Ignite Creation Date:
2024-05-06 @ 7:48 PM
Last Modification Date:
2024-10-26 @ 3:14 PM
Study NCT ID:
NCT06146478
Status:
COMPLETED
Last Update Posted:
2023-11-24
First Post:
2023-11-19
Brief Title:
Deciphering Effects of Thalidomide on Red Blood Cells in Transfusion Dependents Beta Thalassemia Patients
Sponsor:
Blood Care Clinic
Organization:
Blood Care Clinic
Study Overview
Official Title:
Deciphering Effects of Thalidomide on Red Blood Cells in Transfusion Dependents Beta Thalassemia Patients A Pharmacodynamics and Pharmacogenetics Analysis
Status:
COMPLETED
Status Verified Date:
2023-11
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
The goal of this Non-Randomized Clinical Trial is to determine the effects of thalidomide on red blood cells in transfusion dependent beta thalassemia patients The main aims of this study are
To determine the therapeutic effect of Thalidomide on hemoglobin
To analyze association of different β- globin mutations with response to thalidomide in β-thalassemia patients
To analyze association of Single Nucleotide Polymorphisms SNPS of HBG2 BCL11A and HBS1L-MYB with response to thalidomide in β-thalassemia patients
To correlate GATA1 and KLF1 gene expression with response to thalidomide in β-thalassemia patients
Patients will be grouped into thalidomide and non-thalidomide groups on the basis of their willingness to receive thalidomide therapy Thalidomide will be given at an average dose of 15mgkgday range 1-2mgkgday Patients will be followed up for 12 months and data will be collected at different visits After 12 months of thalidomide therapy patients will be divided into responders and non-responders for comparative analyses on the basis of increase in hemoglobin level
To determine the therapeutic effect of Thalidomide on hemoglobin
To analyze association of different β- globin mutations with response to thalidomide in β-thalassemia patients
To analyze association of Single Nucleotide Polymorphisms SNPS of HBG2 BCL11A and HBS1L-MYB with response to thalidomide in β-thalassemia patients
To correlate GATA1 and KLF1 gene expression with response to thalidomide in β-thalassemia patients
Patients will be grouped into thalidomide and non-thalidomide groups on the basis of their willingness to receive thalidomide therapy Thalidomide will be given at an average dose of 15mgkgday range 1-2mgkgday Patients will be followed up for 12 months and data will be collected at different visits After 12 months of thalidomide therapy patients will be divided into responders and non-responders for comparative analyses on the basis of increase in hemoglobin level
Detailed Description:
Thalassemias are a group of genetic disorder of hemoglobin synthesis characterized by a decreased synthesis of globin chain Thalassemias are classified as α-β- γ-or δ-thalassemias depending upon the chain whose synthesis is reduced Among these β-thalassemia is more common In β-thalassemia there is a decreased or absent hemoglobin A HbA Normal adult hemoglobin is primarily HbA which represents approximately 98 of circulating hemoglobin HbA is formed from 2 α and 2 β chains α2β2 Combination of 2 α and 2 δ α2δ2 form hemoglobin A2 HbA2 Combination of 2 α and 2 γ α2γ2 form hemoglobin F HbF which is a major form of hemoglobin in fetal life but comprises less than 1 of adult hemoglobin Human beta-globin protein is encoded by HBB gene on chromosome 11 which contributes two β polypeptide chains Therefore one chain is inherited from the mother and one inherited from the father In normal homozygote both genes are normal and produce normal β polypeptide chains to normal quantity In heterozygote one gene is normal and other is abnormal which does not produce β polypeptide chain Such condition is called β-thalassemia minor In such a person normal gene produces enough β chain to maintain hemoglobin level In abnormal homozygote both beta chain genes are abnormal and do not produce β polypeptide chain Such condition is called β-thalassemia major Reduced or absent production of β-globin chains with relative excess of α-chains cause imbalance and free α chains precipitate within the red blood cells This result in extensive premature destruction of red cell precursors in the bone marrow referred to as ineffective erythropoiesis The imbalance causes peripheral hemolysis as well The two phenomena culminate in clinically significant anemia
Severity of anemia due to β-thalassemia depends upon the type of mutations in β-globin gene Mostly point mutations and frame shift mutations in intronic as well exonic region are reported in Pakistani β-thalassemia patients Some mutations completely block the β-gene and thus no β globin chain is produced βo while in other mutations there is production of some β globin chains β In β-thalassemia major both β globin alleles undergo mutations βoβo and disease is severe In β-thalassemia minor only one of β globin alleles are mutated ββ or βoβ and patient is asymptomatic β-thalassemia intermedia ββ or βoβ is the form of disease which is milder than thalassemia major but more severe than thalassemia minor Besides less severe β mutations inheritance of HbF inducing genetic variations and co-inheritance of alpha globin mutations can also ameliorate the clinical severity of the disease In regards to HbF induction genetic association studies have shown that there are at least three major loci that play a major role in increasing HbF and are associated with severity of β-thalassemia These include -158 C T in the promoter gene Gamma 2 locus XmnI intergenic regions HBS1L-MYB in the 6q233 chromosomal region and the BCL11A gene on chromosome 2p161
Annually about 60000 babies are born with thalassemia all over the world Global annual incidence of β-thalassemia is estimated at a rate of 1100000 Carrier rate for β-thalassemia in Pakistan ranges between 5-8 and around 5000 children are diagnosed each year with the disease
