Long-term Effects of Thalidomide for Recurrent Gastrointestinal Bleeding Due to Vascular Malformation
Primary Purpose
Obscure Gastrointestinal Bleeding, Angiodysplasia, Gastric Antral Vascular Ectasia
Status
Completed
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
Thalidomide
Iron
Sponsored by
About this trial
This is an interventional treatment trial for Obscure Gastrointestinal Bleeding focused on measuring vascular malformation, gastrointestinal bleeding, thalidomide
Eligibility Criteria
Inclusion Criteria:
- 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;
- Endoscopic appearance of GAVE (also known as watermelon stomach), indicated by longitudinal antral folds converging on the pylorus, containing visible columns of tortuous red ecstatic vessels.
Exclusion Criteria:
- Patients were excluded if their bleeding history were less than 1 year;
- if they had cirrhotic or portal hypertension gastropathy; severe co-morbidities of cardiac, pulmonary, renal, liver, hematological, rheumatologic disorders, or uncontrollable diabetes mellitus or hypertension;
- if they had a history of severe bilateral peripheral neuropathy or seizure activity, thromboembolic disease, known thalidomide or iron allergy, or prior treatment of gastrointestinal bleeding with thalidomide;
- if they had 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;
- Currently pregnant or lactating or currently undergoing systemic cancer chemotherapy or receiving radiation
- if they were undergoing systemic cancer chemotherapy or receiving radiation.
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Other
Arm Label
Thalidomide Group
Iron-controlled Group
Arm Description
Outcomes
Primary Outcome Measures
Participants Whose Rebleeds Decreased From Baseline by ≥ 50% at 12 Months
The primary end point was defined as the patients whose rebleeds decreased from baseline by ≥ 50% at 12 months. Reduction of rebleeds = [(total bleeding episode at 12 months - total bleeding episodes at a year before randomization)/total bleeding episodes at a year before randomization(baseline)]*100%. Rebleeding was defined based on a positive fecal occult blood test (FOBT) (monoclonal colloidal gold color technology) at any visit after treatment.
Cessation of Bleeding
The cessation of bleeding was defined as repeated negative faecal occult blood test (FOBT) (monoclonal colloidal gold color technology) during our observation period. Rebleeding was defined based on a positive FOBT at any visit after treatment.
Secondary Outcome Measures
Change From Baseline in Hemoglobin (Hb) Level at 12 Months
The change from baseline in average hemoglobin (Hb) level(tested every month) at 12 months.
Change From Baseline in Bleeding Episodes at 12 Months
The Change from baseline in bleeding episodes at 12 months
Change From Baseline in Bleeding Duration at 12 Months
The change from baseline in bleeding duration at 12 months
Participants Dependent on Blood Transfusions
Numbers of participants dependent on blood transfusions
Change From Baseline in Total Transfused Red Cell Requirements at 12 Months
Change of total transfused red cell requirements at 12 months after randomization from one year before baseline in transfusion dependent patients
Full Information
NCT ID
NCT00964496
First Posted
August 24, 2009
Last Updated
November 17, 2015
Sponsor
Shanghai Jiao Tong University School of Medicine
1. Study Identification
Unique Protocol Identification Number
NCT00964496
Brief Title
Long-term Effects of Thalidomide for Recurrent Gastrointestinal Bleeding Due to Vascular Malformation
Official Title
Long-term Effects of Thalidomide for Recurrent Gastrointestinal Bleeding Due to Vascular Malformation : An Open-label, Randomized, Parallel Controlled Study
Study Type
Interventional
2. Study Status
Record Verification Date
August 2009
Overall Recruitment Status
Completed
Study Start Date
November 2004 (undefined)
Primary Completion Date
November 2007 (Actual)
Study Completion Date
August 2009 (Actual)
3. Sponsor/Collaborators
Name of the Sponsor
Shanghai Jiao Tong University School of Medicine
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
Background: Repeated episodes of bleeding from gastrointestinal vascular malformations refractory to endoscopic or surgical therapy often pose a major therapeutic challenge.
