A Study of Subcutaneous Abatacept to Treat Diffuse Cutaneous Systemic Sclerosis

Phase 2

Completed

• Conditions: Diffuse Cutaneous Systemic Sclerosis
• Interventions: Drug: Placebo; Drug: Abatacept

• Registration Number: NCT02161406
• Lead Sponsor: Dinesh Khanna, MD, MS

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2014-06-03
• Study First Submitted QC: 2014-06-09
• Study First Posted: 2014-06-11
• Study Start: 2014-09
• Primary Completion: 2018-09-12
• Study Completion: 2018-10-17
• Results First Submitted: 2019-04-04
• Results First Submitted QC: 2019-05-28
• Results First Posted: 2019-06-18
• Status Verified: 2020-02
• Last Update Submitted: 2020-02-13
• Last Update Posted: 2020-02-17

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 88

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:

   • 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

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 randomization
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, and cyclophosphamide 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 <8.5 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
20. Severe skin thickening (mRSS 3) on the inner aspects of thighs, upper arms, or abdomen
21. Patients with a history of anaphylaxis to abatacept

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	125mg Placebo
Abatacept	Abatacept	125 mg SC abatacept vs SC placebo administered weekly for 12 months, with a 24-week open-label extension

Primary Outcome Measures

Name	Time	Method
Proportion of Participants With at Least One Adverse Events (AEs) or Serious AEs (SAEs) in 1 Year	52 weeks	Safety is measured using AEs, including clinical significant changes in vital signs, laboratory test abnormalities and clinical tolerability of abatacept, and using serious AEs
Change From Baseline in the Modified Rodnan Skin Score (mRSS) to Month 12	Baseline and 52 weeks	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).

Secondary Outcome Measures

Name	Time	Method
Change From Baseline to Month 12 in SHAQ-DI VAS - Burden of Digital Ulcers	Baseline and Week 52	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.
Change From Baseline to Month 12 in PROMIS 29 - Fatigue	Baseline and Week 52	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).
Change From Baseline to Month 12 in PROMIS-29 - Sleep Disturbance	Baseline and Week 52	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).
Change From Baseline to Month 12 in PROMIS-29 - Pain Interference	Baseline and Week 52	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).
Change From Baseline to Month 12 in PROMIS-29 - Ability to Participate in Social Roles & Activities	Baseline and Week 52	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).
Change From Baseline to Month 12 in SHAQ-DI VAS - Breathing	Baseline and Week 52	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.
Change From Baseline to Month 12 in Swollen Joint Count	Baseline and 52 weeks	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.
Change From Baseline to Month 12 in HAQ-DI - Overall	Baseline and Week 52	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.
Change From Baseline to Month 12 in SHAQ-DI VAS - Overall Disease	Baseline and Week 52	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.
Change From Baseline to Month 12 in SHAQ-DI VAS - GI Involvement	Baseline and Week 52	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.
Change From Baseline to Month 12 in Patient Global Assessment for Overall Disease	Baseline and Week 52	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.
Change From Baseline to Month 12 in SHAQ-DI VAS - Raynaud's	Baseline and Week 52	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.
Change From Baseline to Month 12 in Physician Global Assessment for Overall Disease	Baseline and Week 52	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.
Change in % Predicted FVC	Baseline and 52 weeks	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.
Change From Baseline to Month 12 in FVC (in ml)	Baseline and Week 52	FVC = forced vital capacity, a measure of lung function
Change From Baseline to Month 12 in PROMIS-29 - Anxiety	Baseline and Week 52	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).
Change From Baseline to Month 12 in PROMIS-29 - Depression	Baseline and Week 52	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).
Change From Baseline to Month 12 in Tender Joint Counts	Baseline and 52 weeks	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.
Change From Baseline to Month 12 in PROMIS-29 - Physical Function	Baseline and Week 52	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).
Change From Baseline to Month 12 in PROMIS-29 - Pain Intensity	Baseline and Week 52	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).
Change From Baseline to Month 12 in SCTC GIT - Composite Score	Baseline and Week 52	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.
ACR CRISS at 12 Months	Week 52	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.
Change From Baseline to Month 12 in PROMIS - Fatigue	Baseline and Week 52	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).
Change From Baseline to Month 12 in PROMIS - Sleep Disturbance	Baseline and Week 52	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).
Change From Baseline to Month 12 in PROMIS - Sleep Impairment	Baseline and Week 52	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).
Change From Baseline to Month 12 in HAQ-DI - Dressing and Grooming	Baseline and Week 52	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.
Change From Baseline to Month 12 in HAQ-DI - Hygiene	Baseline and Week 52	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.
Change From Baseline to Month 12 in HAQ-DI - Arising	Baseline and Week 52	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.
Change From Baseline to Month 12 in HAQ-DI - Reach	Baseline and Week 52	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.
Change From Baseline to Month 12 in HAQ-DI - Eating	Baseline and Week 52	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.
Change From Baseline to Month 12 in HAQ-DI - Grip	Baseline and Week 52	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.
Change From Baseline to Month 12 in HAQ-DI - Walking	Baseline and Week 52	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.
Change From Baseline to Month 12 in HAQ-DI - Common Daily Activities	Baseline and Week 52	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.

Trial Locations

Locations (27)

Arthritis Associates of Southern California; 🇺🇸 Los Angeles, California, United States

University of California- Los Angeles; 🇺🇸 Los Angeles, California, United States

Stanford University; 🇺🇸 Redwood City, California, United States

Georgetown University; 🇺🇸 Washington, District of Columbia, United States

Northwestern University; 🇺🇸 Chicago, Illinois, United States

Harvard Mass General; 🇺🇸 Boston, Massachusetts, United States

Boston University; 🇺🇸 Boston, Massachusetts, United States

University of Michigan; 🇺🇸 Ann Arbor, Michigan, United States

University of Minnesota; 🇺🇸 Minneapolis, Minnesota, United States

Mayo Clinic; 🇺🇸 Rochester, Minnesota, United States

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