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

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 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.

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.