Methods: The investigators performed a randomized, parallel controlled study of thalidomide as a therapy for recurrent gastrointestinal bleeding due to vascular malformation. 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 25 mg of thalidomide or 100 mg of iron orally four times 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 and the cessation of bleeding. 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 participants dependent on blood transfusions and changes from baseline in transfused packed red cell units, bleeding episodes, bleeding durations, and hemoglobin levels at 12 months. Statistical significance was defined at P < 0.05.
Detailed Description
Protocol Description:
This is an exploratory, randomized, parallel controlled study of thalidomide for recurrent gastrointestinal bleeding from vascular malformations. Informed consent was taken from all subjects and the Institute Ethics Committee approved the study protocol. All procedures were in accordance with the Declaration of Helsinki. The study was supported by no pharmaceutical funding.
Study design and Intervention:
From Nov. 2004 to Nov. 2007, patients with repeated episodes of chronic gastro-intestinal bleeding due to vascular malformations identified by oesophagogastroduodenoscopy, capsule endoscope or double-balloon endoscope were enrolled (according our enrollment criteria).
The patients were randomly assigned to receive a four-month course of either 25 mg of thalidomide or 100mg iron orally at daily time 6 a.m.,12 noon,6 p.m. and 10 p.m., respectively.
Randomization was performed through the proc plan procedure of Statistical Analysis Software (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. Each patient who met the inclusion criteria was consecutively assigned a random number in chronological order, which allocated him or her to one of the treatment groups. A blinded research nurse supervised patient randomization and drug administration.
In the case of an adverse event, the study medication was temporarily or permanently discontinued based on subject inclination and toxicity intolerance. Concomitant therapies, such as blood transfusions and other symptomatic treatments like iron supplementation, were performed in both groups as necessary during the four-month treatment and subsequent follow-up periods. Blood transfusion was indicated and recorded when the hemoglobin (Hb) level reached < 7.0 g/dl. Red-cell transfusions were administered according to patient Hb level as follows: 2 units were administered for 6.1 g/dl ≥ Hb ≤ 7.0 g/dl, 3 units for 5.1 g/dl ≥ Hb ≤ 6.0 g/dl, and 4 units for Hb < 5.0 g/dl. Iron was provided for patients with 7.0 g/dl ≥ Hb ≤ 11.0 g/dl. After the four-month treatment course, all patients discontinued study medications except for cases where symptomatic treatments were necessary as described above.
Assessment of response and adverse events:
The primary end point was defined as the patients whose rebleeds decreased from baseline by ≥ 50% at 12 months and the cessation of bleeding. 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 participants dependent on blood transfusions and changes from baseline in transfused packed red cell units, bleeding episodes, bleeding durations, and hemoglobin levels at 12 months.
Adverse events included any unfavorable change in health, including abnormal laboratory findings, during the study or follow-up period.
Evaluation of Patients and Follow-up:
Certified research nurses collected information on the demographics and medical and social histories of all patients enrolled in the study.
After screening and baseline evaluations, the patients were closely monitored in the hospital for at least one week. They were then followed twice monthly during the four-mouth course of treatment and once a month thereafter.
Clinical follow-up was performed by qualified doctors. At all visits, the bleeding-related parameters (number and duration), a physical examination was performed and laboratory values were obtained for FOBT, complete blood counts, serum chemistries, and hepatic and renal function. Neuropathy and other adverse events were also assessed.
Patients were advised to refrain from any other non-prescribed medicines, especially rebleeding-related medications such as aspirin, nonsteroidal antiinflammatory drugs (NSAIDs), anti-platelet drugs, anticoagulants, and Chinese medications (with salicylates), gingko, or Echinacea.
