Safety and Efficacy of Itacitinib in Adults With Systemic Sclerosis

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

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

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.

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 diffuse SSc, according to Leroy and Medsger dichotomy

• 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)

• If patients receive mycophenolate or methotrexate for SSc, these need to be on stable dose as follows:

  • Mycophenolate mofetil/sodium: stable dose for at least 2 months prior to randomisation
  • Methotrexate: stable dose and route of administration for at least 2 months prior to randomisation

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,
• 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)
• Patient with Systemic Lupus, or Sjögren's syndrome with systemic manifestations justifying immunosuppressive therapy
• Atherosclerotic cardiovascular disease as defined by a history of myocardial infarction, ischaemic stroke, or peripheral artery thrombosis
• Anti-phospholipid syndrome