the Efficiency of Thalidomide for Recurrent Small Intestinal Bleeding Due to Gastrointestinal Vascular Malformation

Study Overview
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Brief Summary
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Gastrointestinal vascular malformation (GIVM), which is an important cause of acute or chronic gastrointestinal bleeding, currently lacks of effective treatment. The investigators' previous study first confirmed thalidomide treatment of GIVM bleeding was safe and effective. This prospective multi-center randomized controlled clinical trial intends to investigate the efficacy of thalidomide to the recurrent small intestinal hemorrhage due to GIVM.

Detailed Description
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This multi-institutional clinical trial investigates the efficacy of thalidomide to the recurrent small intestinal hemorrhage due to GIVM. Patients with annual average bleeding 4 times or more and lesions located in the small intestine which are not suitable for endoscopic therapy will be randomly assigned to receive A(25mg,Thalidomide，qid), B(25mg, Thalidomide, bid& placebo bid ) or placebo(deferred treatment group) for 4 months. The primary endpoints were the effective response of patients with ≥50% reduction of numbers of bleeding episodes, followed by rate of cases with cessation of bleedin, the difference in blood transfusion, hospitalization, transfusion volume of red cell, average bleeding duration, average hemoglobin level, yearly hospitalization times, average hospital stay and yearly bleeding episodes. This study will be done at 10 centers in China.

Official Title
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A Randomized, Multicenter, Double-Blind, Placebo-Controlled Study of Efficacy of Thalidomide for Refractory Small Intestinal Bleeding From Vascular Malformation

Conditions
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Gastrointestinal Vascular Malformation

Intervention / Treatment
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* Drug: Thalidomide (100mg)
* Drug: Thalidomide (50mg)
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects voluntarily signed the informed consent after the nature and the specific procedures of the trial has been verbally explained; they have the opportunity to ask questions. Chinese nationality; Female or male subjects aged 18-75 years. Female subjects must be menopausal or have undergone sterilization such as tubal ligation and hysterectomy, or have no plan to give birth recently and agree to take contraceptive measures such as contraceptive drugs, intrauterine physical birth control rings or contraception condoms; or men must have undergone sterilization or do not plan to have a child recently and agree to take contraceptive measures such as contraceptive drugs, or contraception condoms. These criteria are set to eliminate the risk of subjects of child bearing potential. The subjects must have been diagnosed, by capsule endoscopy and / or balloon-assisted enteroscopy, with small intestinal vascular malformation lesions which are unsuitable or inaccessible to endoscopic therapy or surgical antrectomy. Subjects with persistent, recurrent bleeding, ≥ 4 episodes of overt or occult bleeding over last year. Exclusion Criteria: Subjects with esophageal varices from cirrhosis of the liver; those with uncontrolled hypertension or hyperglycemia (or diabetics who are being treated with insulin), or those with severe heart (e.g., uncontrolled angina pectoris and / or myocardial infarction, congestive heart failure, etc.), respiratory failure, or renal failure with creatinine (Cr) or blood urea nitrogen (BUN) > 2 times the upper limit of normal (ULN), pancreatic or hepatic disease with abnormal hepatic function with alanine aminotransferase (ALT), aspartate aminotransferase (AST) or total bilirubin (TBil) > 2 times ULN 3 months before the enrollment, or those with any other diseases that are not suitable for the study as judged by the Investigator; Subjects with a history of severe peripheral neuropathy or seizures, or a history of thromboembolic disease; Subjects who need to continuously use non-steroidal anti-inflammatory drugs, anticoagulants, antiplatelets, acetylsalicylic acid preparations, or Chinese herbal medicines containing ginkgo and echinacea; or those who need to receive other anti-angiogenic drugs for a long time; Subjects with white blood cell counts persistently <3.5 * 10^9 / L; Subjects with a history of small bowel resection; Subjects known or suspected to be allergic to any component of thalidomide； Subjects with severe gastrointestinal bleeding that is life-threatening and requires immediate surgical treatment; Subjects who have previously received thalidomide for gastrointestinal bleeding 30 days before the enrollment; Alcohol and / or substance abusers with addiction or dependence, or those with poor compliance as judged by a doctor; Subjects who participated in other clinical trial 6 months before enrollment; Subjects without legal capacity or self-awareness.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Thalidomide Group（100mg）<br>Generic name:Thalidomide Dosage form:tablet, 25mg Dosage:100mg/day Frequency: 25mg, QID, Oral Duration:120 days | Drug: Thalidomide (100mg)<br>* Patients were randomly assigned to receive a 120-days course of 100 mg of thalidomide (Pharmaceutical Co., Ltd. of ChangZhou, China).<br>* Other names: Group 1;|
| Experimental: Thalidomide Group（50mg）<br>Generic name:Thalidomide Dosage form:tablet, 25mg&Placebo Dosage:50mg/day Frequency: 25mg BID &Placebo, BID, Oral Duration:120 days | Drug: Thalidomide (50mg)<br>* Patients were randomly assigned to receive a 120-days course of 50 mg of thalidomide (Pharmaceutical Co., Ltd. of ChangZhou, China).<br>* Other names: Group 2;|
| Placebo Comparator: placebo -controlled Group<br>Generic name:Thalidomide Placebo Dosage form:tablet, Placebo Dosage:Placebo Frequency: Placebo, QID, Oral Duration:120 days | Drug: placebo<br>* Patients were randomly assigned to receive a 120-days course of placebo (Pharmaceutical Co., Ltd. of ChangZhou, China).<br>* Other names: Group 3;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| effective response rate | the proportion of patients with effective treatment, patients with ≥50% reduction of numbers of bleeding episodes after treatment during the First 1-year follow-up versus the 1-year Observation Period. | First 1-year follow-up versus the 1-year Observation Period. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| overall rate of cases with cessation of bleeding | The overall rate of cases with cessation of bleeding without rebleeding during the First 1-year Follow-up Period. | First 1-year follow-up versus the 1-year Observation Period. | 
| rate of cases requiring blood transfusion | The rate of cases requiring blood transfusion during the First 1-year follow-up. | First 1-year follow-up versus the 1-year Observation Period. | 
| rate of cases requiring hospitalizations due to bleeding | The rate of cases requiring hospitalizations due to bleeding during the 1st 1-year follow-up | First 1-year follow-up versus the 1-year Observation Period. | 
| change in the transfusion volume of red cell | The change in the transfusion volume of red cell during the First 1-year Follow-up Period versus the Observation Period. | First 1-year follow-up versus the 1-year Observation Period. | 
| change in average bleeding duration | The change in average bleeding duration (days) during the First 1-year Follow-up Period versus the Observation Period. | First 1-year follow-up versus the 1-year Observation Period. | 
| change in average hemoglobin level | The change in average hemoglobin level (g/L) during the First 1-year Follow-up Period versus the Observation Period. | First 1-year follow-up versus the 1-year Observation Period. | 
| change in yearly hospitalization times | The change in yearly hospitalization times due to bleeding during the First 1-year Follow-up Period versus the Observation Period. | First 1-year follow-up versus the 1-year Observation Period. | 
| change in average hospital stay | The change in average hospital stay (days)due to bleeding during the First 1-year Follow-up Period versus the Observation Period. | First 1-year follow-up versus the 1-year Observation Period. | 
| change in yearly bleeding episodes | The change in yearly bleeding episodes during the First 1-year Follow-up Period versus the Observation Period. | First 1-year follow-up versus the 1-year Observation Period. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gastrointestinal vascular malformation, thalidomide, Small intestinal bleeding