Proof-of-concept Trial of IVA337 in Diffuse Cutaneous Systemic Sclerosis
- Conditions
- Scleroderma, DiffuseDiffuse Cutaneous Systemic Sclerosis
- Interventions
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 145
- 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.
- 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 Physical and mental health assessed by SF36 24 and 48 weeks Changes in patient reported outcomes
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
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
Hôpital Pellegrin
🇫🇷Bordeaux, France
Kerckhoff-Klinik
🇩🇪Bad Nauheim, Germany
Hopital Cochin
🇫🇷Paris, France
University Hospital of Strasbourg
🇫🇷Strasbourg, France
Charité- Universitätsmedizin Berlin
🇩🇪Berlin, Germany
Chaité-Universtätsmedezin Berlin
🇩🇪Berlin, Germany
Univertaetsklinikum Carl Gustav Carus
🇩🇪Dresden, Germany
University of Erlangen-Nuremberg
🇩🇪Erlangen, Germany
CIRI GmbH Centrum für Innovative Diagnostik und Therapie
🇩🇪Frankfurt, Germany
University Medical Center Freiburg
🇩🇪Freiburg, Germany
Kilinik für Hautkrankenheiten
🇩🇪Münster, Germany
Klinik fur Dermatologie und Venerologie der Universitat zu Köln
🇩🇪Köln, Germany
Universtätsklinik Ulm
🇩🇪Ulm, Germany
University Hospital in Bydgoszcz
🇵🇱Bydgoszcz, Poland
CM Plejady
🇵🇱Krakow, Poland
Hopital Universitario Gregorio Marañon
🇪🇸Madrid, Spain
Hopital Universitario Sanchinarro
🇪🇸Madrid, Spain
Hospital de la Santa Creu i Sant Pau
🇪🇸Barcelona, Spain
Hopital 12 de Octubre
🇪🇸Madrid, Spain
Hospital La Princesa
🇪🇸Madrid, Spain
Hospital Universitario Dr Peset
🇪🇸Valencia, Spain
Hospital Universitario Ramon y Cajal
🇪🇸Madrid, Spain
University Hospital Zurich
🇨🇭Zurich, Switzerland
Leeds Institut of Rheumatic and Musculoskeletal Medicine
🇬🇧Leeds, United Kingdom
Royal Free Hospital
🇬🇧London, United Kingdom
CHRU de Lille- Hôpital Claude Huriez
🇫🇷Lille, France
Istituto di Clinica Medica Generale Polo Didattico
🇮🇹Ancona, Italy
Azienda Ospedalaria Spedali Civili di Brescia
🇮🇹Brescia, Italy
Azienda Ospedaliera Universitaria Careggi
🇮🇹Firenze, Italy
Ospedale San Salvatore ASL L'Aquila
🇮🇹L'Aquila, Italy
Azienda Ospedaliera Universitaria Federico II
🇮🇹Napoli, Italy
University of Padova
🇮🇹Padova, Italy
Ospedale di Alta Specializzazione "San Camillo"
🇮🇹Roma, Italy
Policlinico Umberto I
🇮🇹Roma, Italy
Universita degli Studi de Verona
🇮🇹Verona, Italy
Hospital La Paz
🇪🇸Madrid, Spain
Centrum Miriada Prywatny
🇵🇱Bialystok, Poland
University Multiprofile Hospital for Active Treatment - "Sveti Ivan Rilski"
🇧🇬Sofia, Bulgaria
University Medical centre Ljubljana
🇸🇮Ljubljana, Slovenia
University Multiprofile Hospital for Active Treatment -Kaspela
🇧🇬Plovdiv, Bulgaria
Leiden University Medical Center
🇳🇱Leiden, Netherlands
Reumed
🇵🇱Lublin, Poland
University Medical Centre Maribor
🇸🇮Maribor, Slovenia
University Hospital Lausanne
🇨🇭Lausanne, Switzerland
Centrum Medyczne Oporow
🇵🇱Wroclaw, Poland
Erasmus MC Universitair Medisch Centrum Rotterdam
🇳🇱Rotterdam, Netherlands
Medycine Centrum Hetmanska Poznan
🇵🇱Poznan, Poland