A Study Evaluating the Efficacy and Safety of Baricitinib in Systemic Sclerosis

Efficacy and Safety of Baricitinib in Systemic Sclerosis: a Phase IV, Double-blinded, Controlled Study.

Systemic Sclerosis (Ssc) is a rare, systemic autoimmune disease characterized by skin fibrosis and vasculopathy. In addition to the skin, it is a heterogeneous disease that affects multiple organs, including the musculoskeletal, cardiac, pulmonary, and gastrointestinal systems. Patients may experience many symptoms such as pain, fatigue, dyspnea, impaired hand function, dry mouth, and difficulty sleeping. As a result of these symptoms, these patients may experience a decrease in activities of daily living, physical activity level and quality of life, while psychological problems such as anxiety and depression may increase.

Study Overview

• Status: Recruiting
• Conditions: Systemic Sclerosis
• Intervention / Treatment: Drug: Baricitinib; Drug: Cyclophosphamide

Detailed Description

This is a 48 weeks, prospective, double-blind, controlled study. The specific objectives of this study are to:

1. Determine whether Baricitinib is effective and safe in the treatment of patients with diffuse cutaneous (dc)SSc when compared to patients treated with CTX. In this study, stand of care of GC is permitted to use.
2. Determine whether Baricitinib is more effective than CTX, as measured by change in CRISS, which is a composite outcome measure provisionally endorsed by the ACR for scleroderma clinical trials. It incorporates change in the mRSS, FVC percent predicted, physician and patient global assessments, and HAQ-DI. Additionally, hemoglobin corrected diffusion capacity (DLCO), Medsger Severity Scale (MSS), and by other physician and patient derived outcome measures will be used.
3. Determine the biological activity of Baricitinib vs CTX as assessed by effect on histology of skin, gene expression of skin and blood, change in B-Cell profiles including assessment of B regulatory cells, and effect on serological and cutaneous biomarkers of disease activity.

• Study Type: Interventional
• Enrollment (Anticipated): 60
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: YIKAI YU; Phone Number: 14849955917; Email: yuyikai@163.com

Study Locations

• China
  • Hubei
    • Wuhan, Hubei, China, 430030
      • Recruiting
      • Tongji Hospital
      • Contact: AIHUA DU, M.D; Phone Number: +86 2783662886
      • Principal Investigator: YIKAI YU, M.D
      • Sub-Investigator: SHAOXIAN HU, M.D
      • Sub-Investigator: WEI TU, M.D
      • Sub-Investigator: RUI XING, M.D
      • Sub-Investigator: CONG YE, M.D
      • Sub-Investigator: FEI YU, M.D
      • Sub-Investigator: GUIFEN SHEN, M.D
      • Sub-Investigator: JIJUN YANG, M.D
      • Sub-Investigator: MEI YU, M.D
      • Sub-Investigator: XIAOFANG LUO, M.D
    • Wuhan, Hubei, China, 430030
      • Recruiting
      • Department of RheumatologyTongji Hospital
      • Contact: YIKAI YU, M.D; Phone Number: 13476069099; Email: yuyikai@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Diagnosis of Systematic Sclerosis (SSc), as defined using the 2013 American College of Rheumatology/ European Union League Against Rheumatism classification of SSc
2. Diffuse Systemic Sclerosis (dcSSc) as defined by LeRoy and Medsger
3. Disease duration of ≤ 36 months (defined as time from the first non-Raynaud phenomenon manifestation)
4. For disease duration of ≤ 18 months: ≥ 10 and ≤ 35 mRSS units at the screening visit
5. For disease duration of >18-36 months: ≥ 15 and ≤ 45 mRSS units at the screening visit and one of the following:

1)Increase ≥ 3 in mRSS units compared with the last visit within previous 1-6 months 2)Involvement of one new body area with ≥ 2 mRSS units compared with the last visit within the previous 1-6 months 3)Involvement of two new body areas with ≥ 1 mRSS units compared with the last visit within the previous 1-6 months 4)Presence of 1 or more Tendon Friction Rub 6.Age ≥ 18 years at the screening visit 7.If female of childbearing potential, the patient must have a negative pregnancy test at screening and baseline visits 8.Oral corticosteroids (≤ 10 mg/day of prednisone or equivalent) and NSAIDs are permitted if the patient is on a stable dose regimen for 2 weeks prior to and including the baseline visit.

9.ACE inhibitors, calcium-channel blockers, proton-pump inhibitors, and/or oral vasodilators are permitted if the patient is on a stable dose for ≥ 2 weeks prior to and including the baseline visit.

Exclusion Criteria:

1. Rheumatic disease other than dcSSc; it is acceptable to include patients with fibromyalgia and scleroderma-associated myopathy
2. Limited cutaneous systemic sclerosis or sine scleroderma at the screening visit
3. Major surgery (including joint surgery) within 8 weeks prior to screening visit
4. Infected ulcer prior to treatment
5. Treatment with any investigational agent within ≤ 4 weeks (or 5 half-lives of the investigational drug, whichever is longer) of the baseline visit
6. Previous treatment with cell-depleting therapies, including investigational agents, including but not limited to, CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-CD19, and ABA
7. Anti-CD20 within 12 months prior to baseline visit.
8. Use of Intravenous Immunoglobulin (IVIG) within 12 weeks prior to baseline visit
9. Previous treatment with chlorambucil, bone marrow transplantation, or total lymphoid irradiation
10. Immunization with a live/attenuated vaccine within ≤ 4 weeks prior to the baseline visit
11. Treatment with methotrexate, hydroxychloroquine, cyclosporine A, azathioprine, mycophenolate mofetil rapamycin, colchicine, or D-penicillamine, within≤ 4 weeks prior to the baseline visit
12. Treatment with etanercept within ≤ 2 weeks, infliximab, certolizumab, golimumab, ABA or adalimumab within ≤ 8 weeks, anakinra within ≤ 1 week prior to the baseline visit
13. Pulmonary disease with FVC ≤ 50% of predicted, or DLCO (uncorrected for hemoglobin ) ≤ 40% of predicted at the screening visit
14. Pulmonary arterial hypertension (PAH) as determined by right heart catheterization or on PAH approved medications for PAH. It is acceptable to use PDFE-5 inhibitors for Raynaud's and digital ulcers.
15. Subjects at risk for tuberculosis (TB). Specifically excluded from this study will be participants with a history of active TB within the last 3 years, even if it was treated; a history of active TB greater than 3 years ago, unless there is documentation that the prior anti-TB treatment was appropriate in duration and type; current clinical, radiographic, or laboratory evidence of active TB; and latent TB that was not successfully treated (≥ 4 weeks).
16. Positive for hepatitis B surface antigen prior to the baseline visit
17. Positive for hepatitis C antigen, if the presence of hepatitis C virus was also shown with polymerase chain reaction or recombinant immunoblot assay prior to baseline visit
18. Subjects at risk for tuberculosis (TB). Specifically excluded from this study will be participants with a history of active TB within the last 3 years, even if it was treated; a history of active TB greater than 3 years ago, unless there is documentation that the prior anti-TB treatment was appropriate in duration and type; current clinical, radiographic, or laboratory evidence of active TB; and latent TB that was not successfully treated (≥ 4 weeks).
19. Any of the following at the screening visit: Hemoglobin <8 g/dL; ANC < 1,000/mm3 (<1 x 109/L); platelets < 100,000/mm3 (<100 x 109/L); serum creatinine > 2 x ULN; serum ALT or AST > 2 x ULN
20. Severe skin thickening (mRSS 3) on the inner aspects of thighs, upper arms, or abdomen
21. Patients with a history of anaphylaxis to Baricitinib or cyclophosphamide

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Baricitinib 4mg; 4mg of oral Baricitinib everyday for 48 weeks.	Drug: Baricitinib; Orally take Baricitinib 4mg everyday for 48 weeks; Other Names: Olumiant
Active Comparator: Cyclophosphamide; Subject received cyclophosphamide 400mg intravenous drip every 2 weeks combined with oral Prednisone 10-15 mg/d （standard of care）through the 24 weeks double blind period. Subsequently, subject were administered oral Baricitinib 4mg everyday through the 24-48 weeks open label period.	Drug: Cyclophosphamide; Subject received cyclophosphamide 400mg intravenous drip every 2 weeks combined with oral Prednisone 10-15 mg/d （standard of care）through the 24 weeks double blind period. Subsequently, subject were administered oral Baricitinib 4mg everyday through the 24-48 weeks open label period.; Other Names: Cytoxan

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in modified Rodnan skin score (mRSS) at week 24	Change in modified Rodnan skin score (mRSS) at week 24 performed by the same investigator at week 0 and week 24 and the change in mRSS will be calculated following the formula: ΔmRSS= mRSSw24 - mRSSw0. 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)	24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of death	Incidence of death	24 & 48 weeks
Incidence of Adverse Events	according to the Common Terminology Criteria for Adverse Events (CTCAE) toxicity grading scale	24 & 48 weeks
Incidence of Severe Adverse Events	according to the Common Terminology Criteria for Adverse Events (CTCAE) toxicity grading scale	24 & 48 weeks
Change in modified Rodnan skin score at 12，24，32，40，48 weeks	Change in modified Rodnan skin score at 12，24，32，40，48 weeks	12，24，32，40，48 weeks
Proportion of patients who improved mRSS at 12，24，32，40，48 weeks	Proportion of patients who improved mRSS at 12，24，32，40，48 weeks	12，24，32，40，48 weeks
Proportion of patients with an active disease according to the European scleroderma trials and research group (EUSTAR)SSc activity score at 12，24，48 weeks	EUSTAR SSc activity index score from 0 to 10 - a cut-off ≥ 2.5 identifies patients with active disease	12，24，32，40，48 weeks
Change in the Combined Response Index in Diffuse Systemic Sclerosis (CRISS) score	composite response index	24，48 weeks
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	12，24，32，40，48 weeks
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)	0, 12，24，32，40，48 weeks
EurolQol-5Domain (EQ-5D) health questionnaire	self reported measure of quality of life - (scale from 0 to 100)	0, 12，24，32，40，48 weeks
Health Assessment Questionnaire Disability Index (HAQ-DI) scale	self administered 20 questions- score range from 0 (no disability) to 3 (severe disability)	0, 12，24，32，40，48 weeks

Collaborators and Investigators

• Sponsor: Tongji Hospital
• Investigators: Study Chair: AIHUA DU, Tongji Hospital

Study record dates

Study Major Dates

• Study Start (Actual): March 8, 2022
• Primary Completion (Anticipated): March 1, 2023
• Study Completion (Anticipated): April 1, 2023

Study Registration Dates

• First Submitted: March 20, 2022
• First Submitted That Met QC Criteria: March 20, 2022
• First Posted (Actual): March 29, 2022

Study Record Updates

• Last Update Posted (Actual): March 29, 2022
• Last Update Submitted That Met QC Criteria: March 20, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: Systemic Sclerosis，Baricitinib
• Additional Relevant MeSH Terms: Pathologic Processes; Skin Diseases; Connective Tissue Diseases; Sclerosis; Scleroderma, Systemic; Scleroderma, Diffuse; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Cyclophosphamide
• Other Study ID Numbers: TJ-SSc202203

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No