Measurement of Vascular Endothelial Growth Factor (VEGF) in Sera:
Laboratory assays for VEGF were performed at baseline and after the four-month treatment course in the thalidomide group, by a technician blinded to the assignment and final assessment. Three milliliters of serum of peripheral venous blood samples were centrifuged (3000 r/min at 4°C, 10 min), extracted, separated into freezing tubes, and stored at -70°C for no more than 4 months. Plasma VEGF levels (in pg/ml) were determined in duplicate using sandwich ELISA kits (R&D Systems, USA) in a laboratory of the Shanghai Research Institute of Digestive Disease. Samples from each patient were batch-tested in a single run. For quality control, all samples were retested two more times in a subsequent run to confirm the results of the first run.
Statistical Analysis:
To our knowledge, no similar such study has previously been performed, and we were thus unable to refer to published studies to determine our samples. To this end, we performed an unpublished preliminary study. Response in the iron-control group and thalidomide group reached 10% and 80%, due to loose inclusion criteria (bleeding history was not restricted). For this study, we estimated that the primary outcome (the proportion of subjects whose number of yearly bleeds had decreased by ≥ 50%) would occur in 10% of the control group and 80% of the thalidomide group patients. An equally divided sample of 11 subjects was deemed sufficient for detecting the primary end point, with a type I error (two-sided) of 5% and a power of 90%. Assuming a 10% volunteer attrition rate to follow-up, we established a target sample size of 13 per group (calculated with nquery advisor software 5.0).
Analyses of the responses and adverse events were performed on all registered patients according to the intention-to-treat principle. Statistical analysis was performed by a blinded biostatistician with the Statistical Product and Service Solutions (SPSS) 13.0 software package. We simultaneously analyzed the primary endpoint of the full analysis set (FAS) and per protocol set (PPS). Continuous variables were compared using a two-sample independent t-test or Wilcoxon rank-sum test. Categorical variables were compared using the chi-squared and Fisher's exact tests. A paired t-test was employed to compare differences in plasma VEGF levels before and after thalidomide treatment. The Breslow-Day test was used to test for the heterogeneity of treatment effects across strata. All reported P-values are two-sided. Data are reported as the mean ± standard deviation (SD) or median (range) for continuous variables and number (%) for categorical variables. Since adjustments to the control group were minimal, we also reported point estimates and 95% confidence intervals (CIs). For all outcomes, a P-value of < 0.05 was considered statistically significant.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Obscure Gastrointestinal Bleeding, Angiodysplasia, Gastric Antral Vascular Ectasia, Thalidomide
Keywords
vascular malformation, gastrointestinal bleeding, thalidomide
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
55 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Thalidomide Group
Arm Type
Active Comparator
Arm Title
Iron-controlled Group
Arm Type
Other
Intervention Type
Drug
Intervention Name(s)
Thalidomide
Other Intervention Name(s)
Softenon;
Intervention Description
Patients were randomly assigned to receive a four-month course of 25 mg of thalidomide (Pharmaceutical Co., Ltd. of Chang-zhou, China). Medications were taken orally four times daily at 6 a.m., 12 noon, 6 p.m., and 10 p.m.
Intervention Type
Drug
Intervention Name(s)
Iron
Other Intervention Name(s)
Ferrous Succinate Tablets
Intervention Description
Patients were randomly assigned to receive a four-month course of 100 mg of iron (Pharmaceutical Co., Ltd. of Nanjing, China). Medications were taken orally four times daily at 6 a.m., 12 noon, 6 p.m., and 10 p.m.
Primary Outcome Measure Information:
Title
Participants Whose Rebleeds Decreased From Baseline by ≥ 50% at 12 Months
Description
The primary end point was defined as the patients whose rebleeds decreased from baseline by ≥ 50% at 12 months. Reduction of rebleeds = [(total bleeding episode at 12 months - total bleeding episodes at a year before randomization)/total bleeding episodes at a year before randomization(baseline)]*100%. Rebleeding was defined based on a positive fecal occult blood test (FOBT) (monoclonal colloidal gold color technology) at any visit after treatment.
