Pharmacogenetic Testing in the Clinical Setting: is Screening for TPMT Genotype a Cost-effective Treatment Strategy? - The First Prospective Randomized Controlled Trial Within the Dutch Health Care System.
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 发起方
- 入组人数
- 853
- 试验地点
- 2
- 主要终点
- Haematological adverse drug reactions
研究概览
简要总结
The purpose of this study is to determine whether thiopurine S-methyltransferase (TPMT) genotyping prior to thiopurine use is cost-effective in patients with inflammatory bowel disease (IBD) in need of immune suppression.
The study is designed to test the hypothesis that optimization of initial thiopurine dose based on pre-treatment TPMT genotyping will maximize treatment efficacy and minimize adverse drug reactions (ADRs) resulting in reduced costs.
详细描述
Immunosuppressives, e.g. azathioprine (AZA) and 6-mercaptopurine (6-MP), are important in induction of remission and long term treatment of (ulcerative) colitis and Crohn's disease when treatment with 5-aminosalicylates and corticosteroids fails. ADRs to immunosuppressive treatment, including myelosuppression and hepatotoxicity, are frequently (15-30%) observed. Genetic variation in the TPMT gene results in 10-11% of the general population in reduced and in 0.3-0.6% to negligible TPMT enzyme activity. In IBD patients, this genetic variation predicts 25-40% of the haematological ADRs necessitating tempering of thiopurine dose or discontinuation of treatment.
Pharmacogenetics aims at providing optimized drug treatment to patients by maximizing efficacy and minimizing adverse drug reactions (ADRs) based on genetic testing. Despite the proven value of pharmacogenetics in clinical practice, its use in medical care is still limited.
The best-established example of a pharmacogenetic test is genotyping of thiopurine S-methyltransferase (TPMT) in the treatment of patients with immunosuppressive thiopurines. Nonetheless, it is not used on a large scale in clinical practice so far, which might be due to: insufficient information transfer from research to clinic; lack of cost-effectiveness analyses (CEAs); lack of availability of (or access to) fast and/or cheap genotyping; or lack of test reimbursement by health insurance.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Supportive Care
- 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
- •Age 18 or older
- •Diagnosis of a form of IBD
- •Indication for azathioprine/6-MP treatment
- •Patient giving (written) informed consent
排除标准
- •Previous treatment with azathioprine/6-MP
- •Co-prescription of allopurinol (this treatment blocks xanthine oxidase, an enzyme important for thiopurine metabolism)
- •Baseline leukocyte count less then 3x10^9 per litre
- •Reduced liver function at baseline
- •Reduced renal function at baseline
- •Known TPMT phenotype (enzyme activity / Therapeutic Drug Monitoring) or genotype
- •Pregnancy or breastfeeding
研究组 & 干预措施
control
Standard thiopurine treatment
干预措施: azathioprine (AZA) or 6-mercaptopurine (6-MP) (Drug)
结局指标
主要结局
Haematological adverse drug reactions
时间窗: 0-5 months
次要结局
- Non-haematological Adverse Drug Reactions(0- 5 months)
- Clinical outcome (disease activity)(5 months)
- Treatment compliance(0 to 5 months)
- Therapeutic Drug Monitoring of TPMT Metabolites(week 1 and 8)
- Health related quality of life(5 months)
- Cost-efficacy(5 months)
- TPMT enzym activity(at baseline)
研究者
Marieke Coenen
PhD
Radboud University Medical Center