Safety and Efficacy of Itacitinib in Adults With Systemic Sclerosis

Official title

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

Overview

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.

Interventions

• Drug Itacitinib
  200 mg oral for 360 days
• Drug Placebo
  200 mg oral for 360 days

Primary outcome measures

• Change in modified Rodnan skin score (mRSS) at 360 days [Time frame: 360 days]

Secondary outcome measures (11)

• Incidence of death [Time frame: at 180 and 360 days]
• Incidence of Adverse Events [Time frame: at 180 and 360 days]
• Incidence of Severe Adverse Events [Time frame: at 180 and 360 days]
• Change in modified Rodnan skin score at 90, 180, 270 days [Time frame: at 90, 180 and 270 days]
• Proportion of patients who improved mRSS at 90, 180, 270 and 360 days [Time frame: 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 [Time frame: At 90, 180, 270 and 360 days]
• Change in the Combined Response Index in Diffuse Systemic Sclerosis (CRISS) score [Time frame: At 180 and 360 days]
• SSc disease activity [Time frame: At 90, 180, 270 and 360 days]
• Short Form-36 (SF-36) health questionnaire [Time frame: At 0, 15, 90, 180, 270 and 360 days]
• EurolQol-5Domain (EQ-5D) health questionnaire [Time frame: At 0, 15, 90, 180, 270 and 360 days]
• Health Assessment Questionnaire Disability Index (HAQ-DI) scale [Time frame: At 0, 15, 90, 180, 270 and 360 days]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

France · 46 centers

• CH Amiens — Amiens
• CHU Angers — Angers
• CHU Annecy — Annecy
• CHU Besançon — Besançon
• Avicenne Hospital — Bobigny
• CHU Bordeaux — Bordeaux
• CHU Bordeaux — Bordeaux
• Ambroise Paré hospital — Boulogne-Billancourt
• … and 38 more centers

Publications

• Almeida C, Almeida I, Vasconcelos C. Quality of life in systemic sclerosis. Autoimmun Rev. 2015 Dec;14(12):1087-96. doi: 10.1016/j.autrev.2015.07.012. Epub 2015 Jul 23. PMID 26212726
• Mouthon L. SSc in 2011: From mechanisms to medicines. Nat Rev Rheumatol. 2012 Jan 10;8(2):72-4. doi: 10.1038/nrrheum.2011.203. PMID 22231235
• Distler JH, Feghali-Bostwick C, Soare A, Asano Y, Distler O, Abraham DJ. Review: Frontiers of Antifibrotic Therapy in Systemic Sclerosis. Arthritis Rheumatol. 2017 Feb;69(2):257-267. doi: 10.1002/art.39865. No abstract available. PMID 27636741
• Wang Y, Fan PS, Kahaleh B. Association between enhanced type I collagen expression and epigenetic repression of the FLI1 gene in scleroderma fibroblasts. Arthritis Rheum. 2006 Jul;54(7):2271-9. doi: 10.1002/art.21948. PMID 16802366
• Landi C, Bargagli E, Bianchi L, Gagliardi A, Carleo A, Bennett D, Perari MG, Armini A, Prasse A, Rottoli P, Bini L. Towards a functional proteomics approach to the comprehension of idiopathic pulmonary fibrosis, sarcoidosis, systemic sclerosis and pulmonary Langerhans cell histiocytosis. J Proteomics. 2013 May 27;83:60-75. doi: 10.1016/j.jprot.2013.03.006. Epub 2013 Mar 23. PMID 23528693
• Kubo M, Ihn H, Yamane K, Tamaki K. Up-regulated expression of transforming growth factor beta receptors in dermal fibroblasts in skin sections from patients with localized scleroderma. Arthritis Rheum. 2001 Mar;44(3):731-4. doi: 10.1002/1529-0131(200103)44:33.0.CO;2-U. No abstract available. PMID 11263790
• Zhang Y, Liang R, Chen CW, Mallano T, Dees C, Distler A, Reich A, Bergmann C, Ramming A, Gelse K, Mielenz D, Distler O, Schett G, Distler JHW. JAK1-dependent transphosphorylation of JAK2 limits the antifibrotic effects of selective JAK2 inhibitors on long-term treatment. Ann Rheum Dis. 2017 Aug;76(8):1467-1475. doi: 10.1136/annrheumdis-2016-210911. Epub 2017 May 6. PMID 28478401
• Migita K, Izumi Y, Torigoshi T, Satomura K, Izumi M, Nishino Y, Jiuchi Y, Nakamura M, Kozuru H, Nonaka F, Eguchi K, Kawakami A, Motokawa S. Inhibition of Janus kinase/signal transducer and activator of transcription (JAK/STAT) signalling pathway in rheumatoid synovial fibroblasts using small molecule compounds. Clin Exp Immunol. 2013 Dec;174(3):356-63. doi: 10.1111/cei.12190. PMID 23968543

Identifiers

NCT: NCT04789850 · APHP180613 · 2019-003430-16

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