Time Frame
baseline and 12 months
Title
Cessation of Bleeding
Description
The cessation of bleeding was defined as repeated negative faecal occult blood test (FOBT) (monoclonal colloidal gold color technology) during our observation period. Rebleeding was defined based on a positive FOBT at any visit after treatment.
Time Frame
52 months
Secondary Outcome Measure Information:
Title
Change From Baseline in Hemoglobin (Hb) Level at 12 Months
Description
The change from baseline in average hemoglobin (Hb) level(tested every month) at 12 months.
Time Frame
baseline and 12 months
Title
Change From Baseline in Bleeding Episodes at 12 Months
Description
The Change from baseline in bleeding episodes at 12 months
Time Frame
baseline and 12 months
Title
Change From Baseline in Bleeding Duration at 12 Months
Description
The change from baseline in bleeding duration at 12 months
Time Frame
baseline and 12 months
Title
Participants Dependent on Blood Transfusions
Description
Numbers of participants dependent on blood transfusions
Time Frame
52 months
Title
Change From Baseline in Total Transfused Red Cell Requirements at 12 Months
Description
Change of total transfused red cell requirements at 12 months after randomization from one year before baseline in transfusion dependent patients
Time Frame
baseline and 12 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
40 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
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;
Endoscopic appearance of GAVE (also known as watermelon stomach), indicated by longitudinal antral folds converging on the pylorus, containing visible columns of tortuous red ecstatic vessels.
Exclusion Criteria:
Patients were excluded if their bleeding history were less than 1 year;
if they had cirrhotic or portal hypertension gastropathy; severe co-morbidities of cardiac, pulmonary, renal, liver, hematological, rheumatologic disorders, or uncontrollable diabetes mellitus or hypertension;
if they had a history of severe bilateral peripheral neuropathy or seizure activity, thromboembolic disease, known thalidomide or iron allergy, or prior treatment of gastrointestinal bleeding with thalidomide;
if they had 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;
Currently pregnant or lactating or currently undergoing systemic cancer chemotherapy or receiving radiation
if they were undergoing systemic cancer chemotherapy or receiving radiation.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Zhizheng Ge, MD. Ph.D
Organizational Affiliation
Shanghai Ren Ji Hospital
Official's Role
Principal Investigator
12. IPD Sharing Statement
Citations:
PubMed Identifier
9154767
Citation
Jacobson JM, Greenspan JS, Spritzler J, Ketter N, Fahey JL, Jackson JB, Fox L, Chernoff M, Wu AW, MacPhail LA, Vasquez GJ, Wohl DA. Thalidomide for the treatment of oral aphthous ulcers in patients with human immunodeficiency virus infection. National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group. N Engl J Med. 1997 May 22;336(21):1487-93. doi: 10.1056/NEJM199705223362103.
Results Reference
background
PubMed Identifier
15016759
Citation
Bauditz J, Schachschal G, Wedel S, Lochs H. Thalidomide for treatment of severe intestinal bleeding. Gut. 2004 Apr;53(4):609-12. doi: 10.1136/gut.2003.029710.
Results Reference
background
PubMed Identifier
12526972
Citation
Shurafa M, Kamboj G. Thalidomide for the treatment of bleeding angiodysplasias. Am J Gastroenterol. 2003 Jan;98(1):221-2. doi: 10.1111/j.1572-0241.2003.07201.x. No abstract available.
Results Reference
background
Links:
URL
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Overview&DrugName=THALOMID&CFID=21312735&CFTOKEN=394df9d228870faa-4F4FD0A6-1372-5AE1-6AD225831B3F092E
Description
Approved drug page at FDA's Drugs@FDA web site.
Learn more about this trial
Long-term Effects of Thalidomide for Recurrent Gastrointestinal Bleeding Due to Vascular Malformation
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