Diffuse Cutaneous Systemic Sclerosis, Scleroderma, Diffuse
Conditions
Keywords
diffuse cutaneous systemic sclerosis, scleroderma, IVA337, dcSSc, lanifibranor
Brief summary
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
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.
Interventions
DRUGIVA337
Capsules of 200mg IVA337
DRUGPlacebo
Identical capsules without active substance
Sponsors
Inventiva Pharma
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Measurement of skin thickness by the Modified Rodnan Skin Score (MRSS) | 48 weeks | Mean change of the MRSS from baseline |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Routine and specific laboratory tests (composite) to assess safety and tolerability | 2, 12, 20, 24, 32, 36, 44, 48, and 52 weeks | 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. |
| Change in the Combined Response Index for Systemic Sclerosis (CRISS) | 24 and 48 weeks | Composed of five variables: MRSS, FVC % predicted, physician and patient global assessments, and HAQ-DI score |
| Percent of patients who need escape therapy | 28, 32,40, and 48 weeks | Need for escape therapy |
| Percent of patients who experience a new severe organ involvement | 2, 4, 8,12, 16, 24, 28, 32, 40, 48, and 52 weeks | Severe organ involvement |
| Number of participants with adverse events as a measure of safety and tolerability | 2, 4, 8, 12, 16, 20, 24, 28, 32, 40, 44, 48, and 52 weeks | Frequency and type of AEs |
| Response rates based on MRSS improvement | 12, 24, 32, 48 weeks | 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) |
| Overall progression of the disease: defined as absence of rescue therapy and absence of severe organ involvement | 28, 32,40, and 48 weeks | Overall progression of the disease: defined as absence of rescue therapy and absence of severe organ involvement |
| Lung function measured by FVC% predicted | 24 and 48 weeks | Change in pulmonary function |
| Lung function by cDLCO% predicted | 24 and 48 weeks | Change in pulmonary function |
| Scleroderma Health Assessment Questionnaire (SHAQ) | 24 and 48 weeks | Changes in patient reported outcomes |
| Gastrointestinal tract symptoms severity and its impact on patients' well-being assessed by the UCLA SCTC GIT | 24 and 48 weeks | Changes in patient reported outcomes |
| Patient-reported health status assessed by PROMIS29 | 24 and 48 weeks | Changes in patient reported outcomes |
| Physical and mental health assessed by SF36 | 24 and 48 weeks | Changes in patient reported outcomes |
| 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 | 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 |
| Hand function assessed by the Cochin Hand Function Scale | 12, 24, 32 and 48 weeks | Hand function assessed by the Cochin Hand Function Scale |
| Patient global assessment of disease activity assessed by a visual analogue scale | 24 and 48 weeks | Patient global assessments of disease activity (VAS) |
| Physician global assessment of disease activity assessed by a visual analogue scale | 24 and 48 weeks | Physician global assessment of disease activity (VAS) |
Other
| Measure | Time frame | Description |
|---|---|---|
| Progression of the disease assessed by changes of the activity of specific SSc biomarkers in the skin | 48 weeks | Mean changes in activity biomarkers |
| 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 | — |
| Progression of the disease assessed by changes of the activity of specific SSc biomarkers in the blood | 12, 24, and 48 weeks | Mean changes in activity biomarkers |
| Raynaud attacks assessed by a diary and the Raynaud condition score (VAS) | Daily during week 9 and week 25 | — |
Countries
Bulgaria, France, Germany, Italy, Netherlands, Poland, Slovenia, Spain, Switzerland, United Kingdom
Outcome results
None listed