Retreatment and Its Efficiency of Thalidomide for Vascular Malformation Patients With Failure of First Course Treatment

Background: Repeated episodes of bleeding from gastrointestinal vascular malformations refractory to endoscopic or surgical therapy often pose a major therapeutic challenge.

Methods: The investigators will perform a randomized, double blind, placebo controlled study of thalidomide as a retreatment therapy for recurrent gastrointestinal bleeding due to vascular malformation. Patients with failure of first course treatment of thalidomide will be randomly grouped, prescribed a second four-month course regimen of 25 mg of thalidomide or placebo orally four times daily. All patients will be monitored for at least one year. The primary end point is defined as the patients whose rebleeds decrease from baseline by ≥ 50% at 12 months and the cessation of bleeding. Rebleeding is defined based on a positive fecal occult blood test (FOBT) (monoclonal colloidal gold color technology) at any visit after treatment. Secondary outcomes include the participants dependent on blood transfusions and changes from baseline in transfused packed red cell units, bleeding episodes, and hemoglobin levels at 12 months. Statistical significance is defined at P \< 0.05.

Protocol Description:

This is an exploratory, randomized, double blind, placebo controlled study of thalidomide for retreatment patients with failure of first course thalidomide treatment for recurrent gastrointestinal bleeding from vascular malformations. Informed consent will be taken from all subjects and the Institute Ethics Committee approved the study protocol. All procedures are in accordance with the Declaration of Helsinki. The study is not supported by pharmaceutical funding.

Study design and Intervention:

From Dec. 2014 to Nov. 2015, patients with failure of first course thalidomide treatment and repeated at least four episodes of chronic gastrointestinal bleeding a year due to vascular malformations identified by oesophagogastroduodenoscopy, capsule endoscope or double-balloon endoscope will be enrolled (according our enrollment criteria).

The patients will be randomly assigned to receive a second four-month course of 25 mg of thalidomide or placebo at daily time 6 a.m.,12 noon,6 p.m. and 10 p.m., respectively.

Randomization is performed through the proc plan procedure of Statistical Analysis System (SAS), using the method of randomly permuted blocks of 4. Within each block, the number of patients allocated to each of the two treatments is equal. Each patient who met the inclusion criteria will be consecutively assigned a random number in chronological order, which allocate him or her to one of the treatment groups.

In the case of an adverse event, the study medication will be temporarily or permanently discontinued based on subject inclination and toxicity intolerance.

Concomitant therapies, such as blood transfusions and other symptomatic treatments like iron supplementation, will be performed in both groups as necessary during the four-month treatment and subsequent follow-up periods. Blood transfusion is indicated and recorded when the hemoglobin (Hb) level reaches \< 7.0 g/dl. Red-cell transfusions are administered according to patient Hb level as follows: 2 units will be 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 is 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 are necessary as described above.

Assessment of response and adverse events:

The primary end point is defined as the patients whose rebleeds decrease from baseline by ≥ 50% at 12 months and the cessation of bleeding. Rebleeding is defined based on a positive fecal occult blood test (FOBT) (monoclonal colloidal gold color technology) at any visit after treatment. Secondary outcomes include the participants dependent on blood transfusions and changes from baseline in transfused packed red cell units, bleeding episodes, and hemoglobin levels at 12 months.

Adverse events include 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 will be closely monitored in the hospital for at least one week. They are then followed twice monthly during the four-mouth course of treatment and once a month thereafter.
* Clinical follow-up is performed by qualified doctors. At all visits, the bleeding-related parameters (number and duration) will be collected, a physical examination will be performed and laboratory values obtained for FOBT, complete blood counts, serum chemistries, and hepatic and renal function. Neuropathy and other adverse events were also assessed.
* Patients are advised to refrain from any other non-prescribed medicines, especially rebleeding-related medications such as aspirin, nonsteroidal anti-inflammatory drug(NSAIDs), anti-platelet drugs, anticoagulants, and Chinese medications (with salicylates), gingko, or Echinacea.

Statistical Analysis:

To our knowledge, no similar such study concern on efficiency of thalidomide retreatment has previously been performed, and the investigators are thus unable to refer to published studies to determine our samples. According to our published study, response in the iron-control group and thalidomide group reached 3.7% and 71.4%. And in our preliminary study (unpublished), response of thalidomide retreatment reached 66.7%. For this study, the investigators estimate that the primary outcome (the proportion of subjects whose number of yearly bleeds has decreased by ≥ 50%) will occur in 3.7% of the placebo group and 66.7% of the thalidomide retreatment group patients. An equally divided sample of 9 subjects is 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, the investigators establish a target sample size of 10 per group (calculated with PASS 11). To ensure an adequate power of later stratified analysis, the sample size is approximately increased to be 15 in each group.

Analyses of the responses and adverse events are performed on all registered patients according to the intention-to-treat principle. Statistical analysis is performed by a blinded biostatistician with the SPSS 13.0 software package. The investigators simultaneously analyze the primary endpoint of the full analysis set (FAS) and per protocol set (PPS). Continuous variables are compared using a two-sample independent t-test or Wilcoxon rank-sum test. Categorical variables are compared using the chi-squared and Fisher's exact tests. The Breslow-Day test is 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 are minimal, the investigators also report point estimates and 95% confidence intervals (CIs). For all outcomes, a P-value of \< 0.05 is considered statistically significant.

Eligibility Criteria:
Inclusion Criteria:

* Age between 35-85 years; women are post-menopausal, post-tubal ligation, or on some form of birth control like long-term laying up contraceptive ring or using condom;
* Patients with failure of first course treatment of thalidomide, which means rebleeds decreased from baseline by\< 50% at 12 months follow up ;
* History of at least six documented gastrointestinal bleeding episodes in the year prior first course thalidomide treatment, which are refractory or inaccessible to endoscopic therapy or surgical ectomy; so, patients should have at least four episodes of gastrointestinal bleeding a year prior our study;
* 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 are excluded if first course treatment of thalidomide is effective, which means rebleeds decreased from baseline by ≥ 50% at 12 months follow up;
* if they have cirrhotic or portal hypertension gastropathy; severe co-morbidities of cardiac, pulmonary, renal, liver, hematological, rheumatologic disorders, or uncontrollable diabetes mellitus or hypertension;
* if they have a history of severe bilateral peripheral neuropathy or seizure activity, thromboembolic disease, known thalidomide allergy;
* if they have 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