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| ID | Type | Description | Link |
|---|---|---|---|
| 9598 |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Imatinib mesylate | Experimental | 100 mg daily and increase by 100mg daily every 2 weeks to a maximum of 400 mg daily as tolerated |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Imatinib mesylate | Drug | 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. |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 6 months compared to baseline |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 6 months compared to baseline |
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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.
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| Name | Affiliation | Role |
|---|---|---|
| Lorinda S Chung | Stanford University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Stanford University School of Medicine | Stanford | California | 94305 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 14530402 | Background | Whitfield ML, Finlay DR, Murray JI, Troyanskaya OG, Chi JT, Pergamenschikov A, McCalmont TH, Brown PO, Botstein D, Connolly MK. Systemic and cell type-specific gene expression patterns in scleroderma skin. Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12319-24. doi: 10.1073/pnas.1635114100. Epub 2003 Oct 6. | |
| 19180499 | Result |
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| ID | Title | Description |
|---|---|---|
| FG000 | Imatinib Mesylate | All patients were treated with imatinib mesylate at a mean dosage of 300 mg daily. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | Imatinib Mesylate | All patients were treated with imatinib mesylate at a mean dosage of 300 mg daily. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Participants who completed the protocol were included in the analysis | Posted | Mean | Standard Deviation | percentage of change in MRSS | 6 months compared to baseline |
|
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Imatinib Mesylate | All patients were treated with imatinib mesylate at a mean dosage of 300 mg daily. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Death | Infections and infestations | Patient experienced pneumonia, was found to be neutropenic, and died of sepsis prior to week 8 assessment. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| infection | Infections and infestations | 7 patients (78%) experienced infections throughout study: |
Open label, uncontrolled study. Small study population at a single center.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Lorinda Chung | Stanford University | 650-493-5000 | 62042 | shauwei@stanford.edu |
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| ID | Term |
|---|---|
| D012595 | Scleroderma, Systemic |
| ID | Term |
|---|---|
| D003240 | Connective Tissue Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D012871 | Skin Diseases |
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| ID | Term |
|---|---|
| D000068877 | Imatinib Mesylate |
| ID | Term |
|---|---|
| D001549 | Benzamides |
| D000577 | Amides |
| D009930 | Organic Chemicals |
| D001565 | Benzoates |
| D000146 |
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| 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 | 6 months compared to baseline |
| 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). | 6 months compared to baseline |
| Change in Dermal Thickness and Collagen Separation on Cutaneous Histopathology 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 |
| 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. | 6 months compared to baseline |
| Change in Serum Autoantibody Profile at 6 Months Compared to Baseline | 6 months compared to baseline |
| Chung L, Fiorentino DF, Benbarak MJ, Adler AS, Mariano MM, Paniagua RT, Milano A, Connolly MK, Ratiner BD, Wiskocil RL, Whitfield ML, Chang HY, Robinson WH. Molecular framework for response to imatinib mesylate in systemic sclerosis. Arthritis Rheum. 2009 Feb;60(2):584-91. doi: 10.1002/art.24221. |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Units |
|---|
| Counts |
|---|
| Participants |
|
|
|
| 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. | Participants with available data were included in the analysis | Posted | Mean | Full Range | FVC% predicted | 6 months compared to baseline |
|
|
|
| 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 | No data were collected for this outcome measure | Posted | 6 months compared to baseline |
|
|
| 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). | Participants with available data were included in the analysis | Posted | Mean | Full Range | units on a scale | 6 months compared to baseline |
|
|
|
| Secondary | Change in Dermal Thickness and Collagen Separation on Cutaneous Histopathology at 6 Months Compared to Baseline | Participants with available data were included in the analysis | Posted | Number | mm | 6 months compared to baseline |
|
|
|
| Secondary | Change in Serum Cytokine Profile at 6 Months Compared to Baseline | No data were collected for this outcome measure | Posted | 6 months compared to baseline |
|
|
| 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. | Participants with available data were included in the analysis | Posted | Number | percentage of isolated genes | 6 months compared to baseline | Isolated imantinib-responsive genes | Isolated imantinib-responsive genes |
|
|
|
| Secondary | Change in Serum Autoantibody Profile at 6 Months Compared to Baseline | No data were collected for this outcome measure | Posted | 6 months compared to baseline |
|
|
| 1 |
| 9 |
| 7 |
| 9 |
|
| edema | Blood and lymphatic system disorders |
|
| gastrointestinal symptoms | Gastrointestinal disorders |
|
| new digital ulcers | Vascular disorders |
|
| fever | Infections and infestations |
|
| neutropenia | Immune system disorders |
|
| renal insufficiency | Renal and urinary disorders |
|
| hair loss | Skin and subcutaneous tissue disorders |
|
| muscle cramps | Musculoskeletal and connective tissue disorders |
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| oral ulcer | Skin and subcutaneous tissue disorders |
|
| blurry vision | Eye disorders |
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| cough | Respiratory, thoracic and mediastinal disorders |
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| headache | Nervous system disorders |
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| hypokalemia | Renal and urinary disorders |
|
| rash | Skin and subcutaneous tissue disorders |
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| keratitis | Eye disorders |
|
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| Acids, Carbocyclic |
| D002264 | Carboxylic Acids |
| D001555 | Benzene Derivatives |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D010879 | Piperazines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D011743 | Pyrimidines |
| Title | Measurements |
|---|---|
|
| Multiple cell types |
|