Text Size

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

This study has been terminated.
(Frequent adverse events occurred early in treatment with poor tolerability.)
Sponsor:
Collaborator:
Novartis Pharmaceuticals
Information provided by (Responsible Party):
Janet Pope, Lawson Health Research Institute
ClinicalTrials.gov Identifier:
NCT01545427
First received: March 1, 2012
Last updated: March 6, 2012
Last verified: March 2012
History of Changes
  Purpose

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.


Condition Intervention Phase
Scleroderma
 Drug: Imatinib mesylate
Other: Placebo
 Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Proof of Concept Trial of Gleevec (Imatinib) in Active Diffuse Scleroderma

Resource links provided by NLM:

MedlinePlus related topics: Scleroderma
U.S. FDA Resources

Further study details as provided by Lawson Health Research Institute:

Primary Outcome Measures:
  • Changes in the levels of fibrotic and inflammatory biomarkers in plasma samples. [ Time Frame: Plasma samples were taken at baseline (0), 3 and 6 months (study end). ] [ Designated as safety issue: No ]
    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).

  • Changes in the levels of fibrotic and inflammatory biomarkers in skin biopsies. [ Time Frame: Baseline and 6 months (study end). ] [ Designated as safety issue: No ]
    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).


Secondary Outcome Measures:
  • Modified Rodnan Skin Score (MRSS) [ Time Frame: Baseline, 3 months and 6 months (study end). ] [ Designated as safety issue: No ]
    The Modified Rodnan Skin Score (MRSS) is a validated outcome measurement and is the usual primary outcome measurement for all trials of disease modification in scleroderma. It is positively correlated with internal organ involvement and has been shown to improve or worsen in many patients.

  • Adverse events and serious adverse events [ Time Frame: From treatment start until 4 weeks after after the patient has stopped study participation ] [ Designated as safety issue: Yes ]
    This study will use the CTCAE (NCI Common Terminology Criteria for Adverse Events) versions 3.0 for toxicity and adverse event reporting. If multiple dose-reducing toxicities are present, the greatest dose reduction schedule should be used. Information about all adverse events will be collected and recorded on the Adverse Event Case Report Form and followed as appropriate. Serious adverse events occurring more than 4 weeks after study discontinuation need only be reported if a relationship to the study drug (or therapy) is suspected.

  • Health Assessment Questionnaire [ Time Frame: Baseline, 3 months and 6 months (study end). ] [ Designated as safety issue: No ]
  • Patient Global Assessment [ Time Frame: Baseline, 3 months and 6 months (study end). ] [ Designated as safety issue: No ]
    Patient assessment of global disease activity on a 100 mm visual analog scale.

  • Physician Global Assessment [ Time Frame: Baseline, 3 months and 6 months (study end). ] [ Designated as safety issue: No ]
    Physician global assessment of disease activity on a 100 mm visual analog scale.

  • The Short Form (36) Health Survey [ Time Frame: Baseline and 6 months. ] [ Designated as safety issue: No ]
  • Health Transitiion Score [ Time Frame: Baseline and 6 months. ] [ Designated as safety issue: No ]
    "Compared to 6 months ago, how do you rate your health overall?: Much worse, worse, same, better, much better".


Enrollment: 10
Study Start Date: April 2008
Study Completion Date: December 2008
Primary Completion Date: December 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Gleevec
Gleevec 200 mg bid for 6 months.
 Drug: Imatinib mesylate
200 mg bid for 6 months
Other Name: Gleevec
Placebo Comparator: Placebo
Placebo coated to appear identical to Gleevec.
 Other: Placebo
Placebo coated to match appearance of Gleevec identically.

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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

Exclusion Criteria:

  • 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.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01545427

Locations
Canada, Ontario
Lawson Health Research Institute
London, Ontario, Canada, N6A 4V2
Sponsors and Collaborators
Lawson Health Research Institute
Novartis Pharmaceuticals
Investigators
Principal Investigator: Janet E Pope, MD MPH FRCPC Lawson Health Research Institute, Western University
  More Information

Publications:

Responsible Party: Janet Pope, Principal Investigator, Lawson Health Research Institute
ClinicalTrials.gov Identifier: NCT01545427     History of Changes
Other Study ID Numbers: R-07-214, #031-06
Study First Received: March 1, 2012
Last Updated: March 6, 2012
Health Authority: Canada: Health Canada

Keywords provided by Lawson Health Research Institute:
Scleroderma
Randomized controled trial
Pilot study
Gleevec (imatinib)
Biomarkers

Additional relevant MeSH terms:
Scleroderma, Systemic
Scleroderma, Diffuse
Scleroderma, Localized
Connective Tissue Diseases
Skin Diseases
Imatinib
 Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on May 23, 2013