Scleroderma, Diffuse, Scleroderma, Systemic
Conditions
Brief summary
Systemic sclerosis (scleroderma) is an autoimmune connective tissue disease that involves the skin and other internal organs for which there are few effective treatment options. We hypothesize that treatment with abatacept, a new therapy recently approved for the treatment of rheumatoid arthritis, may reduce the progression of skin thickening and fibrosis in people with scleroderma.
Detailed description
Systemic sclerosis is an autoimmune connective tissue disease of unknown etiology characterized by progressive fibrosis of the skin and internal organs, vascular damage, and autoantibody production. Although the disease is relatively rare, it is associated with considerable morbidity and mortality. There have been improvements in survival over the past few decades; however, this has been related to better management of vascular manifestations of disease including renal crisis, pulmonary hypertension, gastroesophageal reflux disease, and Raynaud's phenomenon. Clinical studies of disease modifying therapies for cutaneous disease to date have been relatively unsuccessful. Although the etiology of the disease remains unknown, several observations support the role of activated T cells in both the blood and skin of affected patients. Abatacept, a recombinant fusion protein that blocks T cell activation, has recently been approved by the FDA for rheumatoid arthritis. We hypothesize that inhibition of T cell activation with abatacept may be efficacious in the treatment of patients with diffuse systemic sclerosis. This is a randomized, double-blinded, placebo-controlled clinical trial of abatacept versus placebo in patients with diffuse systemic sclerosis. Changes in validated measures of skin thickness and disease activity over 6-months of treatment will be compared between patients receiving abatacept and those receiving placebo. Patients will be randomized 2:1 to receive abatacept. The protocol was amended during the study and the outcome measures Change in Serum Autoantibody Profile and Change in Serum Cytokine Profile were changed to exploratory outcomes.
Interventions
DRUGAbatacept
DRUGPlacebo
Sponsors
Bristol-Myers Squibb
Stanford University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of diffuse systemic sclerosis * age 18 years or older * Adequate renal, pulmonary, and cardiovascular function * Willingness to use effective contraception for the duration of the study if subject is of childbearing potential
Exclusion criteria
* Other connective tissues diseases or overlap syndromes including MCTD, SLE, RA, eosinophilic fasciitis, and limited systemic sclerosis or morphea * Use of disease modifying agents including methotrexate, cyclosporine,azathioprine, mycophenolate mofetil, minocycline, doxycycline, minocycline, thalidomide, penicillamine, tamoxifen, colchicine, or investigational agent within 90 days of screening visit * HIV, Hepatitis B or Hepatitis C infection * use of prednisone greater than 10mg daily for 28 days prior to screening visit * women who are breastfeeding or pregnant
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Modified Rodnan Skin Score | 6 months | Modified Rodnan Skin Score measures skin thickness and is the sum of scores from 17 surface anatomic areas rated on a 0-3 scale (0=normal skin; 1=mild thickness; 2=moderate thickness; 3=severe thickness with inability to pinch the skin into a fold). Total modified Rodnan Skin Score ranges from 0 (best possible outcome) to 51 (worst possible outcome). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Oral Aperture at Baseline and Month 6 | Baseline; Month 6 | — |
| Hand Extension at Baseline and Month 6 | Baseline; Month 6 | — |
| Digital Ulcerations at Baseline and Month 6 | Baseline; Month 6 | — |
| Change in Pulmonary Function Tests | 6 months | FVC (Forced Vital Capacity) is the amount of air that can be forcibly exhaled from the lungs after taking the deepest possible breath. DLCO (Diffusing capacity of the lung for carbon monoxide) is the extent to which oxygen passes from the lungs to the blood. |
| Change in Scleroderma Health Assessment Questionnaire | 6 months | The HAQ Disability Index (HAQ-DI) includes 20 items in 8 functional domains (dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities) assessing the patient's usual abilities in the past seven days. Each item is scored on a 0-3 scale (0=without any difficulty; 1=with some difficulty; 2=with much difficulty; 3=unable to do). The use of assistive devices for any domain increases the domain score by 1 point to a maximum of 3. The overall score is calculated by summing the highest item score in each of the domains and dividing the sum by 8, with an overall score of 0 indicating no disability, and a score of 3 indicating severe disability. The time points compared were 6 months to baseline (6 months minus baseline). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Abatacept Abatacept (dosed based upon weight) administered intravenously (IV) on days 1, 15, 30 and monthly thereafter for a total of 7 doses. | 7 |
| IV Fluid Placebo to match abatacept (IV fluid) administered on days 1, 15, 30 and monthly thereafter for a total of 7 doses. | 3 |
| Total | 10 |
Baseline characteristics
| Characteristic | Abatacept | IV Fluid | Total |
|---|---|---|---|
| Age, Continuous | 39.8 years STANDARD_DEVIATION 11.4 | 48.6 years STANDARD_DEVIATION 13.9 | 44.2 years STANDARD_DEVIATION 12.5 |
| Region of Enrollment United States | 7 participants | 3 participants | 10 participants |
| Sex: Female, Male Female | 5 Participants | 3 Participants | 8 Participants |
| Sex: Female, Male Male | 2 Participants | 0 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 6 / 7 | 3 / 3 |
| serious Total, serious adverse events | 1 / 7 | 0 / 3 |
Outcome results
Primary
Change in Modified Rodnan Skin Score
Modified Rodnan Skin Score measures skin thickness and is the sum of scores from 17 surface anatomic areas rated on a 0-3 scale (0=normal skin; 1=mild thickness; 2=moderate thickness; 3=severe thickness with inability to pinch the skin into a fold). Total modified Rodnan Skin Score ranges from 0 (best possible outcome) to 51 (worst possible outcome).
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Abatacept | Change in Modified Rodnan Skin Score | -8.6 MRSS score | Standard Deviation 7.5 |
| IV Fluid | Change in Modified Rodnan Skin Score | -2.3 MRSS score | Standard Deviation 15 |
Secondary
Change in Pulmonary Function Tests
FVC (Forced Vital Capacity) is the amount of air that can be forcibly exhaled from the lungs after taking the deepest possible breath. DLCO (Diffusing capacity of the lung for carbon monoxide) is the extent to which oxygen passes from the lungs to the blood.
Time frame: 6 months
Population: Participants with available data were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Abatacept | Change in Pulmonary Function Tests | FVC % Predicted | 1.3 % Predicted | Standard Deviation 8.5 |
| Abatacept | Change in Pulmonary Function Tests | DLCO % Predicted | 2.0 % Predicted | Standard Deviation 6.3 |
| IV Fluid | Change in Pulmonary Function Tests | FVC % Predicted | .3 % Predicted | Standard Deviation 8.5 |
| IV Fluid | Change in Pulmonary Function Tests | DLCO % Predicted | -7.4 % Predicted | Standard Deviation 10.7 |
Secondary
Change in Scleroderma Health Assessment Questionnaire
The HAQ Disability Index (HAQ-DI) includes 20 items in 8 functional domains (dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities) assessing the patient's usual abilities in the past seven days. Each item is scored on a 0-3 scale (0=without any difficulty; 1=with some difficulty; 2=with much difficulty; 3=unable to do). The use of assistive devices for any domain increases the domain score by 1 point to a maximum of 3. The overall score is calculated by summing the highest item score in each of the domains and dividing the sum by 8, with an overall score of 0 indicating no disability, and a score of 3 indicating severe disability. The time points compared were 6 months to baseline (6 months minus baseline).
Time frame: 6 months
Population: Participants with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Abatacept | Change in Scleroderma Health Assessment Questionnaire | -0.04 HAQ-DI score | Standard Deviation 0.24 |
| IV Fluid | Change in Scleroderma Health Assessment Questionnaire | .25 HAQ-DI score | Standard Deviation 0.25 |
Secondary
Digital Ulcerations at Baseline and Month 6
Time frame: Baseline; Month 6
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Abatacept | Digital Ulcerations at Baseline and Month 6 | Right hand baseline | 0.3 ulcers | Standard Deviation 0.7 |
| Abatacept | Digital Ulcerations at Baseline and Month 6 | Left hand baseline | 0.0 ulcers | Standard Deviation 0 |
| Abatacept | Digital Ulcerations at Baseline and Month 6 | Right hand month 6 | 0.1 ulcers | Standard Deviation 0.35 |
| Abatacept | Digital Ulcerations at Baseline and Month 6 | Left hand month 6 | 0.0 ulcers | Standard Deviation 0 |
| IV Fluid | Digital Ulcerations at Baseline and Month 6 | Left hand month 6 | 1.0 ulcers | Standard Deviation 0.82 |
| IV Fluid | Digital Ulcerations at Baseline and Month 6 | Right hand baseline | 0.7 ulcers | Standard Deviation 0.47 |
| IV Fluid | Digital Ulcerations at Baseline and Month 6 | Right hand month 6 | 1.3 ulcers | Standard Deviation 0.47 |
| IV Fluid | Digital Ulcerations at Baseline and Month 6 | Left hand baseline | 0.7 ulcers | Standard Deviation 0.47 |
Secondary
Hand Extension at Baseline and Month 6
Time frame: Baseline; Month 6
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Abatacept | Hand Extension at Baseline and Month 6 | Right hand baseline | 177.7 mm | Standard Deviation 28.11 |
| Abatacept | Hand Extension at Baseline and Month 6 | Right hand month 6 | 178.9 mm | Standard Deviation 31.38 |
| Abatacept | Hand Extension at Baseline and Month 6 | Left hand baseline | 183.7 mm | Standard Deviation 23.96 |
| Abatacept | Hand Extension at Baseline and Month 6 | Left hand month 6 | 184.3 mm | Standard Deviation 25.23 |
| IV Fluid | Hand Extension at Baseline and Month 6 | Left hand month 6 | 116.3 mm | Standard Deviation 40.58 |
| IV Fluid | Hand Extension at Baseline and Month 6 | Right hand baseline | 98.3 mm | Standard Deviation 20.95 |
| IV Fluid | Hand Extension at Baseline and Month 6 | Left hand baseline | 110.7 mm | Standard Deviation 35.98 |
| IV Fluid | Hand Extension at Baseline and Month 6 | Right hand month 6 | 103.3 mm | Standard Deviation 24.94 |
Secondary
Oral Aperture at Baseline and Month 6
Time frame: Baseline; Month 6
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Abatacept | Oral Aperture at Baseline and Month 6 | Right side baseline | 31.1 mm | Standard Deviation 6.51 |
| Abatacept | Oral Aperture at Baseline and Month 6 | Right side month 6 | 29.4 mm | Standard Deviation 4.98 |
| Abatacept | Oral Aperture at Baseline and Month 6 | Left side baseline | 30.9 mm | Standard Deviation 7.18 |
| Abatacept | Oral Aperture at Baseline and Month 6 | Left side month 6 | 29.3 mm | Standard Deviation 4.65 |
| IV Fluid | Oral Aperture at Baseline and Month 6 | Left side month 6 | 20.0 mm | Standard Deviation 4.08 |
| IV Fluid | Oral Aperture at Baseline and Month 6 | Right side baseline | 21.0 mm | Standard Deviation 4.32 |
| IV Fluid | Oral Aperture at Baseline and Month 6 | Left side baseline | 20.0 mm | Standard Deviation 2.45 |
| IV Fluid | Oral Aperture at Baseline and Month 6 | Right side month 6 | 21.0 mm | Standard Deviation 1.41 |