Scleroderma, Systemic
Conditions
Brief summary
Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs and widespread vasculopathy. Patients with SSc are classified according to the extent of cutaneous sclerosis: patients with limited SSc have skin thickening of the face, neck, and distal extremities, while those with diffuse SSc have involvement of the trunk, abdomen, and proximal extremities as well. The disease course varies depending on the subtype of SSc. However, common features that result in significant morbidity and mortality, in addition to cutaneous fibrosis, include Raynaud's phenomenon and digital ulcerations, interstitial lung disease (ILD), and pulmonary arterial hypertension (PAH). Current therapeutic options for patients with SSc and these clinical manifestations have shown limited efficacy. Imatinib antagonizes specific tyrosine kinases that mediate fibrotic pathways involved in the pathogenesis of SSc, including c-Abl, a downstream mediator of transforming growth factor (TGF)-beta, and platelet derived growth factor (PDGF) receptors. The efficacy of imatinib has also been reported in the treatment of patients with refractory idiopathic PAH through its effects on vascular remodeling. Based on the mechanism of action and preliminary patient data, we hypothesize that imatinib may be effective in the treatment of the fibrotic and vasculopathic features of patients with SSc. This is an open label pilot study to evaluate the safety and efficacy of imatinib in patients with progressive SSc refractory to other treatment(s). Validated measures of skin thickness and disease activity will be determined over 6-months of therapy and compared with baseline measures.
Interventions
DRUGImatinib mesylate
100 mg orally daily increased by 100 mg/day every 2 weeks to maximum of 400 mg daily as tolerated. Treatment for 6 months total.
Sponsors
Stanford University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
Adults with refractory diffuse or limited SSc and any or all of the following: Progressive cutaneous fibrosis, Interstitial lung disease, Pulmonary arterial hypertension, Digital ulcerations.
Exclusion criteria
Uncontrolled congestive heart failure, hypertension, or coronary artery disease. HIV, hepatitis B, and/or hepatitis C infection. Serious infection within the past month. Significant hematologic, renal, or hepatic abnormalities. Concurrent use of intravenous immunoglobulin or cyclophosphamide within 4 weeks of the first treatment dose. Concurrent use of a biologic agent (ie. etanercept, infliximab, adalimumab, abatacept) within 8 weeks of the first treatment dose (6 months for rituximab). Women who are pregnant or breastfeeding.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in Modified Rodnan Skin Score at 6 Months Compared to Baseline | 6 months compared to baseline | Modified Rodnan skin score (mRSS) on scale of 0 (no skin disease) to 51 severe skin disease. %change in mRSS=(score at 6 months - baseline score)/baseline score. Negative values indicate improvement in skin disease. Clinical important improvement defined as \> 25% improvement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Digital Ulcerations at 6 Months Compared to Baseline | 6 months compared to baseline | Number of digital ulcers as measured by physician assessment at 6 months compared to baseline |
| Change in Scleroderma Health Assessment Questionnaire at 6 Months Compared to Baseline | 6 months compared to baseline | Change in Health Assessment Questionnaire disability index at 6 months compared to baseline. The Questionnaire is comprised of a 20 question instrument pertaining to specific activities with possible integer responses of 0 (without any difficulty) to 3 (unable to do), and five additional scleroderma-specific visual analog scale (VAS) domains with possible values ranging from 0.0 to 15.0. The 20 questions are divided into eight domains. A mean score is calculated for each domain ranging from 0 to 3. A composite score is calculated by dividing the summed domain scores by the number of domains answered. The composite score is reported, falling between 0 and 3 on an ordinal scale. The scores are interpreted as 0 (no impairment in function) to 3 (maximal impairment of function). |
| Change in Dermal Thickness and Collagen Separation on Cutaneous Histopathology at 6 Months Compared to Baseline | 6 months compared to baseline | — |
| Change in Pulmonary Function Tests at 6 Months Compared to Baseline | 6 months compared to baseline | Change in % predicted Forced Vital Capacity (FVC) at 6 months compared to baseline. FVC is the volume of air that can forcibly be blown out after taking a full breath. FVC% predicted is defined as FVC% of the patient divided by the average FVC% in the population for any person of similar age, sex and body composition. |
| Cell Types That Contribute to the Gene Expression Changes Associated With Imatinib Therapy | 6 months compared to baseline | To determine which cell types may be contributing to the gene expression changes associated with imatinib therapy, imatinib-responsive genes were isolated from from patient biopsies. From the total number of imatinib-responsive genes that were isolated, the percentage that came from endothelial cells, fibroblasts, B-cells, and multiple cell types was calculated. Reported values do not total to 100% because of rounding. |
| Change in Serum Autoantibody Profile at 6 Months Compared to Baseline | 6 months compared to baseline | — |
| Change in Serum Cytokine Profile at 6 Months Compared to Baseline | 6 months compared to baseline | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Imatinib Mesylate All patients were treated with imatinib mesylate at a mean dosage of 300 mg daily. | 9 |
| Total | 9 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Imatinib Mesylate |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 9 Participants |
| Age, Continuous | 56 years STANDARD_DEVIATION 13 |
| Region of Enrollment United States | 9 participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 7 / 9 |
| serious Total, serious adverse events | 1 / 9 |
Outcome results
Primary
Percent Change in Modified Rodnan Skin Score at 6 Months Compared to Baseline
Modified Rodnan skin score (mRSS) on scale of 0 (no skin disease) to 51 severe skin disease. %change in mRSS=(score at 6 months - baseline score)/baseline score. Negative values indicate improvement in skin disease. Clinical important improvement defined as \> 25% improvement.
