FASST: Proof-of-concept Trial of IVA337 in Diffuse Cutaneous Systemic Sclerosis

Sponsor

Inventiva Pharma (Industry)

Overall Status

Completed

CT.gov ID

NCT02503644

Collaborator

(none)

145

Enrollment

Locations

Arms

35.4

Actual Duration (Months)

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Systemic sclerosis (SSc), or scleroderma is a connective tissue disease of autoimmune origin. It is a life-threatening orphan disease with severe physical and psychosocial consequences. IVA337 has a novel mechanism of action and this study is designed to compare IVA337 at two dose levels with a placebo control treatment. Patients will be unaware of the treatment they are receiving and will be randomized to one of three treatment arms , either IVA337 400mg bid, IVA337 600mg bid or placebo bid. They will receive drug for 48 weeks and during that time assessments will be made to monitor both the efficacy and safety of the treatment.

Condition or Disease	Intervention/Treatment	Phase
Scleroderma, Diffuse Diffuse Cutaneous Systemic Sclerosis	Drug: IVA337 Drug: Placebo	Phase 2

Detailed Description

Study design: randomized, double-blind, placebo-controlled, multicentre phase 2 proof-of-concept trial of IVA337 for the treatment DcSSc.

The treatments are randomly assigned. The randomisation is stratified for background therapy to ensure even distribution of background therapies among treatment groups.

There are 3 parallel treatment groups: placebo, IVA337 400mg bid and IVA337 600mg bid (identical capsules of 200mg IVA337 or placebo). Both, patient and investigator are blinded.

The treatment lasts 48 weeks. A follow-up assessment takes place 4 weeks after the last dose.

Study Design

Study Type:

Interventional

Actual Enrollment :

145 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

A Randomized, Double-blind, Placebo-controlled, Multicentre Proof-of-concept Trial of IVA337 in the Treatment of Diffuse Cutaneous Systemic Sclerosis

Actual Study Start Date :

Oct 29, 2015

Actual Primary Completion Date :

Oct 1, 2018

Actual Study Completion Date :

Oct 12, 2018

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: IVA337 800mg Patients receive twice daily 400mg IVA337.	Drug: IVA337 Capsules of 200mg IVA337 Other Names: lanifibranor
Active Comparator: IVA337 1200mg Patients receive twice daily 600mg IVA337.	Drug: IVA337 Capsules of 200mg IVA337 Other Names: lanifibranor
Placebo Comparator: Placebo Patients receive twice daily placebo.	Drug: Placebo Identical capsules without active substance Other Names: No other names at present

Arm

Intervention/Treatment

Active Comparator: IVA337 800mg

Patients receive twice daily 400mg IVA337.

Drug: IVA337

Capsules of 200mg IVA337

Other Names:

lanifibranor

Active Comparator: IVA337 1200mg

Patients receive twice daily 600mg IVA337.

Drug: IVA337

Capsules of 200mg IVA337

Other Names:

lanifibranor

Placebo Comparator: Placebo

Patients receive twice daily placebo.

Drug: Placebo

Identical capsules without active substance

Other Names:

No other names at present

Outcome Measures

Primary Outcome Measures

Measurement of skin thickness by the Modified Rodnan Skin Score (MRSS) [48 weeks]
Mean change of the MRSS from baseline

