Clinical Trials Register

Summary
EudraCT Number:	2016-001979-70
Sponsor's Protocol Code Number:	IVA_01_337_HNAS_16_002
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2016-09-23
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

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A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2016-001979-70

A.3

Full title of the trial

A randomized, double-blind, placebo-controlled, multicenter, dose-range, proof-of-concept, 24-week treatment study of IVA337 in adult subjects with nonalcoholic steatohepatitis (NASH)

A.3.1

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

A randomized, double-blind, placebo-controlled, multicenter, dose-range, proof-of-concept, 24-week treatment study of IVA337 in adult subjects with nonalcoholic steatohepatitis (NASH)

A.3.2

Name or abbreviated title of the trial where available

IVA_01_337_HNAS_16_002

A.4.1

Sponsor's protocol code number

IVA_01_337_HNAS_16_002

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	Inventiva S.A.
B.1.3.4	Country	France
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	Inventiva S.A.
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	INVENTIVA S.A.
B.5.2	Functional name of contact point	Mathilde Merot, Reguatory Affairs
B.5.3	Address:
B.5.3.1	Street Address	50, Rue de Dijon
B.5.3.2	Town/ city	Daix
B.5.3.3	Post code	21121
B.5.3.4	Country	France
B.5.4	Telephone number	+33 0 380 447 589
B.5.5	Fax number	+33 0 380 447 561
B.5.6	E-mail	mathilde.merot@inventivapharma.com

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	Lanifibranor
D.3.2	Product code	IVA337
D.3.4	Pharmaceutical form	Film-coated 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	Lanifibranor
D.3.9.1	CAS number	927961-18-0
D.3.9.2	Current sponsor code	IVA337
D.3.9.3	Other descriptive name	1-(6-BENZOTHIAZOLYLSULFONYL)-5-CHLORO-1H-INDOLE-2-BUTANOIC ACID
D.3.9.4	EV Substance Code	AS1
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	400
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.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	Film-coated tablet
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

Nonalcoholic steatohepatitis (NASH)

E.1.1.1

Medical condition in easily understood language

Nonalcoholic steatohepatitis (NASH)

E.1.1.2

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	22.0
E.1.2	Level	PT
E.1.2	Classification code	10053219
E.1.2	Term	Non-alcoholic steatohepatitis
E.1.2	System Organ Class	10019805 - Hepatobiliary disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To assess the safety and the efficacy on the activity part of the Steatosis Activity Fibrosis histological score (inflammation and ballooning) of a 24-week treatment with two doses of Lanifibranor (800, 1200 mg/24h) in NASH adult patients.

E.2.2

Secondary objectives of the trial

Pharmacokinetics.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

-Adult subjects, age ≥18 years.
-NASH histological diagnosis according to the currently accepted definition of both EASL and AASLD (1–3), requiring the combined presence of steatosis (any degree ≥ 5%) + lobular inflammation of any degree + liver cell ballooning of any amount, on a liver biopsy performed ≤ 6 months before screening in the study or at screening, and confirmed by central reading during the screening period and
a.SAF Activity score of 3 or 4 (>2)
b.SAF Steatosis score ≥ 1
c.SAF Fibrosis score: < 4
-Subject agrees to have a liver biopsy performed after 24 weeks of treatment
-Compensated liver disease with the following hematologic and biochemical criteria before randomization:
oALT < 10xULN
oHemoglobin ≥ 110 g/L (11 g/dL) for females and ≥ 120 g/L (12 g/dL) for males
oWhite blood cell (WBC) > 2.5 10^9/L (2.5 10^3/µL)
oNeutrophil count > 1.5 10^9/L (1.5 10^3/µL)
oPlatelets > 100 10^9/L (100 10^3/µL)
oTotal bilirubin < 35µmol/L(2.06 mg/dL). Patients with bilirubin ≥ 35µmol/L(2.06 mg/dL) can be included if non-conjugated bilirubin in the setting of a Gilbert syndrome.
oAlbumin > 36 g/L(3.6 g/dL)
oInternational Normalized Ratio (INR) < 1.4
oSerum creatinin < 115 µmol/L (1.3 mg/dL) (men) or < 97 µmol/L (1.1 mg/dL) (women) or estimated glomerular filtration rate ≥ 60 mL/min/1.73m2
-No other cause of chronic liver disease (autoimmune, primary biliary cholangitis, HBV, HCV, Wilson’s, α-1-antitrypsin deficiency, hemochromatosis etc…)considered to have an impact on the patient's safety or on the efficacy evaluation
-If applicable, have a stable type 2 diabetes, defined as HbA1c ≤ 8.5% and fasting glycemia <10 mmol/L(180 mg/dL), no introduction of new medication in the previous 6 months, and no new symptoms associated with decompensated diabetes in the previous 3 months. Minor modifications of anti-diabetic treatments or dosages are allowed if done in a context of stable type 2 diabetes, i.e. HbA1c ≤ 8.5% in the previous 6 months.
-Have a stable weight since the liver biopsy was performed defined by no more than a 5 % loss of initial body weight Negative pregnancy test or post menopausal. Women with childbearing potential (i.e. fertile, following menarche and until becoming postmenopausal unless permanently sterile) must be using a highly effective method of contraception (i.e. combined (estrogen and progestogen containing) hormonal/ progestogen-only hormonal contraception associated with inhibition of ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomised partner). The contraceptive method will have to be followed for at least one menstruation cycle after the end of the study
- Subjects having given her/his written informed consent.

