Safety & Efficacy of Thalidomide in Children With Transfusion Dependent Thalassemia

Study Overview
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Brief Summary
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Transfusion Dependent Thalassemia (TDT) is emerging as a global public health concern. Hemopoietic stem cell transplantation (HSCT) is the only curative treatment. But its adoption is limited due to lack of Human leukocyte antigen (HLA) matched donor, experienced centers and high initial cost. So, researches are going on in search of an effective, safe, easily available treatment option. Thalidomide a Fetal Hemoglobin (HbF) inducing drug shown to be effective in treatment of TDT patients in few case reports and small scale prospective and retrospective studies. However, most of these researches were done in adolescent and adult population. No randomized control trial was done to determine the safety and efficacy of Thalidomide in TDT children. So, this study will predict the safety and efficacy of Thalidomide in TDT children and will play an important role in planning a cost effective and affordable treatment option for TDT children. This single centered non blinded quasi randomized clinical trial will be conducted at the Department of Pediatric Hematology and Oncology in Bangabandhu Sheikh Mujib Medical University (BSMMU), Bangladesh for one year of period. The objective of this study is to assess the safety and efficacy of Thalidomide in TDT children 30 transfusion dependent thalassemia children of 3-18 years old will be included. This study will involve minimum physical risk to the patient. Written informed consent will be taken from parents or study subjects after brief explanation of the purpose and procedure. They will also be informed about the freedom to participate or not to participate at any time. Privacy and confidentiality will be safe guarded. History regarding age, sex, height, weight of these patients will be taken. Through physical examinations and laboratory investigations including complete blood count (CBC), Hb electrophoresis, serum Ferritin, serum creatinine, serum glutamic pyruvic transaminase (SGPT), serum lactate dehydrogenase (LDH) will be done. Data will be collected in a predesigned questionnaire and will be kept confidential. Statistical analysis will be done using the statistical package for social science (SPSS) software .

Detailed Description
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Study design: Quasi-randomized controlled tria Period of Study: From March 2023 to February 2023 Place of study: Department of Pediatric Hematology & Oncology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh. Study Population: TDT patients of either gender and 3-18 years of age attending in the Department of Pediatric Hematology and Oncology, Bangabandhu Sheikh Mujib Medical University, Dhaka and will receive Thalidomide during the study period. Sample size will be calculated by using following formula: ((u+v)^2 (σ₁²+σ₀²))/((μ₁-μ₀)²) Here, u = .842 (if power= 80%) v = 1.96 (if significance level= 5%) μ₀ (mean Hb level before treatment with Thalidomide) = 71 μ₁ (mean Hb level in after treatment with Thalidomide) = 95 σ₀ = assumed population standard deviation for Placebo group = 30 σ₁ = assumed population standard deviation for Thalidomide group = 30 Calculated sample size is: ((u+v)^2 (σ₁²+σ₀²))/((μ₁-μ₀)²) (1.96+0.842)2 ( 30² +30²)/ (24)2 = 24.5  25 Group sample sizes of 25 in each group, considering 10% drop out it may increase up to 30 as some cases may be lost to follow up during study period. So, sample size will be 30+30 = 60. Sampling technique: From the date of start of study, patient will be selected purposively by inclusion and exclusion criteria during the desired study period. The patients will be randomized 1:1 to receive placebo or thalidomide. Block or restricted randomization will be used to select the intervention group and control. All odd number patients (1,3,7…) will be considered as block & will be assigned to intervention group by lottery and then all even number patients (2,4,6…) will be assigned to the other group. Data collection procedure: This study will be conducted in the Department of Pediatric Hematology and Oncology, Bangabandhu Sheikh Mujib Medical University (BSMMU). Children aged 3 to 18 years of both sexes diagnosed as TDT visiting the hematology out patient department (OPD) between March 2023 to February 2024 will be included in this study. Informed written consent from the patients or parents or guardians will be obtained at the time of study enrollment. After recruitment, subjects will be randomly divided into two groups according to the Thalidomide therapy as follows: Experimental Group: Patients who will receive Thalidomide along with regular drugs. Control Group: Patients who will receive placebo with other regular drugs are considered as in the control group. Data will be collected using a preformed data collection sheet (questionnaire). Demographic data such as age, sex, socio-economic status, family history of thalassemia will be collected from guardian or parents. Medical data regarding age, sex, age at first transfusion, red cell transfusion in last 1 year will be compiled. Clinical information such as pallor, pulse, blood pressure, respiratory rate, spleen size and other systemic clinical parameters will be taken. Thalidomide and placebo will be given to randomly selected patients as per inclusion criteria attending in the outpatient department. The instruction will be given by the principal investigator according to study design. Patients diagnosed with transfusion-dependent thalassemia will be randomized to receive placebo or Thalidomide treatment at a dose of 2-5 mg/kg/day. The initial evaluation will be performed before the patients started Thalidomide. Patients will get transfusion with red blood cells at 10 ml/kg at any time during the study period if their Hb level < 70 g/L. The patients are followed up every 14 days for the first 12 weeks, and every 3 months thereafter. The efficacy will be evaluated after 12 weeks of treatment. Additionally, in patients with an obvious elevation in Hb who are free from blood transfusions for at least 6 weeks, the original treatment will be continuously administered for further evaluation. When the last patient is enrolled and completes their first 12 weeks of follow-up, the placebo-controlled period of the study will end. Each evaluation will be included in a data collection sheet that will record crucial information such as the evaluation number, age, sex, type of diagnosis, Hb level, transfusion requirement etc. All participants will be asked to report any adverse reactions and will be questioned about adverse events during study visit.

Official Title
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Safety & Efficacy of Thalidomide in Children With Transfusion Dependent Thalassemia: a Quasi Randomized Control Trial in a Tertiary Care Hospital in Bangladesh

Conditions
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Transfusion-dependent Thalassemia

Intervention / Treatment
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* Drug: Thalidomide Capsules
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients diagnosed as transfusion dependent thalassemia Age ranged from 3-18 years Blood transfusion for more than 1 year. Exclusion Criteria: Active systemic illness, Abnormal liver and kidney functions; Severe cardiopulmonary or cerebrovascular diseases; Recent fracture or recent major surgery Use of drugs that might affect Hb levels 3 months before enrollment; Any bleeding disorder .

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Thalidomide group<br>Thalidomide group | Drug: Thalidomide Capsules<br>* To see safety and efficacy of Thalidomide in Transfusion depended thalassemia<br>|
| Placebo Comparator: Placebo group<br>Placebo group | Drug: Placebo<br>* compare with Thalidomide<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| change in Hb level | gm/dl | 12 weeks after treatment initiation. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| blood transfusion volume | ml/kg | 3 months from initiation of treatment | 
| change in Hb F |  | 3 months after initiation of treatment |