Secondary Outcome Measures

Response rates based on MRSS improvement [12, 24, 32, 48 weeks]
MRSS response rates: Initial definition: improvers are defined by a reduction ≥5 points and ≥25 % of MRSS; Additional definition: improvers are defined by a reduction ≥ 4 points and ≥ 20% of MRSS based on Quillinan et al. (2014, 2017)
Overall progression of the disease: defined as absence of rescue therapy and absence of severe organ involvement [28, 32,40, and 48 weeks]
Overall progression of the disease: defined as absence of rescue therapy and absence of severe organ involvement
Lung function measured by FVC% predicted [24 and 48 weeks]
Change in pulmonary function
Lung function by cDLCO% predicted [24 and 48 weeks]
Change in pulmonary function
Scleroderma Health Assessment Questionnaire (SHAQ) [24 and 48 weeks]
Changes in patient reported outcomes
Gastrointestinal tract symptoms severity and its impact on patients' well-being assessed by the UCLA SCTC GIT [24 and 48 weeks]
Changes in patient reported outcomes
Patient-reported health status assessed by PROMIS29 [24 and 48 weeks]
Changes in patient reported outcomes
Physical and mental health assessed by SF36 [24 and 48 weeks]
Changes in patient reported outcomes
Digital ulcer net burden (defined as total number of ulcers at a certain time point minus number of ulcers at baseline) and proportion of patients who do not develop new ulcers [12, 24, 32 and 48 weeks]
Digital ulcer net burden (defined as total number of ulcers at a certain time point minus number of ulcers at baseline) and proportion of patients who do not develop new ulcers
Hand function assessed by the Cochin Hand Function Scale [12, 24, 32 and 48 weeks]
Hand function assessed by the Cochin Hand Function Scale
Patient global assessment of disease activity assessed by a visual analogue scale [24 and 48 weeks]
Patient global assessments of disease activity (VAS)
Physician global assessment of disease activity assessed by a visual analogue scale [24 and 48 weeks]
Physician global assessment of disease activity (VAS)
Change in the Combined Response Index for Systemic Sclerosis (CRISS) [24 and 48 weeks]
Composed of five variables: MRSS, FVC % predicted, physician and patient global assessments, and HAQ-DI score
Percent of patients who need escape therapy [28, 32,40, and 48 weeks]
Need for escape therapy
Percent of patients who experience a new severe organ involvement [2, 4, 8,12, 16, 24, 28, 32, 40, 48, and 52 weeks]
Severe organ involvement
Number of participants with adverse events as a measure of safety and tolerability [2, 4, 8, 12, 16, 20, 24, 28, 32, 40, 44, 48, and 52 weeks]
Frequency and type of AEs
Routine and specific laboratory tests (composite) to assess safety and tolerability [2, 12, 20, 24, 32, 36, 44, 48, and 52 weeks]
creatine kinase, N-terminal pro-brain natriuretic peptide, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, γ-glutamyl transferase, total bilirubin, direct bilirubin,RBC and WBC count, reticulocytes, haemoglobin, haematocrit, albumin , Quick, aPTT, INR, BUN, plasma creatinine, microalbuminuria, homocysteine, urinalysis (dip stick), glycated haemoglobin, creatine phosphokinase increase, platelet counts, plasma osteocalcin, serum beta C-terminal telopeptide (β-CTx or B-Crosslaps), Differential: neutrophils, eosinophils, basophils, monocytes, lymphocytes, cholesterol, triglycerides, albumin, total protein, C-reactive protein (CRP), adiponectin, serology HIV and hepatitis infection: Hep. A antibodies, B antibodies and antigen, C antibodies, serum b-HCG.

Other Outcome Measures

Raynaud attacks assessed by a diary and the Raynaud condition score (VAS) [Daily during week 9 and week 25]
Progression of the disease assessed by changes of the activity of specific SSc biomarkers in the blood [12, 24, and 48 weeks]
Mean changes in activity biomarkers
Progression of the disease assessed by changes of the activity of specific SSc biomarkers in the skin [48 weeks]
Mean changes in activity biomarkers
Population pharmacokinetics to confirm the pharmacokinetic profile, including Cmax, Tmax, AUC, half-life (t1/2), clearance (CL/F) and volume of distribution (Vd/F) [2, 24, and 48 weeks]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Informed Consent documented by signature
Systemic sclerosis according to ACR/EULAR 2103 criteria (van de Hoogen 2013)
Diffuse cutaneous SSc subset according to LeRoy's criteria
Diagnosis within the past 3 years as defined by the first non-Raynaud's symptom
MRSS between 10 and 25
Age between 18 and 75, male or female

Patients on stable treatment (for >3 months) with prednisone ≤ 10 mg, methotrexate≤ 20 mg/w, azathioprine ≤ 150 mg/d, mycophenolate mofetil ≤ 2g/d, or leflunomide ≤ 20 mg/d may be included in the study; the therapy must be maintained as background therapy.

Exclusion Criteria:

Cyclophosphamide during the past 3 months
Requirement of IV prostanoids for pulmonary hypertension in the last 3 months
Renal insufficiency defined by a creatinine clearance of less than 30 ml/min (CKD-EPI or MDRD formula) and/or past/current renal crisis
Hepatic impairment i.e. primary biliary cirrhosis and unexplained persistent liver function abnormality,
Gallbladder disease (Cholelithiasis is not an exclusion criterion)
Diabetic ketoacidosis
Severe cardiac (LVEF <45%) and/or pulmonary disease (FVC < 50% or pulmonary hypertension proven by right heart catheterisation)
History of heart failure, symptomatic coronary artery disease, significant ventricular tachyarrhythmia, stent placement, coronary artery bypass surgery, and/or myocardial infarction.
Recipient of solid organ transplant
Gastrointestinal involvement preventing oral administration of study drug
Chronic infections, positive serology for infection with hepatitis B or C.
Pregnancy, Lactation. Woman of childbearing potential unwilling to use a medically acceptable form of birth control
History of malignancy within the last 5 years, except for resected basal or squamous cell carcinoma, treated cervical dysplasia, or treated in situ cervical cancer
A recent history of alcohol or drug abuse, non-compliance with other medical therapies
Participation in a clinical study involving another investigational drug or device within 4 weeks before the Pre-treatment Visit
Laboratory parameters at the pre-treatment visit showing any of the following abnormal results: transaminases > 2x the upper limit of normal (ULN) and/or bilirubin > 2x ULN; neutrophil count < 1,500/mm3; platelet count < 100,000/mm3; haemoglobin < 9 g/dL
Known hypersensitivity or allergy to class of drugs or the investigational product
Any condition or treatment, which in the opinion of the investigator, places the subject at unacceptable risk as a patient in the trial
Co-therapy with biologics: Wash-out period: Any anti-TNF agent in the last 3-months: adalimumab, certolizumab, etanercept, golimumab, infliximab; abatacept and tocilizumab in the last 3 months; rituximab in the last 6 months.
Any other significant heart disease or any clinically significant ECG abnormality reported by central ECG reading.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	University Multiprofile Hospital for Active Treatment - Dr. Georgi Stranski	Pleven	Bulgaria
2	Multiprofile Hospital for Active Treatment Plovdiv	Plovdiv	Bulgaria
3	University Multiprofile Hospital for Active Treatment -Kaspela	Plovdiv	Bulgaria
4	University Multiprofile Hospital for Active Treatment - "Sveti Ivan Rilski"	Sofia	Bulgaria
5	Hôpital Pellegrin	Bordeaux	France	33076
6	CHRU de Lille- Hôpital Claude Huriez	Lille	France	59037
7	Hopital Cochin	Paris	France	75014
8	University Hospital of Strasbourg	Strasbourg	France	67098
9	Kerckhoff-Klinik	Bad Nauheim	Germany	61231
10	Charité- Universitätsmedizin Berlin	Berlin	Germany	10117
11	Chaité-Universtätsmedezin Berlin	Berlin	Germany
12	Univertaetsklinikum Carl Gustav Carus	Dresden	Germany	01307
13	University of Erlangen-Nuremberg	Erlangen	Germany	91054
14	CIRI GmbH Centrum für Innovative Diagnostik und Therapie	Frankfurt	Germany
15	University Medical Center Freiburg	Freiburg	Germany	79106
16	Klinik fur Dermatologie und Venerologie der Universitat zu Köln	Köln	Germany	50931
17	Kilinik für Hautkrankenheiten	Münster	Germany	48149
18	Universtätsklinik Ulm	Ulm	Germany	89081
19	Istituto di Clinica Medica Generale Polo Didattico	Ancona	Italy	60020
20	Azienda Ospedalaria Spedali Civili di Brescia	Brescia	Italy	25123
21	Azienda Ospedaliera Universitaria Careggi	Firenze	Italy	50139
22	Ospedale San Salvatore ASL L'Aquila	L'Aquila	Italy	67100
23	Azienda Ospedaliera Universitaria Federico II	Napoli	Italy	80131
24	University of Padova	Padova	Italy	35128
25	Ospedale di Alta Specializzazione "San Camillo"	Roma	Italy	00152
26	Policlinico Umberto I	Roma	Italy	00161
27	Universita degli Studi de Verona	Verona	Italy	37134
28	Leiden University Medical Center	Leiden	Netherlands
29	Erasmus MC Universitair Medisch Centrum Rotterdam	Rotterdam	Netherlands
30	Centrum Miriada Prywatny	Bialystok	Poland
31	University Hospital in Bydgoszcz	Bydgoszcz	Poland
32	CM Plejady	Krakow	Poland
33	Reumed	Lublin	Poland
34	Medycine Centrum Hetmanska Poznan	Poznan	Poland
35	Centrum Medyczne Oporow	Wroclaw	Poland
36	University Medical centre Ljubljana	Ljubljana	Slovenia
37	University Medical Centre Maribor	Maribor	Slovenia
38	Hospital de la Santa Creu i Sant Pau	Barcelona	Spain	08026
39	Hopital Universitario Gregorio Marañon	Madrid	Spain	28007
40	Hopital 12 de Octubre	Madrid	Spain	28041
41	Hopital Universitario Sanchinarro	Madrid	Spain	28050
42	Hospital La Paz	Madrid	Spain
43	Hospital La Princesa	Madrid	Spain
44	Hospital Universitario Ramon y Cajal	Madrid	Spain
45	Hospital Universitario Dr Peset	Valencia	Spain	46017
46	University Hospital Lausanne	Lausanne	Switzerland
47	University Hospital Zurich	Zurich	Switzerland
48	Leeds Institut of Rheumatic and Musculoskeletal Medicine	Leeds	United Kingdom	LS7 4SA
49	Royal Free Hospital	London	United Kingdom	NW3 2QG

Sponsors and Collaborators

Inventiva Pharma

Investigators

Principal Investigator: Yannick Allanore, Professor, Université Paris Descartes, Hôpital Cochin, Service de Rhumatologie A & INSERM, Paris, France,
Principal Investigator: Christopher Denton, Professor, Royal Free Hospital NHS Foundation Trust