A Study of Subcutaneous Abatacept to Treat Diffuse Cutaneous Systemic Sclerosis

Study Overview
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Brief Summary
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The study hypothesis is that SC abatacept is safe and shows evidence of efficacy (improvement in modified Rodnan score [mRSS]) in patients with diffuse cutaneous systemic sclerosis (dcScc) compared to matching placebo.

Detailed Description
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This study is a randomized placebo-controlled double-blind phase 2 trial of patients with dcSSc. Eligible participants will be randomized in a 1:1 ratio to either 125 mg SC abatacept or matching placebo, stratified by duration of dcSSc disease duration (<18 months vs >18 to </=36 months). Study participants will be treated for 12 months on double-blind study medication, followed by an additional 24 weeks of open-label SC abatacept therapy. 86 patients will be randomized in approximately 35 centers in the US, Canada and Europe, with the goal of analyzing 74 participants. The investigators study will test whether abatacept is statistically superior to placebo in reducing the MRSS at month 12 and explore the ability of abatacept to prevent or reverse progression in patients with early disease duration and lower MRSS scores, and reverse established disease in patients with longer disease duration and higher MRSS scores.

Official Title
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A Phase 2 Study to Evaluate Subcutaneous Abatacept vs. Placebo in Diffuse Cutaneous Systemic Sclerosis- a Double-blind, Placebo-controlled, Randomized Controlled Trial.

Conditions
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Diffuse Cutaneous Systemic Sclerosis

Intervention / Treatment
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* Drug: Abatacept
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of Systematic Sclerosis (SSc), as defined using the 2013 American College of Rheumatology/ European Union League Against Rheumatism classification of SSc Diffuse Systemic Sclerosis (dcSSc) as defined by LeRoy and Medsger Disease duration of ≤ 36 months (defined as time from the first non-Raynaud phenomenon manifestation) For disease duration of ≤ 18 months: ≥ 10 and ≤ 35 mRSS units at the screening visit For disease duration of >18-36 months: ≥ 15 and ≤ 45 mRSS units at the screening visit and one of the following: Increase ≥ 3 in mRSS units compared with the last visit within previous 1-6 months Involvement of one new body area with ≥ 2 mRSS units compared with the last visit within the previous 1-6 months Involvement of two new body areas with ≥ 1 mRSS units compared with the last visit within the previous 1-6 months Presence of 1 or more Tendon Friction Rub Age ≥ 18 years at the screening visit If female of childbearing potential, the patient must have a negative pregnancy test at screening and baseline visits 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. 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: Rheumatic disease other than dcSSc; it is acceptable to include patients with fibromyalgia and scleroderma-associated myopathy Limited cutaneous systemic sclerosis or sine scleroderma at the screening visit Major surgery (including joint surgery) within 8 weeks prior to screening visit Infected ulcer prior to randomization Treatment with any investigational agent within ≤ 4 weeks (or 5 half-lives of the investigational drug, whichever is longer) of the baseline visit 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 Anti-CD20, and cyclophosphamide within 12 months prior to baseline visit. Use of Intravenous Immunoglobulin (IVIG) within 12 weeks prior to baseline visit Previous treatment with chlorambucil, bone marrow transplantation, or total lymphoid irradiation Immunization with a live/attenuated vaccine within ≤ 4 weeks prior to the baseline visit Treatment with methotrexate, hydroxychloroquine, cyclosporine A, azathioprine, mycophenolate mofetil rapamycin, colchicine, or D-penicillamine, within≤ 4 weeks prior to the baseline visit Treatment with etanercept within ≤ 2 weeks, infliximab, certolizumab, golimumab, ABA or adalimumab within ≤ 8 weeks, anakinra within ≤ 1 week prior to the baseline visit Pulmonary disease with FVC ≤ 50% of predicted, or DLCO (uncorrected for hemoglobin ) ≤ 40% of predicted at the screening visit 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. 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). Positive for hepatitis B surface antigen prior to the baseline visit 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 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). Any of the following at the screening visit: Hemoglobin <8.5 g/dL; WBC < 3,000/mm3 (<3 x 109/L); platelets < 100,000/mm3 (<3 x 109/L); serum creatinine > 2 x ULN; serum ALT or AST > 2 x ULN Severe skin thickening (mRSS 3) on the inner aspects of thighs, upper arms, or abdomen Patients with a history of anaphylaxis to abatacept

