Clinical trial NCT02503644: Proof-of-concept Trial of IVA337 in Diffuse Cutaneous Systemic Sclerosis
Official title: A Randomized, Double-blind, Placebo-controlled, Multicentre Proof-of-concept Trial of IVA337 in the Treatment of Diffuse Cutaneous Systemic Sclerosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Scleroderma, Diffuse
Diffuse Cutaneous Systemic Sclerosis
Keywords: diffuse cutaneous systemic sclerosis
scleroderma
IVA337
dcSSc
lanifibranor
Lead sponsor: Inventiva Pharma
Sponsor class: INDUSTRY
First posted: 2015-07-21
Enrollment: 145
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Measurement of skin thickness by the Modified Rodnan Skin Score (MRSS)
timeFrame: 48 weeks
Secondary outcomes:
measure: Response rates based on MRSS improvement
timeFrame: 12, 24, 32, 48 weeks
measure: Overall progression of the disease: defined as absence of rescue therapy and absence of severe organ involvement
timeFrame: 28, 32,40, and 48 weeks
measure: Lung function measured by FVC% predicted
timeFrame: 24 and 48 weeks
measure: Lung function by cDLCO% predicted
timeFrame: 24 and 48 weeks
measure: Scleroderma Health Assessment Questionnaire (SHAQ)
timeFrame: 24 and 48 weeks
measure: Gastrointestinal tract symptoms severity and its impact on patients' well-being assessed by the UCLA SCTC GIT
timeFrame: 24 and 48 weeks
measure: Patient-reported health status assessed by PROMIS29
timeFrame: 24 and 48 weeks
measure: Physical and mental health assessed by SF36
timeFrame: 24 and 48 weeks
measure: 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
timeFrame: 12, 24, 32 and 48 weeks
measure: Hand function assessed by the Cochin Hand Function Scale
timeFrame: 12, 24, 32 and 48 weeks
measure: Patient global assessment of disease activity assessed by a visual analogue scale
timeFrame: 24 and 48 weeks
measure: Physician global assessment of disease activity assessed by a visual analogue scale
timeFrame: 24 and 48 weeks
measure: Change in the Combined Response Index for Systemic Sclerosis (CRISS)
timeFrame: 24 and 48 weeks
measure: Percent of patients who need escape therapy
timeFrame: 28, 32,40, and 48 weeks
measure: Percent of patients who experience a new severe organ involvement
timeFrame: 2, 4, 8,12, 16, 24, 28, 32, 40, 48, and 52 weeks
measure: Number of participants with adverse events as a measure of safety and tolerability
timeFrame: 2, 4, 8, 12, 16, 20, 24, 28, 32, 40, 44, 48, and 52 weeks
measure: Routine and specific laboratory tests (composite) to assess safety and tolerability
timeFrame: 2, 12, 20, 24, 32, 36, 44, 48, and 52 weeks
Other outcomes:
measure: Raynaud attacks assessed by a diary and the Raynaud condition score (VAS)
timeFrame: Daily during week 9 and week 25
measure: Progression of the disease assessed by changes of the activity of specific SSc biomarkers in the blood
timeFrame: 12, 24, and 48 weeks
measure: Progression of the disease assessed by changes of the activity of specific SSc biomarkers in the skin
timeFrame: 48 weeks
measure: Population pharmacokinetics to confirm the pharmacokinetic profile, including Cmax, Tmax, AUC, half-life (t1/2), clearance (CL/F) and volume of distribution (Vd/F)
timeFrame: 2, 24, and 48 weeks
Locations:
city: Pleven
country: Bulgaria
facility: University Multiprofile Hospital for Active Treatment - Dr. Georgi Stranski
city: Plovdiv
country: Bulgaria
facility: Multiprofile Hospital for Active Treatment Plovdiv
city: Plovdiv
country: Bulgaria
facility: University Multiprofile Hospital for Active Treatment -Kaspela
city: Sofia
country: Bulgaria
facility: University Multiprofile Hospital for Active Treatment - "Sveti Ivan Rilski"
city: Bordeaux
country: France
facility: Hôpital Pellegrin
city: Lille
country: France
facility: CHRU de Lille- Hôpital Claude Huriez
city: Paris
country: France
facility: Hopital Cochin
city: Strasbourg
country: France
facility: University Hospital of Strasbourg
city: Bad Nauheim
country: Germany
facility: Kerckhoff-Klinik
city: Berlin
country: Germany
facility: Charité- Universitätsmedizin Berlin
city: Berlin
country: Germany
facility: Chaité-Universtätsmedezin Berlin
city: Dresden
country: Germany
facility: Univertaetsklinikum Carl Gustav Carus
city: Erlangen
country: Germany
facility: University of Erlangen-Nuremberg
city: Frankfurt
country: Germany
facility: CIRI GmbH Centrum für Innovative Diagnostik und Therapie
city: Freiburg
country: Germany
facility: University Medical Center Freiburg
city: Köln
country: Germany
facility: Klinik fur Dermatologie und Venerologie der Universitat zu Köln
city: Münster
country: Germany
facility: Kilinik für Hautkrankenheiten
city: Ulm
country: Germany
facility: Universtätsklinik Ulm
city: Ancona
country: Italy
facility: Istituto di Clinica Medica Generale Polo Didattico
city: Brescia
country: Italy
facility: Azienda Ospedalaria Spedali Civili di Brescia
city: Firenze
country: Italy
facility: Azienda Ospedaliera Universitaria Careggi
city: L'Aquila
country: Italy
facility: Ospedale San Salvatore ASL L'Aquila
city: Napoli
country: Italy
facility: Azienda Ospedaliera Universitaria Federico II
city: Padova
country: Italy
facility: University of Padova
city: Roma
country: Italy
facility: Ospedale di Alta Specializzazione "San Camillo"
city: Roma
country: Italy
facility: Policlinico Umberto I
city: Verona
country: Italy
facility: Universita degli Studi de Verona
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
city: Rotterdam
country: Netherlands
facility: Erasmus MC Universitair Medisch Centrum Rotterdam
city: Bialystok
country: Poland
facility: Centrum Miriada Prywatny
city: Bydgoszcz
country: Poland
facility: University Hospital in Bydgoszcz
city: Krakow
country: Poland
facility: CM Plejady
city: Lublin
country: Poland
facility: Reumed
city: Poznan
country: Poland
facility: Medycine Centrum Hetmanska Poznan
city: Wroclaw
country: Poland
facility: Centrum Medyczne Oporow
city: Ljubljana
country: Slovenia
facility: University Medical centre Ljubljana
city: Maribor
country: Slovenia
facility: University Medical Centre Maribor
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau
city: Madrid
country: Spain
facility: Hopital Universitario Gregorio Marañon
city: Madrid
country: Spain
facility: Hopital 12 de Octubre
city: Madrid
country: Spain
facility: Hopital Universitario Sanchinarro
city: Madrid
country: Spain
facility: Hospital La Paz
city: Madrid
country: Spain
facility: Hospital La Princesa
city: Madrid
country: Spain
facility: Hospital Universitario Ramon y Cajal
city: Valencia
country: Spain
facility: Hospital Universitario Dr Peset
city: Lausanne
country: Switzerland
facility: University Hospital Lausanne
city: Zurich
country: Switzerland
facility: University Hospital Zurich
city: Leeds
country: United Kingdom
facility: Leeds Institut of Rheumatic and Musculoskeletal Medicine
city: London
country: United Kingdom
facility: Royal Free Hospital
Study officials:
affiliation: Université Paris Descartes, Hôpital Cochin, Service de Rhumatologie A & INSERM, Paris, France,
name: Yannick Allanore, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Royal Free Hospital NHS Foundation Trust
name: Christopher Denton, Professor
role: PRINCIPAL_INVESTIGATOR
References: