Clinical trial NCT02161406: A Study of Subcutaneous Abatacept to Treat Diffuse Cutaneous Systemic Sclerosis
Official title: A Phase 2 Study to Evaluate Subcutaneous Abatacept vs. Placebo in Diffuse Cutaneous Systemic Sclerosis- a Double-blind, Placebo-controlled, Randomized Controlled Trial.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Diffuse Cutaneous Systemic Sclerosis
Keywords: Scleroderma
Lead sponsor: University of Michigan
Sponsor class: OTHER
Collaborators: name: Bristol-Myers Squibb
name: National Institute of Allergy and Infectious Diseases (NIAID)
First posted: 2014-06-11
Enrollment: 88
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Proportion of Participants With at Least One Adverse Events (AEs) or Serious AEs (SAEs) in 1 Year
timeFrame: 52 weeks
measure: Change From Baseline in the Modified Rodnan Skin Score (mRSS) to Month 12
timeFrame: Baseline and 52 weeks
Secondary outcomes:
measure: Change From Baseline to Month 12 in Patient Global Assessment for Overall Disease
timeFrame: Baseline and Week 52
measure: Change From Baseline to Month 12 in Physician Global Assessment for Overall Disease
timeFrame: Baseline and Week 52
measure: Change in % Predicted FVC
timeFrame: Baseline and 52 weeks
measure: Change From Baseline to Month 12 in FVC (in ml)
timeFrame: Baseline and Week 52
measure: Change From Baseline to Month 12 in HAQ-DI - Overall
timeFrame: Baseline and Week 52
measure: Change From Baseline to Month 12 in SHAQ-DI VAS - Overall Disease
timeFrame: Baseline and Week 52
measure: Change From Baseline to Month 12 in SHAQ-DI VAS - Breathing
timeFrame: Baseline and Week 52
measure: Change From Baseline to Month 12 in SHAQ-DI VAS - Raynaud's
timeFrame: Baseline and Week 52
measure: Change From Baseline to Month 12 in SHAQ-DI VAS - Burden of Digital Ulcers
timeFrame: Baseline and Week 52
measure: Change From Baseline to Month 12 in SHAQ-DI VAS - GI Involvement
timeFrame: Baseline and Week 52
measure: Change From Baseline to Month 12 in Swollen Joint Count
timeFrame: Baseline and 52 weeks
measure: Change From Baseline to Month 12 in Tender Joint Counts
timeFrame: Baseline and 52 weeks
measure: Change From Baseline to Month 12 in PROMIS-29 - Physical Function
timeFrame: Baseline and Week 52
measure: Change From Baseline to Month 12 in PROMIS-29 - Anxiety
timeFrame: Baseline and Week 52
measure: Change From Baseline to Month 12 in PROMIS-29 - Depression
timeFrame: Baseline and Week 52
measure: Change From Baseline to Month 12 in PROMIS 29 - Fatigue
timeFrame: Baseline and Week 52
measure: Change From Baseline to Month 12 in PROMIS-29 - Sleep Disturbance
timeFrame: Baseline and Week 52
measure: Change From Baseline to Month 12 in PROMIS-29 - Pain Interference
timeFrame: Baseline and Week 52
measure: Change From Baseline to Month 12 in PROMIS-29 - Ability to Participate in Social Roles & Activities
timeFrame: Baseline and Week 52
measure: Change From Baseline to Month 12 in PROMIS-29 - Pain Intensity
timeFrame: Baseline and Week 52
measure: Change From Baseline to Month 12 in SCTC GIT - Composite Score
timeFrame: Baseline and Week 52
measure: ACR CRISS at 12 Months
timeFrame: Week 52
measure: Change From Baseline to Month 12 in PROMIS - Fatigue
timeFrame: Baseline and Week 52
measure: Change From Baseline to Month 12 in PROMIS - Sleep Disturbance
timeFrame: Baseline and Week 52
measure: Change From Baseline to Month 12 in PROMIS - Sleep Impairment
timeFrame: Baseline and Week 52
measure: Change From Baseline to Month 12 in HAQ-DI - Dressing and Grooming
timeFrame: Baseline and Week 52
measure: Change From Baseline to Month 12 in HAQ-DI - Hygiene
timeFrame: Baseline and Week 52
measure: Change From Baseline to Month 12 in HAQ-DI - Arising
timeFrame: Baseline and Week 52
measure: Change From Baseline to Month 12 in HAQ-DI - Reach
timeFrame: Baseline and Week 52
measure: Change From Baseline to Month 12 in HAQ-DI - Eating
timeFrame: Baseline and Week 52
measure: Change From Baseline to Month 12 in HAQ-DI - Grip
timeFrame: Baseline and Week 52
measure: Change From Baseline to Month 12 in HAQ-DI - Walking
timeFrame: Baseline and Week 52
measure: Change From Baseline to Month 12 in HAQ-DI - Common Daily Activities
timeFrame: Baseline and Week 52
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Arthritis Associates of Southern California
state: California
city: Los Angeles
country: United States
facility: University of California- Los Angeles
state: California
city: Redwood City
country: United States
facility: Stanford University
state: California
city: Washington
country: United States
facility: Georgetown University
state: District of Columbia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Boston
country: United States
facility: Harvard Mass General
state: Massachusetts
city: Boston
country: United States
facility: Boston University
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: New Brunswick
country: United States
facility: Rutgers University Clinical Research Center
state: New Jersey
city: Albany
country: United States
facility: Steffens Scleroderma Center
state: New York
city: Great Neck
country: United States
facility: NorthWell Health
state: New York
city: New York
country: United States
facility: Hospital for Special Surgery
state: New York
city: New York
country: United States
facility: Columbia University
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Columbus
country: United States
facility: Ohio State University Medical Center
state: Ohio
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Houston
country: United States
facility: University of Texas Health Center at Houston
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Seattle
country: United States
facility: Swedish Health Services
state: Washington
city: London
country: Canada
facility: St. Joseph Health Care London
state: Ontario
city: Toronto
country: Canada
facility: Mount Sinai Hospital
state: Ontario
city: Montreal
country: Canada
facility: Jewish General Hospital
state: Quebec
city: London
country: United Kingdom
facility: Royal Free Hospital
Study officials:
affiliation: University of Michigan
name: Dinesh Khanna, MD, MS
role: PRINCIPAL_INVESTIGATOR
References:
citation: Chung L, Spino C, McLain R, Johnson SR, Denton CP, Molitor JA, Steen VD, Lafyatis R, Simms RW, Kafaja S, Frech TM, Hsu V, Domsic RT, Pope JE, Gordon JK, Mayes MD, Sandorfi N, Hant FN, Bernstein EJ, Chatterjee S, Castelino FV, Ajam A, Allanore Y, Matucci-Cerinic M, Whitfield ML, Distler O, Singer O, Young A, Nagaraja V, Fox DA, Furst DE, Khanna D. Safety and efficacy of abatacept in early diffuse cutaneous systemic sclerosis (ASSET): open-label extension of a phase 2, double-blind randomised trial. Lancet Rheumatol. 2020 Dec;2(12):e743-e753. doi: 10.1016/S2665-9913(20)30237-X. Epub 2020 Oct 19.
citation: Khanna D, Spino C, Johnson S, Chung L, Whitfield ML, Denton CP, Berrocal V, Franks J, Mehta B, Molitor J, Steen VD, Lafyatis R, Simms RW, Gill A, Kafaja S, Frech TM, Hsu V, Domsic RT, Pope JE, Gordon JK, Mayes MD, Schiopu E, Young A, Sandorfi N, Park J, Hant FN, Bernstein EJ, Chatterjee S, Castelino FV, Ajam A, Wang Y, Wood T, Allanore Y, Matucci-Cerinic M, Distler O, Singer O, Bush E, Fox DA, Furst DE. Abatacept in Early Diffuse Cutaneous Systemic Sclerosis: Results of a Phase II Investigator-Initiated, Multicenter, Double-Blind, Randomized, Placebo-Controlled Trial. Arthritis Rheumatol. 2020 Jan;72(1):125-136. doi: 10.1002/art.41055. Epub 2019 Dec 10.