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Abatacept<br>125 mg SC abatacept vs SC placebo administered weekly for 12 months, with a 24-week open-label extension | Drug: Abatacept<br>* Subjects will be treated with injections of 125 mg of abatacept or placebo weekly for 52 weeks<br>* Other names: Orencia;|
| Placebo Comparator: Placebo<br>125mg Placebo | Drug: Placebo<br>* 125 mg of Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Participants With at Least One Adverse Events (AEs) or Serious AEs (SAEs) in 1 Year | Safety is measured using AEs, including clinical significant changes in vital signs, laboratory test abnormalities and clinical tolerability of abatacept, and using serious AEs | 52 weeks | 
| Change From Baseline in the Modified Rodnan Skin Score (mRSS) to Month 12 | The efficacy of treatment on skin fibrosis will be measured by changes from baseline to month 12 in mRSS, a measure of skin thickness. mRSS scores have a range from 0 to 51, with higher score indicating greater severity of SSc (worse outcome). | Baseline and 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Month 12 in Patient Global Assessment for Overall Disease | Patient global assessment for overall disease represents the patient's assessment of the patient's global scleroderma on a 0 (excellent) -10 (extremely poor) Likert scale. Higher score means worse outcome. | Baseline and Week 52 | 
| Change From Baseline to Month 12 in Physician Global Assessment for Overall Disease | This assessment represents the physician's assessment of the patient's current disease activity on a 0 (excellent) -10 (extremely poor) Likert scale. Higher score means worse outcome. | Baseline and Week 52 | 
| Change in % Predicted FVC | FVC is Forced vital capacity, a measure of lung function. FVC % Predicted is calculated using equations from Hankinson [Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values from a sample of the general U.S. population. Am J Respir Crit Care Med. 1999;159(1):179-87], incorporating age, gender, and race. It is calculated as the (FVC Observed / FVC predicted) * 100, where FVC predicted is calculated relative to a reference population. | Baseline and 52 weeks | 
| Change From Baseline to Month 12 in FVC (in ml) | FVC = forced vital capacity, a measure of lung function | Baseline and Week 52 | 
| Change From Baseline to Month 12 in HAQ-DI - Overall | The HAQ-DI is the Health Assessment Question Disability Index that assesses the extent of a patient's functional ability. The HAQ-DI overall score ranges from 0 (no disability) to 3 (severe disability). Higher score means worse outcome. | Baseline and Week 52 | 
| Change From Baseline to Month 12 in SHAQ-DI VAS - Overall Disease | Scleroderma-Health Assessment Question Disability Index visual analogue scales (VAS) assess the burden of digital ulcers, Raynaud's, gastrointestinal involvement, breathing, and overall disease. The VAS scale for disease severity ranges from 0 (no disease) to 150 (very severe). A higher score means a worse outcome. | Baseline and Week 52 | 
| Change From Baseline to Month 12 in SHAQ-DI VAS - Breathing | Scleroderma-Health Assessment Question Disability Index visual analogue scales (VAS) assess the burden of digital ulcers, Raynaud's, gastrointestinal involvement, breathing, and overall disease. The VAS scale for how much breathing problems interfered with daily activities ranges from 0 (do not limit activities) to 150 (very severe limitation). A higher score means a worse outcome. | Baseline and Week 52 | 
| Change From Baseline to Month 12 in SHAQ-DI VAS - Raynaud's | Scleroderma-Health Assessment Question Disability Index visual analogue scales (VAS) assess the burden of digital ulcers, Raynaud's, gastrointestinal involvement, breathing, and overall disease. The VAS scale for how much Raynaud's interfered with daily activities ranges from 0 (does not limit activities) to 150 (very severe limitation). A higher score means a worse outcome. | Baseline and Week 52 | 
| Change From Baseline to Month 12 in SHAQ-DI VAS - Burden of Digital Ulcers | Scleroderma-Health Assessment Question Disability Index visual analogue scales (VAS) assess the burden of digital ulcers, Raynaud's, gastrointestinal involvement, breathing, and overall disease. The VAS scale for how much finger ulcers interfered with daily activities ranges from 0 (do not limit activities) to 150 (very severe limitation). A higher score means a worse outcome. | Baseline and Week 52 | 
| Change From Baseline to Month 12 in SHAQ-DI VAS - GI Involvement | Scleroderma-Health Assessment Question Disability Index visual analogue scales (VAS) assess the burden of digital ulcers, Raynaud's, gastrointestinal involvement, breathing, and overall disease. The VAS scale for how much intestinal problems interfered with daily activities ranges from 0 (do not limit activities) to 150 (very severe limitation). A higher score means a worse outcome. | Baseline and Week 52 | 
