Proof of Concept Trial of Gleevec (Imatinib) in Active Diffuse Scleroderma

NCT01545427 | Terminated Phase 2 DMC

• 2 other identifiers: R-07-214#031-06
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to investigate the effectiveness and safety of the drug Gleevec (imatinib) as a new treatment for patients with active diffuse scleroderma. This drug has not been used previously to treat scleroderma, but it has been found to advance the treatment and life span of patients with a type of leukemia called chronic myeloid leukemia or CML. Gleevec acts on chemical signals in the cells that may decrease fibrosis (the hardening of the skin that occurs in scleroderma). It works by interfering in the process that activates many molecules that cause fibrosis, including TGFbeta (which may be a key part of disease activity in scleroderma). This study proposes to treat patients that have significant diffuse scleroderma with Gleevec for 6 months and investigate several measures of scleroderma disease activity before, during and at the end of treatment (0, 3 months and 6 months). This is a randomized, double blind, placebo-controlled trial: 20 patients will be divided into two groups in a 4:1 ratio, with 16 patients taking 400mg of Gleevec per day and 4 taking a placebo. The differences between the groups that will be measured include safety, Modified Rodnan skin score (mRSS), Health Assessment Questionnaire (HAQ), global assessments (100mm VAS) and changes in biomarkers in blood and skin biopsies.

Conditions

Scleroderma

Keywords

Scleroderma; Randomized controled trial; Pilot study; Gleevec (imatinib); Biomarkers

Outcome Measures

Primary Outcomes (2)

• Changes in the levels of fibrotic and inflammatory biomarkers in plasma samples.

  Twenty-six fibrotic and inflammatory biomarkers were measured: PDGF-AA, PDGF-AB/BB, IL-13, IL-17, VEGF, TGF-beta1, sVCAM-1, sICAM-1, sE-selectin, MMP-9, tPAI-1, IL-1alpha, IL-1 beta, IL-4, IL-6, IL-10, IL-12p70, IL-13, TNF- alpha, sCD40L, IFN- gamma, MCP-1, MCP-3, MIP-1 alpha, MIP-1 beta, and chemokine ligand 5 (CCL5 - also known as RANTES). Biomarkers were measured using multiplexed immunoassays (Millipore Corp., MA) and ELISA for TGF- beta 1 (BD Biosciences, NJ).

  Plasma samples were taken at baseline (0), 3 and 6 months (study end).

• Changes in the levels of fibrotic and inflammatory biomarkers in skin biopsies.

  Twenty-six fibrotic and inflammatory biomarkers were measured: PDGF-AA, PDGF-AB/BB, IL-13, IL-17, VEGF, TGF-beta1, sVCAM-1, sICAM-1, sE-selectin, MMP-9, tPAI-1, IL-1alpha, IL-1 beta, IL-4, IL-6, IL-10, IL-12p70, IL-13, TNF- alpha, sCD40L, IFN- gamma, MCP-1, MCP-3, MIP-1 alpha, MIP-1 beta, and chemokine ligand 5 (CCL5 - also known as RANTES). Biomarkers were measured using multiplexed immunoassays (Millipore Corp., MA) and ELISA for TGF- beta 1 (BD Biosciences, NJ).

  Baseline and 6 months (study end).

Secondary Outcomes (7)

• Modified Rodnan Skin Score (MRSS)

  Baseline, 3 months and 6 months (study end).

• Adverse events and serious adverse events

  From treatment start until 4 weeks after after the patient has stopped study participation

• Health Assessment Questionnaire

  Baseline, 3 months and 6 months (study end).

• Patient Global Assessment

  Baseline, 3 months and 6 months (study end).

• Physician Global Assessment

  Baseline, 3 months and 6 months (study end).

Study Arms (2)

Gleevec

EXPERIMENTAL

Gleevec 200 mg bid for 6 months.

Drug: Imatinib mesylate

Placebo

PLACEBO COMPARATOR

Placebo coated to appear identical to Gleevec.

Other: Placebo

Interventions

Imatinib mesylate DRUG

200 mg bid for 6 months

Also known as: Gleevec

Gleevec

Placebo OTHER

Placebo coated to match appearance of Gleevec identically.

