A Proof of Concept Trial of Gleevec (Imatinib) in Active Diffuse Scleroderma
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 10
- 试验地点
- 1
- 主要终点
- Changes in the levels of fibrotic and inflammatory biomarkers in plasma samples.
研究概览
简要总结
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.
详细描述
Purpose:
Scleroderma is a connective tissue disease that is prototypical for fibrosis with autoantibodies and vascular abnormalities including vasomotor instability (Raynaud's) at one end and blood vessel obliteration at the other (1,2). Scleroderma occurs in > 2/10,000 (with thousands of Canadians affected) and has no proven therapy to modify the disease overall (3). The purpose of this study is to investigate the potential of Gleevec to be used as a novel therapy in the treatment of scleroderma.
Background:
There are two subtypes of systemic scleroderma: diffuse and limited (2). Limited skin involvement includes skin involvement distal to the elbows and knees and may include the neck and face, but spares the trunk and proximal extremities. Diffuse scleroderma has more extensive skin involvement including trunk or proximal extremities and is associated with more internal organ involvement and increased mortality (4). For instance, significant interstitial lung disease, cardiomyopathy and scleroderma renal crisis are more common in diffuse scleroderma than limited. The extent of organ involvement in these areas may correlate with the extent of skin involvement and worsening skin involvement is associated with increased mortality and worse overall health function as measured by the Health Assessment Questionnaire (HAQ) (5).
Formulation of Objective:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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 >
- •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.
研究组 & 干预措施
Placebo
Placebo coated to appear identical to Gleevec.
干预措施: Placebo (Other)
Gleevec
Gleevec 200 mg bid for 6 months.
干预措施: Imatinib mesylate (Drug)
结局指标
主要结局
Changes in the levels of fibrotic and inflammatory biomarkers in plasma samples.
时间窗: Plasma samples were taken at baseline (0), 3 and 6 months (study end).
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.
时间窗: Baseline and 6 months (study end).
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).
次要结局
- 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).)
- The Short Form (36) Health Survey(Baseline and 6 months.)
- Health Transitiion Score(Baseline and 6 months.)
研究者
Janet Pope
Principal Investigator
Lawson Health Research Institute