| Change From Baseline to Month 12 in Swollen Joint Count | 28 joints are assessed for swelling (positive or negative). The number of swollen joint count ranges from 0 to 28. A higher number indicates worse outcome. | Baseline and 52 weeks | 
| Change From Baseline to Month 12 in Tender Joint Counts | 28 joints are assessed for tenderness (positive or negative). The number of tender joint counts ranges from 0 to 28. A higher number indicates worse outcome. | Baseline and 52 weeks | 
| Change From Baseline to Month 12 in PROMIS-29 - Physical Function | The Patient-Reported Outcomes Measurement Information System (PROMIS) 29-item short-form health-reported quality of life measures (PROMIS-29) were administered. The transformed score (T-score) for the physical function domain was used, where 50 (10) is the mean (standard deviation) of a relevant reference population. Higher scores equals more of the concept being measured (i.e., better outcome). | Baseline and Week 52 | 
| Change From Baseline to Month 12 in PROMIS-29 - Anxiety | The Patient-Reported Outcomes Measurement Information System (PROMIS) 29-item short-form health-reported quality of life measures (PROMIS-29) were administered. The transformed score (T-score) for the anxiety domain was used, where 50 (10) is the mean (standard deviation) of a relevant reference population. Higher scores equals more of the concept being measured (i.e., worse outcome). | Baseline and Week 52 | 
| Change From Baseline to Month 12 in PROMIS-29 - Depression | The Patient-Reported Outcomes Measurement Information System (PROMIS) 29-item short-form health-reported quality of life measures (PROMIS-29) were administered. The transformed score (T-score) for the depression domain was used, where 50 (10) is the mean (standard deviation) of a relevant reference population. Higher scores equals more of the concept being measured (i.e., worse outcome). | Baseline and Week 52 | 
| Change From Baseline to Month 12 in PROMIS 29 - Fatigue | The Patient-Reported Outcomes Measurement Information System (PROMIS) 29-item short-form health-reported quality of life measures (PROMIS-29) were administered. The transformed score (T-score) for the fatigue domain was used, where 50 (10) is the mean (standard deviation) of a relevant reference population. Higher scores equals more of the concept being measured (i.e., worse outcome). | Baseline and Week 52 | 
| Change From Baseline to Month 12 in PROMIS-29 - Sleep Disturbance | The Patient-Reported Outcomes Measurement Information System (PROMIS) 29-item short-form health-reported quality of life measures (PROMIS-29) were administered. The transformed score (T-score) for the sleep disturbance domain was used, where 50 (10) is the mean (standard deviation) of a relevant reference population. Higher scores equals more of the concept being measured (i.e.,worse outcome). | Baseline and Week 52 | 
| Change From Baseline to Month 12 in PROMIS-29 - Pain Interference | The Patient-Reported Outcomes Measurement Information System (PROMIS) 29-item short-form health-reported quality of life measures (PROMIS-29) were administered. The transformed score (T-score) for the pain interference domain was used, where 50 (10) is the mean (standard deviation) of a relevant reference population. Higher scores equals more of the concept being measured (i.e., worse outcome). | Baseline and Week 52 | 
| Change From Baseline to Month 12 in PROMIS-29 - Ability to Participate in Social Roles & Activities | The Patient-Reported Outcomes Measurement Information System (PROMIS) 29-item short-form health-reported quality of life measures (PROMIS-29) were administered. The transformed score (T-score) for the ability to participate in social roles and activities domain was used, where 50 (10) is the mean (standard deviation) of a relevant reference population. Higher scores equals more of the concept being measured (i.e., better outcome). | Baseline and Week 52 | 
| Change From Baseline to Month 12 in PROMIS-29 - Pain Intensity | The Patient-Reported Outcomes Measurement Information System (PROMIS) 29-item short-form health-reported quality of life measures (PROMIS-29) were administered. The transformed score (T-score) for the pain intensity domain was used, where 50 (10) is the mean (standard deviation) of a relevant reference population. Higher scores equals more of the concept being measured (i.e., worse outcome). | Baseline and Week 52 | 
| Change From Baseline to Month 12 in SCTC GIT - Composite Score | The SCTC GIT is the UCLA Scleroderma Clinical Trial Consortium Gastrointestinal Instrument. It assesses scleroderma-related gastrointestinal symptoms. The composite score ranges from 0 to 2.83; 0 indicates better health and higher score indicates worse health. | Baseline and Week 52 | 
