Gastrointestinal Vascular Malformation Clinical Trial
Official title:
The Study of the Optimal Treatment Strategy for Patients With Gastrointestinal Bleeding Due to Gastrointestinal Vascular Malformation: a Randomized, Double Blind, Placebo Controlled Study
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.
;
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Recruiting |
NCT02716545 -
the Efficiency of Endoscopic Treatment for Recurrent Small Intestinal Bleeding Due to Gastrointestinal Vascular Malformation
|
N/A | |
| Completed |
NCT02707484 -
the Efficiency of Thalidomide for Recurrent Small Intestinal Bleeding Due to Gastrointestinal Vascular Malformation
|
Phase 3 |