FASST banner Inventiva website FASST home page
Presentation
of the trial
A randomized, double-blind, placebo-controlled, multicentre proof-of-concept trial of IVA337 in the treatment of diffuse cutaneous systemic sclerosis

To learn more about this study, you may contact the study research staff:
Mari Carmen DELATTE
mari-carmen.delatte@inventivapharma.com

Purpose (presentation of the treatment: IVA337)

IVA 337 is a new chemical entity (4-[1-(1,3-benzothiazol-6-ylsulfonyl)-5-chloro-1H-indol-2-yl]butanoic acid) that activates all three Peroxisome Proliferator-Activated Receptors (PPAR) isotypes PPARα, PPARδ and PPARγ.

The PPARs are ligand-activated transcription factors belonging to the nuclear hormone receptor family that regulate a range of physiological activities (metabolic activities, vascular function, anti-inflammatory, anti fibrotic). PPAR activation inhibits the fibrogenic process at multiple entry points:
  • Inflammation, growth factors, cytokines & chemokines
  • Fibroblast proliferation & differentiation
  • Myofibroblast proliferation, survival & migration
  • Extracellular matrix deposition
  • Fibrosis
IVA337 was designed to produce moderate panPPAR activation, with partial activation of PPARγ. It has demonstrated consistent anti-fibrotic activity in vitro and in vivo across multiple models and several organs: skin, kidney, lung and liver. In Phase I trials, the clinical program involved 100 volunteers treated. 47 patients were also treated in a 4-week phase IIa in Type 2 Diabetes Mellitus (T2DM).

more/less

Trial Objective

The primary objective of this study is to evaluate in patients suffering from diffuse cutaneous SSc (DcSSc) the effect of 800mg and 1200mg IVA337 daily on the skin compared to placebo. The modified Rodnan Skin Score (mRSS) will be used to determine the changes in skin.

Secondary objectives include additional efficacy evaluations (details in the protocol), assessment of adverse events (AEs), and determination of population PK parameters of IVA337 in patients.

Trial Rationale

IVA337 potentially offers a new therapeutic approach for DcSSc for which no curative treatment is available: patients with DcSSc suffer from a high risk of premature mortality and have considerable morbidity from their disease due to skin fibrosis and excessive collagen deposition in various organs including the lungs, kidney, heart and gastrointestinal tract.

Choice of the study population The EUSTAR network has recently reported that low mRSS at baseline was a consistent predictor of skin fibrosis worsening in patients with early DcSSc. Indeed, patients with DcSSc who have a baseline mRSS of 7–22 (out of 51) were most likely to have progression of skin fibrosis, whereas patients with higher scores rarely progressed.
Capturing patients with skin progression is of paramount importance for increasing the possibility to differentiate an efficient drug from placebo in a clinical trial measuring skin changes. This finding is of importance for study design, as it strongly supports the existence of a therapeutic window of opportunity for patients with early DcSSc.
Therefore, the targeted population in this trial is patients with SSc fulfilling the criteria of the DcSSc subset, of less than 3 years of disease duration and with baseline mRSS of 10 to 25.

more/less

Study Design

Randomized, double-blind, placebo-controlled, multicentre phase 2 proof-of-concept trial of IVA337 for the treatment of 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 twice a day
  • IVA337 600mg twice a day
Both, patient and investigator are blinded. The treatment duration lasts 48 weeks. A follow-up assessment takes place 12 weeks after the last dose.

Eligibility and Inclusion Criteria

Eligibility criteria:

  • Patients on stable immunosuppressive therapy meeting the criteria may be included in the study
  • Patients on stable treatment (for > 3 months):
    • prednisone ≤ 10 mg,
    • methotrexate ≤ 20 mg/w,
    • azathioprine ≤ 150 mg/d,
    • mycophenolate mofetil ≤ 2g/d
    • leflunomide ≤ 20 mg/d
  • Therapy to be maintained as background therapy

Inclusion criteria:
  • Patient 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

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 and/or past/current renal crisis
  • Hepatic impairment i.e. primary biliary cirrhosis and unexplained persistent liver function abnormality
  • Gallbladder disease
  • 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 of the skin, 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 the past 4 weeks or during the study
  • 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; abnormal haemoglobin
  • 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
  • Women of childbearing potential therefore need to use an effective contraceptive measure until at least 2 weeks after treatment discontinuation

more/less

Outcomes

Primary and secondary endpoints:

  • Primary endpoint
    • The mean change of the mRSS from baseline to 48 weeks
  • Secondary endpoints
    • mRSS response rates; improvers are defined by a reduction ≥ 5 points and ≥ 25 % of mRSS

    • Overall progression of the disease: defined as absence of rescue therapy and absence of severe organ involvement
    • Change in pulmonary function tests (FVC% predicted and cDLCO% predicted)
    • Changes in patient reported outcomes (SHAQ, UCLA SCTC GIT, PROMIS29, SF36)
    • 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
    • Cochin Hand Function Scale
    • Physician and patient global assessments of disease activity (VAS)
    • Change in the Combined Response Index for Systemic Sclerosis (CRISS), consisting of five variables: mRSS, FVC % predicted, physician and patient global assessments, and HAQ-DI score (from SHAQ patient reported outcome)
    • Need for escape therapy (% patients)
    • Severe organ involvement (% patients) defined by Prof Denton in the next presentation.
    • Frequency and type of AEs
    • Lab tests: mean change and frequency of values outside the normal range
    • Raynaud phenomenon (Raynaud’s condition score)
    • Mean changes in activity biomarkers
    • Follow-up visit to evaluate any changes that might occur within 12 weeks after completion of the treatment.
Schedule of procedures: Alternate Text

more/less

contact us | © Inventiva 2016