Imatinib in Systemic Sclerosis

NCT00506831 | Completed Phase 1 Results FDA Drug

• 1 other identifier: 9598
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 1

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.

Conditions

Scleroderma, Systemic

Outcome Measures

Primary Outcomes (1)

• 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

Secondary Outcomes (7)

• Change in Pulmonary Function Tests at 6 Months Compared to Baseline

  6 months compared to baseline

• Change in Digital Ulcerations at 6 Months Compared to Baseline

  6 months compared to baseline

• Change in Scleroderma Health Assessment Questionnaire at 6 Months Compared to Baseline

  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

Study Arms (1)

Imatinib mesylate

EXPERIMENTAL

100 mg daily and increase by 100mg daily every 2 weeks to a maximum of 400 mg daily as tolerated

Drug: Imatinib mesylate

Interventions

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.

Imatinib mesylate

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Stanford University: lead

Study Sites (1)

Stanford University School of Medicine

Stanford, California, 94305, United States

Location

Related Publications (2)

• 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.

  PMID: 14530402 BACKGROUND

• 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.

  PMID: 19180499 RESULT

MeSH Terms

Conditions

Scleroderma, Systemic

Interventions

Imatinib Mesylate

Condition Hierarchy (Ancestors)

Connective Tissue Diseases; Skin and Connective Tissue Diseases; Skin Diseases

Intervention Hierarchy (Ancestors)

Benzamides; Amides; Organic Chemicals; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrimidines

Limitations and Caveats

Open label, uncontrolled study. Small study population at a single center.

Results Point of Contact

• Title: Lorinda Chung
• Organization: Stanford University

shauwei@stanford.edu

650-493-5000

Study Officials

• Lorinda S Chung

  Stanford University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor of Medicine

Study Record Dates

• First Submitted: July 24, 2007
• First Posted: July 25, 2007
• Study Start: July 1, 2007
• Primary Completion: September 1, 2010
• Study Completion: September 1, 2010
• Last Updated: August 13, 2018
• Results First Posted: August 17, 2012

Record last verified: 2018-08

Locations

US (1)