Placebo

Eligibility Criteria

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

You may qualify if:

• Subjects must be able to give informed consent.
• Subjects must meet preliminary criteria for scleroderma.
• Subjects must have diffuse skin involvement.
• Disease must appear to be active as measured by worsening skin score and/or increased ESR.
• Serum SGOT \< 1.5 times upper limit of normal.
• Bilirubin \< 1.5 times upper limit of normal.
• AST/ALT \< 2.5 times upper limit of normal

You may not qualify if:

• Any past exposure to Gleevec.
• Women of child bearing potential must be practicing an acceptable form of contraception (OCP, depo-provera, IUD, condoms with spermicidal or sterilization of subject or partner).
• Women who are breastfeeding.
• Men whose partners could conceive must be practicing acceptable contraception (see above).
• Certain abnormal labs including: Neutrophil count \<1.5X109/L, platelets \< 50X109/L.
• Serious comorbidity that may impair the ability to complete the study (such as severe heart disease, severe pulmonary hypertension) and other comorbidities.
• Prednisone at doses of \>10mg/od.
• Other potential disease modifying drugs such as cyclophosphamide, mycophenylate and methotrexate.
• Serious liver disease.
• Creatinine \>200.
• Excluded: Ketoconazole and fluconazole, cyclosporine, rifampin, phenytoin nefazodone, pimozide, propafenone, quinidine, sibutramine and sildenafil where drug interactions could occur.
• Subjects taking endothelin receptor blockers such as bosentan and sitaxsentan.
• Alcohol consumption of \> 3 drinks per week.

Sponsors & Collaborators

• London Health Sciences Centre Research Institute OR Lawson Research Institute of St. Joseph's: lead
• Novartis Pharmaceuticals: collaborator

Study Sites (1)

Lawson Health Research Institute

London, Ontario, N6A 4V2, Canada

Location

Related Publications (10)

• Nadashkevich O, Davis P, Fritzler MJ. A proposal of criteria for the classification of systemic sclerosis. Med Sci Monit. 2004 Nov;10(11):CR615-21. Epub 2004 Oct 26.

  PMID: 15507853 BACKGROUND

• LeRoy EC, Black C, Fleischmajer R, Jablonska S, Krieg T, Medsger TA Jr, Rowell N, Wollheim F. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol. 1988 Feb;15(2):202-5. No abstract available.

  PMID: 3361530 BACKGROUND

• Thompson AE, Pope JE. Increased prevalence of scleroderma in southwestern Ontario: a cluster analysis. J Rheumatol. 2002 Sep;29(9):1867-73.

  PMID: 12233880 BACKGROUND

• Haugeberg G, Brodin C, Johnsen V. [Systemic sclerosis. A rare connective tissue disease with manifestations in many organs]. Tidsskr Nor Laegeforen. 1995 Nov 30;115(29):3619-21. Norwegian.

  PMID: 8539716 BACKGROUND

• Fries JF, Spitz P, Kraines RG, Holman HR. Measurement of patient outcome in arthritis. Arthritis Rheum. 1980 Feb;23(2):137-45. doi: 10.1002/art.1780230202.

  PMID: 7362664 BACKGROUND

• Lankat-Buttgereit B, Horsch D, Barth P, Arnold R, Blocker S, Goke R. Effects of the tyrosine kinase inhibitor imatinib on neuroendocrine tumor cell growth. Digestion. 2005;71(3):131-40. doi: 10.1159/000084647. Epub 2005 Mar 22.

  PMID: 15785039 BACKGROUND

• Newell DR. How to develop a successful cancer drug--molecules to medicines or targets to treatments? Eur J Cancer. 2005 Mar;41(5):676-82. doi: 10.1016/j.ejca.2004.12.024.

  PMID: 15763642 BACKGROUND

• Bonner JC. Regulation of PDGF and its receptors in fibrotic diseases. Cytokine Growth Factor Rev. 2004 Aug;15(4):255-73. doi: 10.1016/j.cytogfr.2004.03.006.

  PMID: 15207816 BACKGROUND

• Ghofrani HA, Seeger W, Grimminger F. Imatinib for the treatment of pulmonary arterial hypertension. N Engl J Med. 2005 Sep 29;353(13):1412-3. doi: 10.1056/NEJMc051946. No abstract available.

  PMID: 16192491 BACKGROUND

• Pope J, Walker KM, de Leon F, Vanderhoek L, Seney S, Summers KL. Correlations between changes in cytokines and clinical outcomes for early phase (proof of concept) trials in active diffuse systemic sclerosis using data from an imatinib study. Rheumatology (Oxford). 2014 Oct;53(10):1830-4. doi: 10.1093/rheumatology/keu216. Epub 2014 May 20.

  PMID: 24850877 DERIVED

MeSH Terms

Conditions

Scleroderma, Diffuse

Interventions

Imatinib Mesylate

Condition Hierarchy (Ancestors)

Scleroderma, Systemic; 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

Study Officials

• Janet E Pope, MD MPH FRCPC

  Lawson Health Research Institute, Western University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: March 1, 2012
• First Posted: March 6, 2012
• Study Start: April 1, 2008
• Primary Completion: December 1, 2008
• Study Completion: December 1, 2008
• Last Updated: March 7, 2012

Record last verified: 2012-03

Locations

CA (1)