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:
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.
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.
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:
Primary and secondary endpoints: