Safety and Efficacy of Itacitinib in Adults With Systemic Sclerosis
- Registration Number
- NCT04789850
- Lead Sponsor
- Assistance Publique - Hôpitaux de Paris
- Brief Summary
The purpose of this study is to determine whether itacitinib is safe and effective in the treatment of systemic sclerosis in adults.
- Detailed Description
Systemic sclerosis (SSc) is a rare systemic autoimmune connective tissue-disease characterized by fibrosis, inflammation, and vasculopathy. SSc is responsible for skin fibrosis that can either be limited or diffuse. The latter phenotype of the disease is commonly associated with visceral involvement and therefore similar to graft versus host disease (GvHD) reaction. It can be life threatening in case of pulmonary or cardiovascular involvement. Nonetheless SSc remains a severe disease responsible for important disability and a poor quality of life.
There is a growing body of evidence that supports the implication of the JAK-STAT tyrosine kinases pathway in the activation of fibroblasts of patients with SSc. A genetic polymorphism of STAT4 was found to be associated with the diffuse form of the disease and inhibition of STAT4 gene is associated with a decrease in TGF-ß and IL-6 cytokines activation, which are two major cytokines implicated in SSc pathogenesis. Recently, Pedroza et al. confirmed the implication of STAT3 in skin fibrosis mechanisms. Indeed, the authors showed an enhanced activation of STAT3 and demonstrated in vivo that the inhibition of STAT3 phosphorylation prevented skin fibrosis in a murine model of SSc. These data were confirmed by a work of Zhang et al. who showed that the inhibition of JAK1 was also needed to prevent skin and lung fibrosis. Altogether these works confirmed the implication of the JAK pathway in fibrosis mechanism.
Itacitinib is a Janus kinase inhibitor that specifically targets JAK1 and decreases STAT3 phosphorylation. Itacitinib was shown to efficiently treat patients with myelofibrosis, rheumatoid arthritis, and chronic plaque psoriasis. Very interestingly, itacitinib efficacy has also been reported in patients with acute GvHD. Altogether these data and studies reinforced the investigator's working hypothesis.
The efficacy and safety of this proposal must be tested.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 74
- Adult patient (≥18 years old)
- Patient with a diagnosis of diffuse SSc, as defined by the American College of Rheumatology / EULAR 2013 criteria,
- Patient with a SSc disease duration of less than 36 months (defined as time from first non-Raynaud phenomenon manifestation) or with an active SSc disease, as defined by EUSTAR disease activity score,
- Patient with a modified Rodnan skin score (mRSS) ≥ 10 and ≤ 35 units at screening,
- Negative pregnancy test for woman of childbearing potential, woman of childbearing potential should have reliable contraception for the 12 months' duration of the study,
- Patient able to give written informed consent prior to participation in the study,
- Affiliation to a social security scheme (profit or being entitled).
- Previous treatment with itacitinib or a Janus kinase (JAK) inhibitor,
- Contra-indications to itacitinib or Janus kinase inhibitor,
- Failure to sign the informed consent or unable to consent
- Patient participating in another investigational therapeutic study,
- Acute or chronic active infections, including HBV, HCV, HIV,
- Patient with other uncontrolled diseases, including drug or alcohol abuse, severe psychiatric diseases, that could interfere with participation in the trial according to the protocol,
- Patient suspected not to be observant to the proposed treatments,
- Patient who have white blood cell count ≤ 4,000/mm3,
- Patient who have platelet count ≤ 100,000/mm3,
- Patients who have ALT or AST level greater that 3 times the upper limit of normal,
- Patient who have triglyceride level greater than 5g/L
- Pregnant or breastfeeding woman,
- Protected adults (including individual under guardianship by court order),
- Patient receiving or having received cyclophosphamide or rituximab within the last three months (possible inclusion beyond 3 months),
- Patient receiving or having received a biotherapy (anti-TNF, abatacept or tocilizumab) in the last 3 months (possible inclusion beyond 3 months)
- Atherosclerotic cardiovascular disease as defined by a history of myocardial infarction, ischaemic stroke, or peripheral artery thrombosis
- Anti-phospholipid syndrome
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Itacitinib Itacitinib 200mg of oral Itacitinib everyday for 360 days. Placebo Placebo Oral placebo everyday for 360 days.
- Primary Outcome Measures
Name Time Method Change in modified Rodnan skin score (mRSS) at 360 days 360 days performed by the same investigator at day 0 and day 360 and the change in mRSS will be calculated following the formula: ΔmRSS= mRSSd360 - mRSSd0.
