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

Phase 2

Completed

• Conditions: Scleroderma, Diffuse; Diffuse Cutaneous Systemic Sclerosis
• Interventions: Drug: IVA337; Drug: Placebo

• Registration Number: NCT02503644
• Lead Sponsor: Inventiva Pharma

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.

Study Timeline

• Study First Submitted: 2015-06-30
• Study First Submitted QC: 2015-07-20
• Study First Posted: 2015-07-21
• Study Start: 2015-10-29
• Primary Completion: 2018-10
• Study Completion: 2018-10-12
• Status Verified: 2019-03
• Last Update Submitted: 2019-03-01
• Last Update Posted: 2019-03-04

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 145

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
IVA337 1200mg	IVA337	Patients receive twice daily 600mg IVA337.
Placebo	Placebo	Patients receive twice daily placebo.
IVA337 800mg	IVA337	Patients receive twice daily 400mg IVA337.

Primary Outcome Measures

Name	Time	Method
Measurement of skin thickness by the Modified Rodnan Skin Score (MRSS)	48 weeks	Mean change of the MRSS from baseline

Secondary Outcome Measures

Name	Time	Method
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
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
Physical and mental health assessed by SF36	24 and 48 weeks	Changes in patient reported outcomes
Lung function by cDLCO% predicted	24 and 48 weeks	Change in pulmonary function
Patient-reported health status assessed by PROMIS29	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
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)
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
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
Hand function assessed by the Cochin Hand Function Scale	12, 24, 32 and 48 weeks	Hand function assessed by the Cochin Hand Function Scale
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
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.

Trial Locations

Locations (49)

University Multiprofile Hospital for Active Treatment - Dr. Georgi Stranski; 🇧🇬 Pleven, Bulgaria

Multiprofile Hospital for Active Treatment Plovdiv; 🇧🇬 Plovdiv, Bulgaria

University Multiprofile Hospital for Active Treatment -Kaspela; 🇧🇬 Plovdiv, Bulgaria

University Multiprofile Hospital for Active Treatment - "Sveti Ivan Rilski"; 🇧🇬 Sofia, Bulgaria

Hôpital Pellegrin; 🇫🇷 Bordeaux, France

CHRU de Lille- Hôpital Claude Huriez; 🇫🇷 Lille, France

Hopital Cochin; 🇫🇷 Paris, France

University Hospital of Strasbourg; 🇫🇷 Strasbourg, France

Kerckhoff-Klinik; 🇩🇪 Bad Nauheim, Germany

Charité- Universitätsmedizin Berlin; 🇩🇪 Berlin, Germany

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