Clinical Trials Register

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:	Ongoing
Date on which this record was first entered in the EudraCT database:	2014-11-19
Trial 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

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A. Protocol Information

A.1

Member State Concerned

Italy - Italian Medicines Agency

A.2

EudraCT number

2014-002358-38

A.3

Full 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.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A.4.1

Sponsor's protocol code number

RET-D-001

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Retrophin, Inc
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Retrophin, Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	CTI Clincal Trial and Consulting Services Europe GmbH
B.5.2	Functional name of contact point	CTI EU Office
B.5.3	Address:
B.5.3.1	Street Address	Schillerstrasse 1/15
B.5.3.2	Town/ city	Ulm
B.5.3.3	Post code	89077
B.5.3.4	Country	Germany
B.5.4	Telephone number	4907314000 84-10

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Sparsentan
D.3.2	Product code	RE-021
D.3.4	Pharmaceutical form	Capsule
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Aprovel (150 mg)
D.2.1.1.2	Name of the Marketing Authorisation holder	Sanofi
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Aprovel 150 mg Tablets
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Irbesartan
D.3.9.1	CAS number	138402-11-6
D.3.9.3	Other descriptive name	IRBESARTAN
D.3.9.4	EV Substance Code	SUB08293MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	150
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Yes
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

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	17.1
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 (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.2.2

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 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.2.3

Trial contains a sub-study

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.
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.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. 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.5.1

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 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.5.2.1

Timepoint(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.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Ibesartan

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

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

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

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

Belgium

Czech Republic

Italy

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 + 40 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

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

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)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In 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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2014-12-10

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-12-15

P. End of Trial
P.	End of Trial Status	Ongoing

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