To measure mRSS, skin thickness of the patient is rated by palpation at each of 17 anatomic sites using a scale of 0-3 (0 = normal skin; 1= mild thickness; 2= moderate thickness; 3=severe thickness with an inability to pinch the skin into a fold). The scores at each site are summed with a minimum of 0 and a maximum of 51 (17 sites)
- Secondary Outcome Measures
Name Time Method Change in the Combined Response Index in Diffuse Systemic Sclerosis (CRISS) score At 180 and 360 days composite response index
Incidence of death at 180 and 360 days Proportion of patients with an active disease according to the European scleroderma trials and research group (EUSTAR)SSc activity score at 90, 180, 270 and 360 days At 90, 180, 270 and 360 days EUSTAR SSc activity index score from 0 to 10 - a cut-off ≥ 2.5 identifies patients with active disease
SSc disease activity At 90, 180, 270 and 360 days * Physicians visual analogue scale range from 0 (min) to 10 (max) - 0=no activity, 10=maximum activity
* Patients visual analogue scale range from 0 (min) to 10 (max) - 0=no activity, 10=maximum activityHealth Assessment Questionnaire Disability Index (HAQ-DI) scale At 0, 15, 90, 180, 270 and 360 days self administered 20 questions- score range from 0 (no disability) to 3 (severe disability)
Change in modified Rodnan skin score at 90, 180, 270 days at 90, 180 and 270 days Proportion of patients who improved mRSS at 90, 180, 270 and 360 days At 90, 180, 270 and 360 days Incidence of Adverse Events at 180 and 360 days according to the Common Terminology Criteria for Adverse Events (CTCAE) toxicity grading scale
Incidence of Severe Adverse Events at 180 and 360 days according to the Common Terminology Criteria for Adverse Events (CTCAE) toxicity grading scale
EurolQol-5Domain (EQ-5D) health questionnaire At 0, 15, 90, 180, 270 and 360 days self reported measure of quality of life - (scale from 0 to 100)
Short Form-36 (SF-36) health questionnaire At 0, 15, 90, 180, 270 and 360 days self-administered questionnaire of 36 items assessing the following 8 domains : physical functioning, bodily pain, role limitations attributable to physical health problems, general health perceptions, mental health, role limitations to emotional problems, vitality and social functioning (scale from 0 to 100)
Trial Locations
- Locations (42)
CH de Cornouaille
🇫🇷Quimper, France
CH Amiens
🇫🇷Amiens, France
CHU Angers
🇫🇷Angers, France
CHU Annecy
🇫🇷Annecy, France
CHU Besançon
🇫🇷Besançon, France
Avicenne Hospital
🇫🇷Bobigny, France
CHU Bordeaux
🇫🇷Bordeaux, France
Ambroise Paré hospital
🇫🇷Boulogne-Billancourt, France
Hôpital de la Cavale Blanche
🇫🇷Brest, France
CHU Caen
🇫🇷Caen, France
CHU Gabriel Montpied
🇫🇷Clermont-Ferrand, France
Henry Mondor hospital
🇫🇷Créteil, France
CH Dax-Côte d'ARgent
🇫🇷Dax, France
CHU Dijon
🇫🇷Dijon, France
CHU Grenoble
🇫🇷Grenoble, France
CH Le Mans
🇫🇷Le Mans, France
CHU Lille
🇫🇷Lille, France
CHU Limoges
🇫🇷Limoges, France
CHU Lyon sud
🇫🇷Lyon, France
Hôpital Nord
🇫🇷Marseille, France
La Timone Hospital
🇫🇷Marseille, France
Robert Schuman Hospital
🇫🇷Metz, France
CHU Montpellier - rhumatology
🇫🇷Montpellier, France
CHU Montpellier - St Eloi Hospital
🇫🇷Montpellier, France
CHU Nancy
🇫🇷Nancy, France
CHU Nantes
🇫🇷Nantes, France
Hopital L'Archet 1
🇫🇷Nice, France
Hospital Pasteur - CHU Nice
🇫🇷Nice, France
Saint Antoine Hospital
🇫🇷Paris, France
La Pitié-Salpêtrière
🇫🇷Paris, France
Cochin Hospital
🇫🇷Paris, France
Hospital Croix St Simon
🇫🇷Paris, France
CHU Poitiers
🇫🇷Poitiers, France
Robert Debré Hospital
🇫🇷Reims, France
Hôpital Sud
🇫🇷Rennes, France
CHU Rouen
🇫🇷Rouen, France
CHU Saint Etienne
🇫🇷Saint-Étienne, France
Nouvel Hospital Civil
🇫🇷Strasbourg, France
Rangueil Hospital
🇫🇷Toulouse, France
CHU Tours
🇫🇷Tours, France
CH Valenciennes
🇫🇷Valenciennes, France
Hôpitaux de Barbois
🇫🇷Vandœuvre-lès-Nancy, France