Clinical trial NCT00506831: Imatinib in Systemic Sclerosis
Official title: A Pilot Study of Imatinib in the Treatment of Refractory Systemic Sclerosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Scleroderma, Systemic
Lead sponsor: Stanford University
Sponsor class: OTHER
First posted: 2007-07-25
Enrollment: 9
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Percent Change in Modified Rodnan Skin Score at 6 Months Compared to Baseline
timeFrame: 6 months compared to baseline
Secondary outcomes:
measure: Change in Pulmonary Function Tests at 6 Months Compared to Baseline
timeFrame: 6 months compared to baseline
measure: Change in Digital Ulcerations at 6 Months Compared to Baseline
timeFrame: 6 months compared to baseline
measure: Change in Scleroderma Health Assessment Questionnaire at 6 Months Compared to Baseline
timeFrame: 6 months compared to baseline
measure: Change in Dermal Thickness and Collagen Separation on Cutaneous Histopathology at 6 Months Compared to Baseline
timeFrame: 6 months compared to baseline
measure: Change in Serum Cytokine Profile at 6 Months Compared to Baseline
timeFrame: 6 months compared to baseline
measure: Cell Types That Contribute to the Gene Expression Changes Associated With Imatinib Therapy
timeFrame: 6 months compared to baseline
measure: Change in Serum Autoantibody Profile at 6 Months Compared to Baseline
timeFrame: 6 months compared to baseline
Other outcomes:
Locations:
city: Stanford
country: United States
facility: Stanford University School of Medicine
state: California
Study officials:
affiliation: Stanford University
name: Lorinda S Chung
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.