Safety and Efficacy of Itacitinib in Adults With Systemic Sclerosis
NCT ID: NCT04789850
Last Updated: 2025-11-20
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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RECRUITING
PHASE2
74 participants
INTERVENTIONAL
2023-02-02
2026-02-28
Brief Summary
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Detailed Description
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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.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
QUADRUPLE
Study Groups
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Itacitinib
200mg of oral Itacitinib everyday for 360 days.
Itacitinib
200 mg oral for 360 days
Placebo
Oral placebo everyday for 360 days.
Placebo
200 mg oral for 360 days
Interventions
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Itacitinib
200 mg oral for 360 days
Placebo
200 mg oral for 360 days
Eligibility Criteria
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Inclusion Criteria
* 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
* 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
18 Years
ALL
No
Sponsors
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URC-CIC Paris Descartes Necker Cochin
OTHER
Assistance Publique - Hôpitaux de Paris
OTHER
Responsible Party
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Principal Investigators
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Luc Mouthon, MD-PhD
Role: STUDY_CHAIR
Assistance Publique - Hôpitaux de Paris
Benjamin Chaigne, MD
Role: PRINCIPAL_INVESTIGATOR
Assistance Publique - Hôpitaux de Paris
Locations
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CH Amiens
Amiens, , France
CHU Angers
Angers, , France
CHU Annecy
Annecy, , France
CHU Besançon
Besançon, , France
Avicenne Hospital
Bobigny, , France
CHU Bordeaux
Bordeaux, , 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
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
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
La Pitié-Salpêtrière
Paris, , France
Cochin Hospital
Paris, , France
Hospital Croix St Simon
Paris, , France
CHU Poitiers
Poitiers, , France
CH de Cornouaille
Quimper, , France
Robert Debré Hospital
Reims, , France
Hôpital Sud
Rennes, , France
CHU Rouen
Rouen, , France
CHU Saint Etienne
Saint-Etienne, , 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
Countries
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Central Contacts
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Facility Contacts
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References
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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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Other Identifiers
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2019-003430-16
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
APHP180613
Identifier Type: -
Identifier Source: org_study_id
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