| ACR CRISS at 12 Months | The American College of Rheumatology Combined Response Index in Systemic Sclerosis is a composite endpoint. It is determined in a 2-step process. The first step assesses whether the patient has had a significant decline in renal or cardiopulmonary involvement. If none of these apply, the second step assesses the probability of improvement by measuring changes in five outcomes and integrating them into a single number using an equation described in Khanna D, Berrocal VJ, et al. [The American College of Rheumatology Provisional Composite Response Index for Clinical Trials in Early Diffuse Cutaneous Systemic Sclerosis. Arthritis and Rheumatology. 2016; 68(2):299-311.]. It incorporates changes in the modified Rodnan skin score, percent predicted forced vital capacity (FVC), patient and physician global assessments, and SHAQ-DI over 1 year. The score ranges from 0 to 1; a higher score indicates better outcome. | Week 52 | 
| Change From Baseline to Month 12 in PROMIS - Fatigue | The Patient-Reported Outcomes Measurement Information System (PROMIS) 8-question short-form health-reported quality of life measure fatigue domain was administered. The transformed score (T-score) was used, where 50 (10) is the mean (standard deviation) of a relevant reference population. Higher scores equals more of the concept being measured (i.e., worse outcome). | Baseline and Week 52 | 
| Change From Baseline to Month 12 in PROMIS - Sleep Disturbance | The Patient-Reported Outcomes Measurement Information System (PROMIS) 4-question short-form health-reported quality of life measure sleep disturbance domain was administered. The transformed score (T-score) was used, where 50 (10) is the mean (standard deviation) of a relevant reference population. Higher scores equals more of the concept being measured (i.e., better outcome). | Baseline and Week 52 | 
| Change From Baseline to Month 12 in PROMIS - Sleep Impairment | The Patient-Reported Outcomes Measurement Information System (PROMIS) 8-question short-form health-reported quality of life measure sleep impairment domain was administered. The transformed score (T-score) was used, where 50 (10) is the mean (standard deviation) of a relevant reference population. Higher scores equals more of the concept being measured (i.e., worse outcome). | Baseline and Week 52 | 
| Change From Baseline to Month 12 in HAQ-DI - Dressing and Grooming | The HAQ-DI is the Health Assessment Question Disability Index that assesses the extent of a patient's functional ability. The HAQ-DI subscore ranges from 0 (no disability) to 3 (severe disability). A higher score means worse outcome. | Baseline and Week 52 | 
| Change From Baseline to Month 12 in HAQ-DI - Hygiene | The HAQ-DI is the Health Assessment Question Disability Index that assesses the extent of a patient's functional ability. The HAQ-DI subscore ranges from 0 (no disability) to 3 (severe disability). A higher score means worse outcome. | Baseline and Week 52 | 
| Change From Baseline to Month 12 in HAQ-DI - Arising | The HAQ-DI is the Health Assessment Question Disability Index that assesses the extent of a patient's functional ability. The HAQ-DI subscore ranges from 0 (no disability) to 3 (severe disability). A higher score means worse outcome. | Baseline and Week 52 | 
| Change From Baseline to Month 12 in HAQ-DI - Reach | The HAQ-DI is the Health Assessment Question Disability Index that assesses the extent of a patient's functional ability. The HAQ-DI subscore ranges from 0 (no disability) to 3 (severe disability). A higher score means worse outcome. | Baseline and Week 52 | 
| Change From Baseline to Month 12 in HAQ-DI - Eating | The HAQ-DI is the Health Assessment Question Disability Index that assesses the extent of a patient's functional ability. The HAQ-DI subscore ranges from 0 (no disability) to 3 (severe disability). A higher score means worse outcome. | Baseline and Week 52 | 
| Change From Baseline to Month 12 in HAQ-DI - Grip | The HAQ-DI is the Health Assessment Question Disability Index that assesses the extent of a patient's functional ability. The HAQ-DI subscore ranges from 0 (no disability) to 3 (severe disability). A higher score means worse outcome. | Baseline and Week 52 | 
| Change From Baseline to Month 12 in HAQ-DI - Walking | The HAQ-DI is the Health Assessment Question Disability Index that assesses the extent of a patient's functional ability. The HAQ-DI subscore ranges from 0 (no disability) to 3 (severe disability). A higher score means worse outcome. | Baseline and Week 52 | 
| Change From Baseline to Month 12 in HAQ-DI - Common Daily Activities | The HAQ-DI is the Health Assessment Question Disability Index that assesses the extent of a patient's functional ability. The HAQ-DI subscore ranges from 0 (no disability) to 3 (severe disability). A higher score means worse outcome. | Baseline and Week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Scleroderma