Safety and Efficacy of Itacitinib in Adults With Systemic Sclerosis

Study Overview
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Brief Summary
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The purpose of this study is to determine whether itacitinib is safe and effective in the treatment of systemic sclerosis in adults.

Detailed Description
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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.

Official Title
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Safety and Efficacy of Itacitinib in Adults With Systemic Sclerosis: a Phase II, Randomized, Controlled Trial

Conditions
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Systemic Sclerosis

Intervention / Treatment
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* Drug: Itacitinib
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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). Exclusion Criteria: 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, Current, or history of recurrent 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 mycophenolate mofetil or methotrexate within the last month (possible inclusion beyond one month), 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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Itacitinib<br>200mg of oral Itacitinib everyday for 360 days. | Drug: Itacitinib<br>* 200 mg oral for 360 days<br>|
| Placebo Comparator: Placebo<br>Oral placebo everyday for 360 days. | Drug: Placebo<br>* 200 mg oral for 360 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in modified Rodnan skin score (mRSS) at 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) | 360 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of death |  | at 180 and 360 days | 
| Incidence of Adverse Events | according to the Common Terminology Criteria for Adverse Events (CTCAE) toxicity grading scale | at 180 and 360 days | 
| Incidence of Severe Adverse Events | according to the Common Terminology Criteria for Adverse Events (CTCAE) toxicity grading scale | at 180 and 360 days | 
| 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 | 
| 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 | EUSTAR SSc activity index score from 0 to 10 - a cut-off ≥ 2.5 identifies patients with active disease | At 90, 180, 270 and 360 days | 
| Change in the Combined Response Index in Diffuse Systemic Sclerosis (CRISS) score | composite response index | At 180 and 360 days | 
| SSc disease activity | 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 activity | At 90, 180, 270 and 360 days | 
| Short Form-36 (SF-36) health questionnaire | 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) | At 0, 15, 90, 180, 270 and 360 days | 
| EurolQol-5Domain (EQ-5D) health questionnaire | self reported measure of quality of life - (scale from 0 to 100) | At 0, 15, 90, 180, 270 and 360 days | 
| Health Assessment Questionnaire Disability Index (HAQ-DI) scale | self administered 20 questions- score range from 0 (no disability) to 3 (severe disability) | At 0, 15, 90, 180, 270 and 360 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Systemic sclerosis, Itacitinib