Clinical trial NCT04789850: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Systemic Sclerosis
Keywords: Systemic sclerosis
Itacitinib
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2021-03-10
Enrollment: 74
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Change in modified Rodnan skin score (mRSS) at 360 days
timeFrame: 360 days
Secondary outcomes:
measure: Incidence of death
timeFrame: at 180 and 360 days
measure: Incidence of Adverse Events
timeFrame: at 180 and 360 days
measure: Incidence of Severe Adverse Events
timeFrame: at 180 and 360 days
measure: Change in modified Rodnan skin score at 90, 180, 270 days
timeFrame: at 90, 180 and 270 days
measure: Proportion of patients who improved mRSS at 90, 180, 270 and 360 days
timeFrame: At 90, 180, 270 and 360 days
measure: 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
timeFrame: At 90, 180, 270 and 360 days
measure: Change in the Combined Response Index in Diffuse Systemic Sclerosis (CRISS) score
timeFrame: At 180 and 360 days
measure: SSc disease activity
timeFrame: At 90, 180, 270 and 360 days
measure: Short Form-36 (SF-36) health questionnaire
timeFrame: At 0, 15, 90, 180, 270 and 360 days
measure: EurolQol-5Domain (EQ-5D) health questionnaire
timeFrame: At 0, 15, 90, 180, 270 and 360 days
measure: Health Assessment Questionnaire Disability Index (HAQ-DI) scale
timeFrame: At 0, 15, 90, 180, 270 and 360 days
Other outcomes:
Locations:
city: Amiens
country: France
facility: CH Amiens
city: Angers
country: France
facility: CHU Angers
city: Annecy
country: France
facility: CHU Annecy
city: Besançon
country: France
facility: CHU Besançon
city: Bobigny
country: France
facility: Avicenne Hospital
city: Bordeaux
country: France
facility: CHU Bordeaux
city: Bordeaux
country: France
facility: CHU Bordeaux
city: Boulogne-Billancourt
country: France
facility: Ambroise Paré hospital
city: Brest
country: France
facility: Hôpital de la Cavale Blanche
city: Caen
country: France
facility: CHU Caen
city: Clermont-Ferrand
country: France
facility: CHU Gabriel Montpied
city: Créteil
country: France
facility: Henry Mondor hospital
city: Dax
country: France
facility: CH Dax-Côte d'ARgent
city: Dijon
country: France
facility: CHU Dijon
city: Grenoble
country: France
facility: CHU Grenoble
city: Grenoble
country: France
facility: CHU Grenoble
city: Le Mans
country: France
facility: CH Le Mans
city: Lille
country: France
facility: CHU Lille
city: Limoges
country: France
facility: CHU Limoges
city: Lyon
country: France
facility: CHU Lyon sud
city: Marseille
country: France
facility: Hôpital Nord
city: Marseille
country: France
facility: La Timone Hospital
city: Marseille
country: France
facility: La Timone Hospital
city: Metz
country: France
facility: Robert Schuman Hospital
city: Montpellier
country: France
facility: CHU Montpellier - rhumatology
city: Montpellier
country: France
facility: CHU Montpellier - St Eloi Hospital
city: Nancy
country: France
facility: CHU Nancy
city: Nantes
country: France
facility: CHU Nantes
city: Nice
country: France
facility: Hopital L'Archet 1
city: Nice
country: France
facility: Hospital Pasteur - CHU Nice
city: Paris
country: France
facility: Saint Antoine Hospital
city: Paris
country: France
facility: La Pitié-Salpêtrière
city: Paris
country: France
facility: La Pitié-Salpêtrière
city: Paris
country: France
facility: Cochin Hospital
city: Paris
country: France
facility: Hospital Croix St Simon
city: Poitiers
country: France
facility: CHU Poitiers
city: Quimper
country: France
facility: CH de Cornouaille
city: Reims
country: France
facility: Robert Debré Hospital
city: Rennes
country: France
facility: Hôpital Sud
city: Rouen
country: France
facility: CHU Rouen
city: Saint-Étienne
country: France
facility: CHU Saint Etienne
city: Strasbourg
country: France
facility: Nouvel Hospital Civil
city: Toulouse
country: France
facility: Rangueil Hospital
city: Tours
country: France
facility: CHU Tours
city: Valenciennes
country: France
facility: CH Valenciennes
city: Vandœuvre-lès-Nancy
country: France
facility: Hôpitaux de Barbois
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: Luc Mouthon, MD-PhD
role: STUDY_CHAIR
affiliation: Assistance Publique - Hôpitaux de Paris
name: Benjamin Chaigne, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
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citation: 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.
citation: 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.
citation: Xu Y, Wang W, Tian Y, Liu J, Yang R. Polymorphisms in STAT4 and IRF5 increase the risk of systemic sclerosis: a meta-analysis. Int J Dermatol. 2016 Apr;55(4):408-16. doi: 10.1111/ijd.12839. Epub 2015 Dec 29.
citation: Avouac J, Furnrohr BG, Tomcik M, Palumbo K, Zerr P, Horn A, Dees C, Akhmetshina A, Beyer C, Distler O, Schett G, Allanore Y, Distler JH. Inactivation of the transcription factor STAT-4 prevents inflammation-driven fibrosis in animal models of systemic sclerosis. Arthritis Rheum. 2011 Mar;63(3):800-9. doi: 10.1002/art.30171.
citation: Kremer JM, Bloom BJ, Breedveld FC, Coombs JH, Fletcher MP, Gruben D, Krishnaswami S, Burgos-Vargas R, Wilkinson B, Zerbini CA, Zwillich SH. The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: Results of a double-blind, placebo-controlled phase IIa trial of three dosage levels of CP-690,550 versus placebo. Arthritis Rheum. 2009 Jul;60(7):1895-905. doi: 10.1002/art.24567.
citation: Fridman JS, Scherle PA, Collins R, Burn T, Neilan CL, Hertel D, Contel N, Haley P, Thomas B, Shi J, Collier P, Rodgers JD, Shepard S, Metcalf B, Hollis G, Newton RC, Yeleswaram S, Friedman SM, Vaddi K. Preclinical evaluation of local JAK1 and JAK2 inhibition in cutaneous inflammation. J Invest Dermatol. 2011 Sep;131(9):1838-44. doi: 10.1038/jid.2011.140. Epub 2011 Jun 16.
citation: Deverapalli SC, Rosmarin D. The use of JAK inhibitors in the treatment of progressive systemic sclerosis. J Eur Acad Dermatol Venereol. 2018 Aug;32(8):e328. doi: 10.1111/jdv.14876. Epub 2018 Mar 6. No abstract available.
citation: Gordon JK, Martyanov V, Franks JM, Bernstein EJ, Szymonifka J, Magro C, Wildman HF, Wood TA, Whitfield ML, Spiera RF. Belimumab for the Treatment of Early Diffuse Systemic Sclerosis: Results of a Randomized, Double-Blind, Placebo-Controlled, Pilot Trial. Arthritis Rheumatol. 2018 Feb;70(2):308-316. doi: 10.1002/art.40358. Epub 2017 Dec 29.