-002358-38
    Sponsor's Protocol Code Number:RET-D-001
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-11-19
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2014-002358-38
    A.3Full title of the trial
    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
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    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
    A.4.1Sponsor's protocol code numberRET-D-001
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorRetrophin, Inc
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportRetrophin, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCTI Clincal Trial and Consulting Services Europe GmbH
    B.5.2Functional name of contact pointCTI EU Office
    B.5.3 Address:
    B.5.3.1Street AddressSchillerstrasse 1/15
    B.5.3.2Town/ cityUlm
    B.5.3.3Post code89077
    B.5.3.4CountryGermany
    B.5.4Telephone number4907314000 84-10
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameSparsentan
    D.3.2Product code RE-021
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Aprovel (150 mg)
    D.2.1.1.2Name of the Marketing Authorisation holderSanofi
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameAprovel 150 mg Tablets
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNIrbesartan
    D.3.9.1CAS number 138402-11-6
    D.3.9.3Other descriptive nameIRBESARTAN
    D.3.9.4EV Substance CodeSUB08293MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Yes
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    FOCAL SEGMENTAL GLOMERULOSCLEROSIS (FSGS)
    E.1.1.1Medical condition in easily understood language
    FOCAL SEGMENTAL GLOMERULOSCLEROSIS (FSGS)
    E.1.1.2Therapeutic area Diseases [C] - Symptoms and general pathology [C23]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.1
    E.1.2Level PT
    E.1.2Classification code 10067757
    E.1.2Term Focal segmental glomerulosclerosis
    E.1.2System Organ Class 10038359 - Renal and urinary disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    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.
    E.2.2Secondary 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 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
    E.2.3Trial contains a sub-study No
    E.3Principal 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.
    E.4Principal 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 unable to comply with the study procedures and assessments, including the ability swallow the study drug or control capsules.
    E.5 End points
    E.5.1Primary 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.5.1.1Timepoint(s) of evaluation of this end point
    from baseline to the Week 8 visit
    E.5.2Secondary 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
    E.5.2.1Timepoint(s) of evaluation of this end point
    after the Week 8 visit and after open label phase week 48
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Ibesartan
    E.8.2.4Number of treatment arms in the trial2
    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.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA6
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Belgium
    Czech Republic
    Italy
    E.8.7Trial 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 + 40 week Open-Label Extension Period
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months10
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 100
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 50
    F.4.2.2In the whole clinical trial 100
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    none
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2014-12-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-12-15
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2024-02-29
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