E.4

Principal exclusion criteria

-Evidence of another form of liver disease,considered to have an impact
on the patient's safety or on the efficacy evaluation.
-History of sustained excess alcohol ingestion in the year before the pre-study
treatment biopsy: daily alcohol consumption > 30 g/day (3 drinks per day) for males and > 20 g/day (2 drinks/day) for females.
-Unstable metabolic condition: Weight change > 5% in the last three months, diabetes with poor glycemic control (HbA1c > 8.5%), introduction of an antidiabetic or of an anti-obesity drug or restrictive bariatric (weight loss) surgery in the past 6 months prior to screening.
-History of gastrointestinal malabsorptive bariatric surgery within less than 5 years or ingestion of drugs known to produce hepatic steatosis including oral corticosteroids (at dose >5mg/day prednisone equivalent), estrogens (at doses greater than those used for contraception or hormone replacement), tamoxifen, methotrexate, tetracycline or amiodarone in the previous 6 months.Corticosteroids
administered by routes other than oral are allowed. One short (<2 weeks) course of oral corticosteroids, more than 3 months before the pre-study treatment biopsy is also allowed.
-Significant systemic or major illnesses other than liver disease, including congestive heart failure (class C and D of the AHA), unstable coronary artery disease, cerebrovascular disease, pulmonary disease, renal failure, organ transplantation, serious psychiatric disease, malignancy that, in the opinion of the investigator, would preclude treatment with lanifibranor and/or adequate follow up.
-HB antigen >0, HCV PCR >0 (patients with a history of HCV infection can be included if HCV PCR is negative since more than 3 years), HIV infection.
-Pregnancy or lactation or inability to adhere to adequate contraception in women of child-bearing potential.
-Active malignancy except cutaneous basocellular carcinoma.
-Any other condition which, in the opinion of the investigator would impede competence or compliance or possibly hinder completion of the study
-Body mass index (BMI) >45 kg/m2.
-Type 1 diabetes and type 2 diabetic patient on insulin.
-Diabetic ketoacidosis
-Fasting Triglycerides > 300 mg/dL (3.39 mmol/L).
-Hemostasis disorders or current treatment with anticoagulants.
-Contra-indication to liver biopsy.
-History of, or current cardiac dysrhythmias and/or a history of cardiovascular disease event, including myocardial infarction, except patients with only well controlled hypertension. Any clinically significant ECG abnormality reported by central ECG reading, confirmed by the Investigator to be Clinically Significant.
-Participation in any other investigational drug study within the previous
3 months.
-Have a known hypersensitivity to any of the ingredients or excipients of
the IMP including: Lactose monohydrate, Hypromellose, Sodium laurilsulfate, Sodium starch glycolate (type A), Magnesium stearate, Opadry™ II 85F18422
-Be possibly dependent on the Investigator or the sponsor (e.g.,including, but not limited to, affiliated employee).
-Creatine phosphokinase (CPK)>5 x ULN
-Patient with history of well documented osteopenia. Patient treated with vitamin D and/or Calcium based supplements for preventive reasons can be included.

(The criteria below are applicable only for patients who will undergo a MRI/LMS in selected centers)
- Claustrophobia to a degree that prevents tolerance of MRI scanning procedure. Sedation is permitted at discretion of investigator.
- Metallic implant of any sort that prevents MRI examination including, but not limited to: aneurysm clips, metallic foreign body, vascular grafts or cardiac implants, neural stimulator, metallic contraceptive device, tattoo, body piercing that cannot be removed, cochlear implant; or any other contraindication to MRI examination.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is a binary outcome (responder / non responder). A responder is defined as a decrease from baseline to week 24 of at least 2 points of the SAF activity score combining hepatocellular inflammatory and ballooning score without fibrosis progression. Responder rates will be compared between the placebo and IMP groups at the end of the treatment period (week 24) using a Cochran Mantel Haenzel test stratified on diabetes.

E.5.1.1

Timepoint(s) of evaluation of this end point

At the end of the treatment period (week 24)

E.5.2

Secondary end point(s)

The following changes from baseline to 24 weeks of treatment will be evaluated:
•NASH improvers defined as subjects with a decrease of at least 2 points in NAS, and no worsening in fibrosis in NASH from baseline to end of treatment (week 24).
•Percent of patients with reversal of NASH (Steatosis without ballooning and with or without mild inflammation and no worsening of fibrosis) from baseline to end of treatment (week 24).
•Percent of patients with a change in components of SAF score from baseline to end of treatment (week 24):
-Steatosis: -1 point
-Lobular inflammation: -1 point
-Balloonning: -1 point
• Percent of patients with at least 1- point improvement of fibrosis score on a 4-point scale (SAF) without worsening of NASH, defined as no increase for ballooning or inflammation, or steatosis, using the SAF scoring system, from baseline to end of treatment (week 24).
•Change in fibrosis score on a 4-point scale (SAF) and modified Ishak: - 1 point from baseline to end of treatment (week 24). Comparison of mean change in fibrosis area assessed by morphometry (CPA) from baseline to end of treatment (week 24).
•Liver enzymes (ALT, AST, γGT) change from baseline to end of treatment (week 24).
•Inflammatory markers (fibrinogen, hs-CRP, alpha2 macroglobulin and haptoglobin levels) change from baseline to end of treatment (week 24).
•Glucose metabolism (fasting glucose and insulin, HOMA index and, in subjects with T2DM, HbA1c) change from baseline to end of treatment (week 24).
•Main plasma lipids levels (TC, HDL-C, calculated LDL-C, TG and apoA1) change from baseline to end of treatment (week 24).
•Adiponectin change from baseline to end of treatment (week 24).

E.5.2.1

Timepoint(s) of evaluation of this end point

From baseline to 24 weeks of treatment

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

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)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

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

Australia

Austria

Belgium

Bulgaria

Canada

Czech Republic

France

Germany

Italy

Mauritius

Netherlands

Poland

Portugal

Spain

Switzerland

United Kingdom

United States

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

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