A Randomised, Double-blind, Placebo-controlled Study of Thalidomide in Gastrointestinal Vascular Malformation Related Bleeding
试验速览
- 阶段
- 2 期
- 状态
- 撤回
- 发起方
- 试验地点
- 1
- 主要终点
- Proportion of subjects whose bleeding episode decreased from baseline by ≥ 50% at 12 months follow-up after 4-month treatment
研究概览
简要总结
Background: Repeated bleeding from gastrointestinal vascular malformations remains to be a major therapeutic challenge.
Methods: The investigators performed a randomised, double-blind, placebo-controlled, single centre study to assess the long-term efficacy and safety of thalidomide 100mg qn p.o. or placebo 100 mg qn p.o. administration for 4 months in subjects with recurrent gastrointestinal bleeding due to vascular malformations. Patients with at least six episodes of bleeding in the prior year due to vascular malformation were randomly grouped, prescribed a four-month regimen of either 100mg of thalidomide or 100 mg of placebo orally one time daily, and monitored for at least one year. The primary end point was defined as the patients whose rebleeds decreased from baseline by ≥ 50% at 12 months. Rebleeding was defined based on a positive fecal occult blood test (FOBT) (monoclonal colloidal gold color technology) at any visit after treatment. Secondary outcomes included the changes from baseline in participants dependent on blood transfusions and transfused packed red cell units, bleeding episodes, bleeding durations, and hemoglobin levels at 12 months. Statistical significance was defined at P < 0.05.
详细描述
Study design:
The study will be carried out as a single-centre, randomized, double-blind, parallel-group, placebo-controlled phase II study in subjects with recurrent gastrointestinal bleeding due to vascular malformations.
Subjects Enrollment and Assignment:
Approximately 100 patients aged between 40-85 years with recurrent gastrointestinal bleeding (melena and/or fresh hematemesis or positive FOBT) at least 6 times within one year, verified as vascular malformation by capsule endoscopies or enteroscopies at baseline.
Randomization was performed through the proc plan procedure of SAS, using the method of randomly permuted blocks of 4. Within each block, the number of patients allocated to each of the two treatments was equal. Subjects who are eligible for randomisation will be given a subject number in consecutive order within blocks, and the investigational products packed corresponding to this number. The subject will be allocated to one of the two treatment groups, i.e. Thalidomide and placebo, according to a computer generated list provided by Pharmaceutical Co., Ltd. of Chang Zhou, China. If a subject discontinues from the study, the subject number will not be reused, and the subject will not be allowed to re-enter the study.
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
- Triple (Participant, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 40 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Age between 40-85 years; women were post-menopausal, post-tubal ligation, or on some form of birth control like long-term laying up contraceptive ring or using condom;
- •History of at least six documented gastrointestinal bleeding episodes in the year prior to randomization, which were refractory or inaccessible to endoscopic therapy or surgical ectomy;
- •Confirmed diagnosis of vascular malformation by esophagogastroduodenoscopy (EGD), capsule endoscope (CE), double-balloon endoscope (DBE), or colonoscopy, but no obvious infectious, neoplastic, or other specific diagnosis;
- •Angiodysplasia at endoscopy characterized by focal or diffused venous/capillary lesions presenting as bright red ectatic vessels or pulsatile red protrusions, with surrounding venous dilatation or patchy erythema with or without oozing;
排除标准
- •Less than 1 year of bleeding history;
- •GI bleeding caused by Esophageal varices, Mallory Weiss syndrome, Zollinger-Ellison syndrome, Suspicion of gastric malignancy at baseline endoscopy, Post-Billroth-resection, Biliary disorders, Gastrointestinal tumors, Crohn's disease or Ulcerative colitis, Hemangioma or unknown source of GI bleeding;
- •Bleeding that needs emergent endoscopic treatment or surgery;
- •Any significant "alarm symptoms" within the past 6 months, such as, unintentional weight loss, signs of gastrointestinal bleeding more than 2 weeks prior to enrolment, jaundice, or any other sign indicating serious or malignant disease;
- •Malignancy or clinically significant cardiovascular, pulmonary, renal, pancreatic, hepatic disease, cirrhotic or portal hypertension gastropathy, rheumatologic disorders, uncontrollable diabetes mellitus or hypertension as judged by the investigator;
- •A history of severe bilateral peripheral neuropathy or seizure activity, thromboembolic disease;
- •A history of treatment with any dose of systemic or oral topical corticosteroids or aspirin, NSAIDs, anti-platelet drugs, anticoagulants, or Chinese medications (with salicylates), gingko, or Echinacea, or other putative immunomodulators or anti-angiogenic agents;
- •Haemorrhagic disorders, platelets<100 x 109/ L, APTT>1.5x upper limit of normal (ULN), or treatment with low-molecular weight heparin;
- •Need for continuous concurrent therapy during the study period with NSAIDs, ASA (including low dose),Warfarin (including other Vit K antagonists), anti-platelet drugs, anticoagulants, mephenytoin, atazanavir or Chinese medications (with salicylates), gingko, or Echinacea, or other putative immunomodulators or anti-angiogenic agents;
- •Pregnancy or lactation. Woman of child-bearing potential must be either non-pregnant or postmenopausal or must use a reliable form of contraception during the study period, as judged by the investigator;
- •Allergy to study medications;
- •Currently undergoing systemic cancer chemotherapy or receiving radiation or had underwent systemic cancer chemotherapy or received radiation treatment.
- •Use of any other investigational compound or participation in another clinical trial within 30 days prior to start of study medication;
- •Alcohol and/or drug abuse (addiction or drug dependence) or any condition associated with poor compliance, including expected non-cooperation, as judged by the investigator;
- •Previous participation in the study;
- •Involvement in the planning and conduct of the study.
研究组 & 干预措施
Thalidomide group
Patients were randomly assigned to the thalidomide group and received 100 mg of thalidomide (Pharmaceutical Co., Ltd. of Chang Zhou, China) orally four times daily at 10 p.m. for four months.
干预措施: Thalidomide (Drug)
Placebo group
Patients were randomly assigned to the placebo group and received 100 mg of thalidomide placebo (Pharmaceutical Co., Ltd. of Chang Zhou, China) orally four times daily at 10 p.m. for four months.
干预措施: Placebo (Drug)
结局指标
主要结局
Proportion of subjects whose bleeding episode decreased from baseline by ≥ 50% at 12 months follow-up after 4-month treatment
时间窗: 12 months
Proportion of subjects whose bleeding episode decreased from baseline by ≥ 50% at 12 months follow-up after 4-month treatment. The details are showed as follows: Reduction of bleeding episode = \[(total bleeding episodes at 12 months - total bleeding episodes at a year before randomisation)/total bleeding episodes at a year before randomisation (baseline)\]\*100%. Rebleeding was defined based on a positive fecal occult blood test (FOBT) (monoclonal colloidal gold color technology) at any visit after treatment.
次要结局
- Change from baseline in bleeding episodes at 12 months(baseline and 12 months)
- Change from baseline in bleeding duration at 12 months(baseline and 12 months)
- Change from baseline in average hemoglobin (Hb) level at 12 months(baseline and 12 months)
- Change from baseline in proportion of subjects who dependent on blood transfusions at 12 months(baseline and 12 months)
- Change from baseline in number of blood units transfused in subjects who dependent on blood transfusions at 12 months(baseline and 12 months)
研究者
Zhizheng Ge
the director of the endoscopy center
Shanghai Jiao Tong University School of Medicine