Clinical trial NCT02707484: the Efficiency of Thalidomide for Recurrent Small Intestinal Bleeding Due to Gastrointestinal Vascular Malformation
Official title: A Randomized, Multicenter, Double-Blind, Placebo-Controlled Study of Efficacy of Thalidomide for Refractory Small Intestinal Bleeding From Vascular Malformation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Gastrointestinal Vascular Malformation
Keywords: Gastrointestinal vascular malformation
thalidomide
Small intestinal bleeding
Lead sponsor: Shanghai Jiao Tong University School of Medicine
Sponsor class: OTHER
Collaborators: name: Peking Union Medical College Hospital
name: Nanfang Hospital, Southern Medical University
name: Xinqiao Hospital of Chongqing
name: Changhai Hospital
name: Shanghai Zhongshan Hospital
name: Huashan Hospital
name: Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
name: Xinhua Hospital, Shanghai Jiao Tong University School of Medicine
name: Ruijin Hospital
First posted: 2016-03-14
Enrollment: 150
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: effective response rate
timeFrame: First 1-year follow-up versus the 1-year Observation Period.
Secondary outcomes:
measure: overall rate of cases with cessation of bleeding
timeFrame: First 1-year follow-up versus the 1-year Observation Period.
measure: rate of cases requiring blood transfusion
timeFrame: First 1-year follow-up versus the 1-year Observation Period.
measure: rate of cases requiring hospitalizations due to bleeding
timeFrame: First 1-year follow-up versus the 1-year Observation Period.
measure: change in the transfusion volume of red cell
timeFrame: First 1-year follow-up versus the 1-year Observation Period.
measure: change in average bleeding duration
timeFrame: First 1-year follow-up versus the 1-year Observation Period.
measure: change in average hemoglobin level
timeFrame: First 1-year follow-up versus the 1-year Observation Period.
measure: change in yearly hospitalization times
timeFrame: First 1-year follow-up versus the 1-year Observation Period.
measure: change in average hospital stay
timeFrame: First 1-year follow-up versus the 1-year Observation Period.
measure: change in yearly bleeding episodes
timeFrame: First 1-year follow-up versus the 1-year Observation Period.
Other outcomes:
Locations:
city: Beijing
country: China
facility: Peking Union Medical College Hospital
state: Beijing
city: Chongqing
country: China
facility: Xinqiao Hospital of Chongqing
state: Chongqing
city: Guangzhou
country: China
facility: Nanfang Hospital of Southern Medical University
state: Guangdong
city: Shanghai
country: China
facility: Ruijin Hospital
state: Shanghai
city: Shanghai
country: China
facility: Shanghai Zhongshan Hospital
state: Shanghai
city: Shanghai
country: China
facility: Huashan Hospital
state: Shanghai
city: Shanghai
country: China
facility: Xinhua Hospital, Shanghai Jiao Tong University School of Medicine
state: Shanghai
city: Shanghai
country: China
facility: Department of Gastroenterology, Renji Hospital, Shanghai Institute of Digestive Diseases, Shanghai Jiao Tong University School of Medicine
state: Shanghai
city: Shanghai
country: China
facility: Changhai Hospital
state: Shanghai
city: Shanghai
country: China
facility: Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
state: Shanghai
Study officials:
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.