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

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

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.

Study Overview

• Status: Completed
• Conditions: Scleroderma, Diffuse; Diffuse Cutaneous Systemic Sclerosis
• Intervention / Treatment: Drug: IVA337; Drug: Placebo

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 Type: Interventional
• Enrollment (Actual): 145
• Phase: Phase 2

Contacts and Locations

Study Locations

• Bulgaria
  • Pleven, Bulgaria
    • University Multiprofile Hospital for Active Treatment - Dr. Georgi Stranski
  • Plovdiv, Bulgaria
    • Multiprofile Hospital for Active Treatment Plovdiv
  • Plovdiv, Bulgaria
    • University Multiprofile Hospital for Active Treatment -Kaspela
  • Sofia, Bulgaria
    • University Multiprofile Hospital for Active Treatment - "Sveti Ivan Rilski"
• France
  • Bordeaux, France, 33076
    • Hopital Pellegrin
  • Lille, France, 59037
    • CHRU de Lille- Hôpital Claude Huriez
  • Paris, France, 75014
    • Hopital Cochin
  • Strasbourg, France, 67098
    • University Hospital of Strasbourg
• Germany
  • Bad Nauheim, Germany, 61231
    • Kerckhoff-Klinik
  • Berlin, Germany, 10117
    • Charité- Universitätsmedizin Berlin
  • Berlin, Germany
    • Chaité-Universtätsmedezin Berlin
  • Dresden, Germany, 01307
    • Univertaetsklinikum Carl Gustav Carus
  • Erlangen, Germany, 91054
    • University of Erlangen-Nuremberg
  • Frankfurt, Germany
    • CIRI GmbH Centrum für Innovative Diagnostik und Therapie
  • Freiburg, Germany, 79106
    • University Medical Center Freiburg
  • Köln, Germany, 50931
    • Klinik fur Dermatologie und Venerologie der Universitat zu Köln
  • Münster, Germany, 48149
    • Kilinik für Hautkrankenheiten
  • Ulm, Germany, 89081
    • Universtätsklinik Ulm
• Italy
  • Ancona, Italy, 60020
    • Istituto di Clinica Medica Generale Polo Didattico
  • Brescia, Italy, 25123
    • Azienda Ospedalaria Spedali Civili di Brescia
  • Firenze, Italy, 50139
    • Azienda Ospedaliera Universitaria Careggi
  • L'Aquila, Italy, 67100
    • Ospedale San Salvatore ASL L'Aquila
  • Napoli, Italy, 80131
    • Azienda Ospedaliera Universitaria Federico II
  • Padova, Italy, 35128
    • University of Padova
  • Roma, Italy, 00161
    • Policlinico Umberto I
  • Roma, Italy, 00152
    • Ospedale di Alta Specializzazione "San Camillo"
  • Verona, Italy, 37134
    • Universita degli Studi de Verona
• Netherlands
  • Leiden, Netherlands
    • Leiden University Medical Center
  • Rotterdam, Netherlands
    • Erasmus MC Universitair Medisch Centrum Rotterdam
• Poland
  • Bialystok, Poland
    • Centrum Miriada Prywatny
  • Bydgoszcz, Poland
    • University Hospital in Bydgoszcz
  • Krakow, Poland
    • CM Plejady
  • Lublin, Poland
    • Reumed
  • Poznan, Poland
    • Medycine Centrum Hetmanska Poznan
  • Wroclaw, Poland
    • Centrum Medyczne Oporow
• Slovenia
  • Ljubljana, Slovenia
    • University Medical Centre Ljubljana
  • Maribor, Slovenia
    • University Medical Centre Maribor
• Spain
  • Barcelona, Spain, 08026
    • Hospital de La Santa Creu I Sant Pau
  • Madrid, Spain
    • Hospital La Paz
  • Madrid, Spain
    • Hospital La Princesa
  • Madrid, Spain
    • Hospital Universitario Ramon Y Cajal
  • Madrid, Spain, 28007
    • Hopital Universitario Gregorio Marañon
  • Madrid, Spain, 28041
    • Hopital 12 de Octubre
  • Madrid, Spain, 28050
    • Hopital Universitario Sanchinarro
  • Valencia, Spain, 46017
    • Hospital Universitario Dr Peset
• Switzerland
  • Lausanne, Switzerland
    • University Hospital Lausanne
  • Zurich, Switzerland
    • University Hospital Zurich
• United Kingdom
  • Leeds, United Kingdom, LS7 4SA
    • Leeds Institut of Rheumatic and Musculoskeletal Medicine
  • London, United Kingdom, NW3 2QG
