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

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

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.

Study Overview

• Status: Completed
• Conditions: Gastrointestinal Vascular Malformation
• Intervention / Treatment: Drug: Thalidomide (100mg); Drug: Thalidomide (50mg); Drug: placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 150
• Phase: Phase 3

Contacts and Locations

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 100032
      • Peking Union Medical College Hospital
  • Chongqing
    • Chongqing, Chongqing, China, 400037
      • Xinqiao Hospital of Chongqing
  • Guangdong
    • Guangzhou, Guangdong, China, 510515
      • Nanfang Hospital of Southern Medical University
  • Shanghai
    • Shanghai, Shanghai, China, 200040
      • Huashan Hospital
    • Shanghai, Shanghai, China, 200433
      • Changhai Hospital
    • Shanghai, Shanghai, China, 200025
      • Ruijin Hospital
    • Shanghai, Shanghai, China, 200127
      • Department of Gastroenterology, Renji Hospital, Shanghai Institute of Digestive Diseases, Shanghai Jiao Tong University School of Medicine
    • Shanghai, Shanghai, China, 200032
      • Shanghai Zhongshan Hospital
    • Shanghai, Shanghai, China, 200092
      • Xinhua Hospital, Shanghai Jiao Tong University School of Medicine
    • Shanghai, Shanghai, China, 201620
      • Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. 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.
2. Chinese nationality;
3. 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.
4. 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:

1. 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;
2. Subjects with a history of severe peripheral neuropathy or seizures, or a history of thromboembolic disease;
3. 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;
4. Subjects with white blood cell counts persistently <3.5 * 10^9 / L;
5. Subjects with a history of small bowel resection;
6. Subjects known or suspected to be allergic to any component of thalidomide；
7. Subjects with severe gastrointestinal bleeding that is life-threatening and requires immediate surgical treatment;
8. Subjects who have previously received thalidomide for gastrointestinal bleeding 30 days before the enrollment;
9. Alcohol and / or substance abusers with addiction or dependence, or those with poor compliance as judged by a doctor;
10. Subjects who participated in other clinical trial 6 months before enrollment;
11. Subjects without legal capacity or self-awareness.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

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.

Collaborators and Investigators

• Sponsor: Shanghai Jiao Tong University School of Medicine
• Collaborators: Changhai Hospital; Peking Union Medical College Hospital; Shanghai Zhongshan Hospital; Huashan Hospital; Nanfang Hospital of Southern Medical University; Ruijin Hospital; Xinhua Hospital, Shanghai Jiao Tong University School of Medicine; Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine; Xinqiao Hospital of Chongqing

Publications and helpful links

General Publications

• Ge ZZ, Chen HM, Gao YJ, Liu WZ, Xu CH, Tan HH, Chen HY, Wei W, Fang JY, Xiao SD. Efficacy of thalidomide for refractory gastrointestinal bleeding from vascular malformation. Gastroenterology. 2011 Nov;141(5):1629-37.e1-4. doi: 10.1053/j.gastro.2011.07.018. Epub 2011 Jul 22.
• Ge ZZ, Chen HY, Gao YJ, Hu YB, Xiao SD. Best candidates for capsule endoscopy for obscure gastrointestinal bleeding. J Gastroenterol Hepatol. 2007 Dec;22(12):2076-80. doi: 10.1111/j.1440-1746.2006.04724.x.
• Tan H, Chen H, Xu C, Ge Z, Gao Y, Fang J, Liu W, Xiao S. Role of vascular endothelial growth factor in angiodysplasia: an interventional study with thalidomide. J Gastroenterol Hepatol. 2012 Jun;27(6):1094-101. doi: 10.1111/j.1440-1746.2011.06967.x.
• Li XB, Ge ZZ, Dai J, Gao YJ, Liu WZ, Hu YB, Xiao SD. The role of capsule endoscopy combined with double-balloon enteroscopy in diagnosis of small bowel diseases. Chin Med J (Engl). 2007 Jan 5;120(1):30-5.
• Tan HH, Ge ZZ, Gao YJ, Chen HM, Fang JY, Chen HY, Liu WZ, Xiao SD. The role of HIF-1, angiopoietin-2, Dll4 and Notch1 in bleeding gastrointestinal vascular malformations and thalidomide-associated actions: a pilot in vivo study. J Dig Dis. 2011 Oct;12(5):349-56. doi: 10.1111/j.1751-2980.2011.00506.x.
• Feng Q, Tan HH, Ge ZZ, Gao YJ, Chen HM, Xiao SD. Thalidomide-induced angiopoietin 2, Notch1 and Dll4 downregulation under hypoxic condition in tissues with gastrointestinal vascular malformation and human umbilical vein endothelial cells. J Dig Dis. 2014 Feb;15(2):85-95. doi: 10.1111/1751-2980.12114.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2016
• Primary Completion (Actual): December 1, 2020
• Study Completion (Actual): April 1, 2021

Study Registration Dates

• First Submitted: November 17, 2015
• First Submitted That Met QC Criteria: March 11, 2016
• First Posted (Estimated): March 14, 2016

Study Record Updates

• Last Update Posted (Actual): June 23, 2023
• Last Update Submitted That Met QC Criteria: June 20, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: thalidomide; Gastrointestinal vascular malformation; Small intestinal bleeding
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Cardiovascular Abnormalities; Hemorrhage; Congenital Abnormalities; Vascular Malformations; Physiological Effects of Drugs; Anti-Infective Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Anti-Bacterial Agents; Leprostatic Agents; Thalidomide
• Other Study ID Numbers: rj(2015)088K-a