Time frame: 6 months compared to baseline
Population: Participants who completed the protocol were included in the analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Imatinib Mesylate | Percent Change in Modified Rodnan Skin Score at 6 Months Compared to Baseline | -32 percentage of change in MRSS | Standard Deviation 22 |
Comparison: Null hypothesis is that the mRSS is not significantly different at month 6 compared with baseline. Paired t-test was used to compare the mean mRSS at month 6 compared with baseline.p-value: 0.005t-test, 2 sided
Secondary
Cell Types That Contribute to the Gene Expression Changes Associated With Imatinib Therapy
To determine which cell types may be contributing to the gene expression changes associated with imatinib therapy, imatinib-responsive genes were isolated from from patient biopsies. From the total number of imatinib-responsive genes that were isolated, the percentage that came from endothelial cells, fibroblasts, B-cells, and multiple cell types was calculated. Reported values do not total to 100% because of rounding.
Time frame: 6 months compared to baseline
Population: Participants with available data were included in the analysis
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Imatinib Mesylate | Cell Types That Contribute to the Gene Expression Changes Associated With Imatinib Therapy | Fibroblasts | 26 percentage of isolated genes |
| Imatinib Mesylate | Cell Types That Contribute to the Gene Expression Changes Associated With Imatinib Therapy | B-cells | 8 percentage of isolated genes |
| Imatinib Mesylate | Cell Types That Contribute to the Gene Expression Changes Associated With Imatinib Therapy | Multiple cell types | 52 percentage of isolated genes |
| Imatinib Mesylate | Cell Types That Contribute to the Gene Expression Changes Associated With Imatinib Therapy | Endothelial cells | 13 percentage of isolated genes |
Secondary
Change in Dermal Thickness and Collagen Separation on Cutaneous Histopathology at 6 Months Compared to Baseline
Time frame: 6 months compared to baseline
Population: Participants with available data were included in the analysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Imatinib Mesylate | Change in Dermal Thickness and Collagen Separation on Cutaneous Histopathology at 6 Months Compared to Baseline | -.5 mm |
Secondary
Change in Digital Ulcerations at 6 Months Compared to Baseline
Number of digital ulcers as measured by physician assessment at 6 months compared to baseline
Time frame: 6 months compared to baseline
Population: No data were collected for this outcome measure
Secondary
Change in Pulmonary Function Tests at 6 Months Compared to Baseline
Change in % predicted Forced Vital Capacity (FVC) at 6 months compared to baseline. FVC is the volume of air that can forcibly be blown out after taking a full breath. FVC% predicted is defined as FVC% of the patient divided by the average FVC% in the population for any person of similar age, sex and body composition.
Time frame: 6 months compared to baseline
Population: Participants with available data were included in the analysis
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Imatinib Mesylate | Change in Pulmonary Function Tests at 6 Months Compared to Baseline | 0 FVC% predicted |
Secondary
Change in Scleroderma Health Assessment Questionnaire at 6 Months Compared to Baseline
Change in Health Assessment Questionnaire disability index at 6 months compared to baseline. The Questionnaire is comprised of a 20 question instrument pertaining to specific activities with possible integer responses of 0 (without any difficulty) to 3 (unable to do), and five additional scleroderma-specific visual analog scale (VAS) domains with possible values ranging from 0.0 to 15.0. The 20 questions are divided into eight domains. A mean score is calculated for each domain ranging from 0 to 3. A composite score is calculated by dividing the summed domain scores by the number of domains answered. The composite score is reported, falling between 0 and 3 on an ordinal scale. The scores are interpreted as 0 (no impairment in function) to 3 (maximal impairment of function).
Time frame: 6 months compared to baseline
Population: Participants with available data were included in the analysis
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Imatinib Mesylate | Change in Scleroderma Health Assessment Questionnaire at 6 Months Compared to Baseline | -.35 units on a scale |
Secondary
Change in Serum Autoantibody Profile at 6 Months Compared to Baseline
Time frame: 6 months compared to baseline
Population: No data were collected for this outcome measure
Secondary
Change in Serum Cytokine Profile at 6 Months Compared to Baseline
Time frame: 6 months compared to baseline
Population: No data were collected for this outcome measure