Safety and Efficacy of Itacitinib in Adults With Systemic Sclerosis

Systemic Sclerosis Clinical Trial

— SCLERITA  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04789850
• Other study ID #: P180613
• Secondary ID: 2019-003430-16
• Status: Recruiting
• Phase: Phase 2
• Start date: February 2, 2023
• Est. completion date: February 2026

Study information

• Verified date: February 2023
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: Benjamin Chaigne, MD
• Phone: +33 1 58 41 41 17
• Email: benjamin.chaigne[@]aphp.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 74
• Est. completion date: February 2026
• Est. primary completion date: February 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Scleroderma, Diffuse
• Scleroderma, Systemic
• Sclerosis
• Systemic Sclerosis

Intervention

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

Locations

Country	Name	City	State
France	CH Amiens	Amiens
France	CHU Angers	Angers
France	CHU Annecy	Annecy
France	Avicenne Hospital	Bobigny
France	CHU Bordeaux	Bordeaux
France	Ambroise Paré hospital	Boulogne-Billancourt
France	CHU Caen	Caen
France	CHU Gabriel Montpied	Clermont-Ferrand
France	Henry Mondor hospital	Créteil
France	CHU Dijon	Dijon
France	CHU Grenoble	Grenoble
France	CHU Grenoble	Grenoble
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	CHU Montpellier - rhumatology	Montpellier
France	CHU Montpellier - St Eloi Hospital	Montpellier
France	CHU Nancy	Nancy
France	CHU Nantes	Nantes
France	Hospital Pasteur - CHU Nice	Nice
France	Cochin Hospital	Paris
France	Hospital Croix St Simon	Paris
France	Saint Antoine Hospital	Paris
France	CHU Poitiers	Poitiers
France	Robert Debré Hospital	Reims
France	Hôpital Sud	Rennes
France	CHU Rouen	Rouen
France	Nouvel Hospital Civil	Strasbourg
France	Rangueil Hospital	Toulouse
France	CHU Tours	Tours
France	CH Valenciennes	Valenciennes

Sponsors (1)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris

Country where clinical trial is conducted

France, 

References & Publications (14)

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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. Erratum In: Arthritis Rheum. 2012 May;64(5):1487. — View Citation

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. — View Citation

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. — View 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. — View 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. — View 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. — View 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. — View 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. — View Citation

* Note: There are 14 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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: ?mRSS= 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	Incidence of death		at 180 and 360 days
Secondary	Incidence of Adverse Events	according to the Common Terminology Criteria for Adverse Events (CTCAE) toxicity grading scale	at 180 and 360 days
Secondary	Incidence of Severe Adverse Events	according to the Common Terminology Criteria for Adverse Events (CTCAE) toxicity grading scale	at 180 and 360 days
Secondary	Change in modified Rodnan skin score at 90, 180, 270 days		at 90, 180 and 270 days
Secondary	Proportion of patients who improved mRSS at 90, 180, 270 and 360 days		At 90, 180, 270 and 360 days
Secondary	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
Secondary	Change in the Combined Response Index in Diffuse Systemic Sclerosis (CRISS) score	composite response index	At 180 and 360 days
Secondary	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
Secondary	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
Secondary	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
Secondary	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