Severe anemia in β-thalassemia patients necessitates frequent transfusions which lead to iron overload Chronic anemia and iron overload lead to several complications including skeletal deformities splenomegaly osteoporosis endocrinopathies growth retardation and cardiac complications Iron overload is treated with iron chelating agents Definitive treatment is bone marrow transplantation 9Thalassemia patients who do not respond well to blood transfusions can take hydroxyurea or thalidomide and sometimes a combination of both
Thalidomide an immuno-modulatory drug is currently approved by FDA for the treatment of multiple myeloma and Leprosy Thalidomide is used off-label for the treatment of β-thalassemia patients worldwide Thalidomide has been reported to reduce or even eliminate the need for red blood cell transfusions in patients with transfusion dependent β-thalassemia Although association of β globin gene mutations and genetic modifiers with severity of β-thalassemia have been well studied but association of these genetic factors with response to thalidomide therapy still needs to be explored A study conducted on 48 Chinese patients showed association of Xmn1 HBG2 BCL11A HBSIL-MYB single nucleotide polymorphisms SNPs with response to thalidomide therapy
Improved terminal erythroid maturation and red blood cells stability are considered effective therapeutic approaches in the treatment of thalassemia GATA1 and KLF1 are important transcription factor in erythroid differentiation which play critical role in regulation of globin gene expression Studies reveal that increased expression of GATA1 and KLF1 causes induction of fetal hemoglobin HbF leading to reduced accumulation of α-globin chains in erythroid precursors and betterment of imbalance between α and β chains thus diminished ineffective erythropoiesis
The current study aims to determine the in-vivo effects of thalidomide on GATA1 KLF1 gene expression in transfusion dependent β-thalassemia patients Findings of the study will provide scientific evidence in support or against the off- label use of thalidomide in β-thalassemia patients Results of the study regarding association of β-globin mutations and Xmn1 HBG2 BCL11A HBSIL-MYB single nucleotide polymorphisms with response to thalidomide therapy will explain variation in inter-individual response to the drug and thus help in predicting response before starting thalidomide therapy
Severity of anemia due to β-thalassemia depends upon the type of mutations in β-globin gene Mostly point mutations and frame shift mutations in intronic as well exonic region are reported in Pakistani β-thalassemia patients Some mutations completely block the β-gene and thus no β globin chain is produced βo while in other mutations there is production of some β globin chains β In β-thalassemia major both β globin alleles undergo mutations βoβo and disease is severe In β-thalassemia minor only one of β globin alleles are mutated ββ or βoβ and patient is asymptomatic β-thalassemia intermedia ββ or βoβ is the form of disease which is milder than thalassemia major but more severe than thalassemia minor Besides less severe β mutations inheritance of HbF inducing genetic variations and co-inheritance of alpha globin mutations can also ameliorate the clinical severity of the disease In regards to HbF induction genetic association studies have shown that there are at least three major loci that play a major role in increasing HbF and are associated with severity of β-thalassemia These include -158 C T in the promoter gene Gamma 2 locus XmnI intergenic regions HBS1L-MYB in the 6q233 chromosomal region and the BCL11A gene on chromosome 2p161
Annually about 60000 babies are born with thalassemia all over the world Global annual incidence of β-thalassemia is estimated at a rate of 1100000 Carrier rate for β-thalassemia in Pakistan ranges between 5-8 and around 5000 children are diagnosed each year with the disease
Severe anemia in β-thalassemia patients necessitates frequent transfusions which lead to iron overload Chronic anemia and iron overload lead to several complications including skeletal deformities splenomegaly osteoporosis endocrinopathies growth retardation and cardiac complications Iron overload is treated with iron chelating agents Definitive treatment is bone marrow transplantation 9Thalassemia patients who do not respond well to blood transfusions can take hydroxyurea or thalidomide and sometimes a combination of both
Thalidomide an immuno-modulatory drug is currently approved by FDA for the treatment of multiple myeloma and Leprosy Thalidomide is used off-label for the treatment of β-thalassemia patients worldwide Thalidomide has been reported to reduce or even eliminate the need for red blood cell transfusions in patients with transfusion dependent β-thalassemia Although association of β globin gene mutations and genetic modifiers with severity of β-thalassemia have been well studied but association of these genetic factors with response to thalidomide therapy still needs to be explored A study conducted on 48 Chinese patients showed association of Xmn1 HBG2 BCL11A HBSIL-MYB single nucleotide polymorphisms SNPs with response to thalidomide therapy
Improved terminal erythroid maturation and red blood cells stability are considered effective therapeutic approaches in the treatment of thalassemia GATA1 and KLF1 are important transcription factor in erythroid differentiation which play critical role in regulation of globin gene expression Studies reveal that increased expression of GATA1 and KLF1 causes induction of fetal hemoglobin HbF leading to reduced accumulation of α-globin chains in erythroid precursors and betterment of imbalance between α and β chains thus diminished ineffective erythropoiesis
The current study aims to determine the in-vivo effects of thalidomide on GATA1 KLF1 gene expression in transfusion dependent β-thalassemia patients Findings of the study will provide scientific evidence in support or against the off- label use of thalidomide in β-thalassemia patients Results of the study regarding association of β-globin mutations and Xmn1 HBG2 BCL11A HBSIL-MYB single nucleotide polymorphisms with response to thalidomide therapy will explain variation in inter-individual response to the drug and thus help in predicting response before starting thalidomide therapy
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None