    • Royal Free Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 73 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Measurement of skin thickness by the Modified Rodnan Skin Score (MRSS)	Mean change of the MRSS from baseline	48 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response rates based on MRSS improvement	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)	12, 24, 32, 48 weeks
Overall progression of the disease: defined as absence of rescue therapy and absence of severe organ involvement	Overall progression of the disease: defined as absence of rescue therapy and absence of severe organ involvement	28, 32,40, and 48 weeks
Lung function measured by FVC% predicted	Change in pulmonary function	24 and 48 weeks
Lung function by cDLCO% predicted	Change in pulmonary function	24 and 48 weeks
Scleroderma Health Assessment Questionnaire (SHAQ)	Changes in patient reported outcomes	24 and 48 weeks
Gastrointestinal tract symptoms severity and its impact on patients' well-being assessed by the UCLA SCTC GIT	Changes in patient reported outcomes	24 and 48 weeks
Patient-reported health status assessed by PROMIS29	Changes in patient reported outcomes	24 and 48 weeks
Physical and mental health assessed by SF36	Changes in patient reported outcomes	24 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	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
Hand function assessed by the Cochin Hand Function Scale	Hand function assessed by the Cochin Hand Function Scale	12, 24, 32 and 48 weeks
Patient global assessment of disease activity assessed by a visual analogue scale	Patient global assessments of disease activity (VAS)	24 and 48 weeks
Physician global assessment of disease activity assessed by a visual analogue scale	Physician global assessment of disease activity (VAS)	24 and 48 weeks
Change in the Combined Response Index for Systemic Sclerosis (CRISS)	Composed of five variables: MRSS, FVC % predicted, physician and patient global assessments, and HAQ-DI score	24 and 48 weeks
Percent of patients who need escape therapy	Need for escape therapy	28, 32,40, and 48 weeks
Percent of patients who experience a new severe organ involvement	Severe organ involvement	2, 4, 8,12, 16, 24, 28, 32, 40, 48, and 52 weeks
Number of participants with adverse events as a measure of safety and tolerability	Frequency and type of AEs	2, 4, 8, 12, 16, 20, 24, 28, 32, 40, 44, 48, and 52 weeks
Routine and specific laboratory tests (composite) to assess safety and tolerability	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.	2, 12, 20, 24, 32, 36, 44, 48, and 52 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Mean changes in activity biomarkers	12, 24, and 48 weeks
Progression of the disease assessed by changes of the activity of specific SSc biomarkers in the skin	Mean changes in activity biomarkers	48 weeks
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

Collaborators and Investigators

• Sponsor: 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

Study record dates

Study Major Dates

• Study Start (Actual): October 29, 2015
• Primary Completion (Actual): October 1, 2018
• Study Completion (Actual): October 12, 2018

Study Registration Dates

• First Submitted: June 30, 2015
• First Submitted That Met QC Criteria: July 20, 2015
• First Posted (Estimate): July 21, 2015

Study Record Updates

• Last Update Posted (Actual): March 4, 2019
• Last Update Submitted That Met QC Criteria: March 1, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Keywords: scleroderma; dcSSc; diffuse cutaneous systemic sclerosis; IVA337; lanifibranor
• Additional Relevant MeSH Terms: Pathologic Processes; Skin Diseases; Connective Tissue Diseases; Sclerosis; Scleroderma, Systemic; Scleroderma, Diffuse
• Other Study ID Numbers: IVA_01_337_HSSC_15_001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No