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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Scleroderma, Diffuse, Diffuse Cutaneous Systemic Sclerosis

Intervention / Treatment
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* Drug: IVA337
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: IVA337 800mg<br>Patients receive twice daily 400mg IVA337. | Drug: IVA337<br>* Capsules of 200mg IVA337<br>* Other names: lanifibranor;|
| Active Comparator: IVA337 1200mg<br>Patients receive twice daily 600mg IVA337. | Drug: IVA337<br>* Capsules of 200mg IVA337<br>* Other names: lanifibranor;|
| Placebo Comparator: Placebo<br>Patients receive twice daily placebo. | Drug: Placebo<br>* Identical capsules without active substance<br>* Other names: No other names at present;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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diffuse cutaneous systemic sclerosis, scleroderma, IVA337, dcSSc, lanifibranor