Study of the Role of Genetic Modifiers in Hemoglobinopathies

Sickle Cell Disease Clinical Trial

— INHERENT  

Official title:

Study of the Role of Genetic Modifiers in Hemoglobinopathies

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05799118
• Other study ID #: 1
• Status: Recruiting
• Start date: October 1, 2022
• Est. completion date: September 30, 2027

Study information

• Verified date: March 2024
• Source: Cyprus Institute of Neurology and Genetics
• Contact: Petros Kountouris, PhD
• Phone: 22392623
• Email: admin[@]inherentnetwork.org
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

This study will investigate the role of genetic modifiers in hemoglobinopathies through a large-scale, multi-ethnic genome-wide association study (GWAS).

Description:

Hemoglobinopathies, including sickle cell disease (SCD) and beta-thalassemia, are prevalent diseases with variable clinical manifestation and severity that are thought to be governed, in part, by genetic modifiers. Despite the identification and characterization of a few putative genetic modifiers by previous studies, these are as yet insufficient to guide treatment recommendations or risk-stratify patients reliably. Also, it is expected that many additional genetic variants exist that can modify disease and its severity. This large-scale genome-wide association study (GWAS) will utilize SNP chips to investigate the genetic profile of individuals with hemoglobinopathies, thereby addressing the challenges of previous studies related to small sample sizes and low statistical power, while promoting the participation of diverse populations worldwide. The study aims to i) discover new genetic modifiers of hemoglobinopathies, ii) validate previously reported genetic modifiers, iii) pool and analyze existing genomic data, iv) standardize phenotypic descriptions, v) develop a research resource of disease-specific data generated in INHERENT, including genomic, phenotypic, and functional data, and vi) develop risk scores that can be used for patient stratification.

The main endpoints include:

1. Worldwide demography, including numbers of patients, main genotypes, and overall disease severity/burden in participating centres

2. Genetic modifiers affecting clinical or laboratory phenotypes of hemoglobinopathies, including

1. overall survival in SCD and/or thalassemia,

2. stroke and/or decreased neurocognitive function in SCD and/or thalassemia,

3. renal impairment in SCD and/or thalassemia,

4. leg ulcers in SCD,

5. priapism in SCD,

6. mild or severe acute pain and/or chronic pain syndromes in SCD,

7. pulmonary hypertension in SCD and/or thalassemia,

8. hyperhemolysis in SCD and/or thalassemia,

9. fetal hemoglobin levels,

10. degree of ineffective erythropoiesis,

11. hepatic fibrosis/cirrhosis and/or cardiac siderosis,

3. Genetic modifiers affecting response to treatment, including

1. response to hydroxyurea,

2. response to iron chelation treatment,

3. response to emerging therapeutic agents

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 30000
• Est. completion date: September 30, 2027
• Est. primary completion date: September 30, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years and older

Eligibility

Inclusion Criteria:

• Clinical diagnosis of an inherited hemoglobinopathy, including sickle cell disease (SCD), ß-thalassemia, and a-thalassemia; all genotypes will be considered.

• Age = 2 years old at the time of the collection of the phenotypic data.

• There will be no limits on study participants in terms of gender, ethnicity, morbidities.

Exclusion Criteria:

• Patients treated with stem cell transplantation or genetic therapy.

• Age < 2 years old at the time of the collection of the phenotypic data.

• Patient or legal representative for minors unwilling or unable to give consent.

Related Conditions & MeSH terms

• alpha-Thalassemia
• Anemia, Sickle Cell
• beta-Thalassemia
• Hemoglobinopathies
• Sickle Cell Disease
• Thalassemia
• Thalassemia Alpha
• Thalassemia, Beta

Intervention

Genetic:
• GWAS
The study will perform a GWAS experiments for all recruited subjects. The blood sample will be collected during routine clinical visits, only if DNA is not already available in existing biobanks. All individuals will provide consent for participation in the study.

Locations

Country	Name	City	State
Angola	Lucrecia Paím Maternity	Luanda
Argentina	University of Buenos Aires	Buenos Aires
Belgium	University Hospitals Leuven	Leuven
Brunei Darussalam	Universiti Brunei Darussalam	Brunei
Congo, The Democratic Republic of the	Centre Hospitalier Monkole	Kinshasa
Cyprus	Larnaca General Hospital	Larnaca
Cyprus	Limassol General Hospital	Limassol
Cyprus	Archbishop Makarios III Hospital	Nicosia
Cyprus	Paphos General Hospital	Paphos
Denmark	Rigshospitalet	Copenhagen
Greece	Hippokrateio Hospital of Athens	Athens
Greece	Laiko General Hospital	Athens
Greece	National and Kapodistrian University of Athens	Athens
Greece	General Hospital of Larissa	Larissa
Israel	Emek Medical Centre	Afula
Italy	University of Turin	Turin
Malaysia	Ampang Hospital	Ampang
Malaysia	Universiti Kebangsaan Malaysia	Bangi
Malaysia	Universiti Sains Malaysia	Kota Bharu
Nigeria	University of Abuja	Abuja
Nigeria	Kaduna State University	Kaduna
Nigeria	Ahmadu Bello University	Zaria
Pakistan	University of Lahore	Lahore
Portugal	Centro Hospitalar e Universitário de Coimbra	Coimbra
Spain	Hospital Clínico San Carlos	Madrid
United States	Boston Children's Hospital	Boston	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
Cyprus Institute of Neurology and Genetics

Countries where clinical trial is conducted

United States,  Angola,  Argentina,  Belgium,  Brunei Darussalam,  Congo, The Democratic Republic of the,  Cyprus,  Denmark,  Greece,  Israel,  Italy,  Malaysia,  Nigeria,  Pakistan,  Portugal,  Spain, 

References & Publications (1)

Kountouris P, Stephanou C, Archer N, Bonifazi F, Giannuzzi V, Kuo KHM, Maggio A, Makani J, Manu-Pereira MDM, Michailidou K, Nkya S, Nnodu OE, Trompeter S, Tshilolo L, Wonkam A, Zilfalil BA, Inusa BPD, Kleanthous M; on behalf of the International Hemoglobinopathy Research Network (INHERENT). The International Hemoglobinopathy Research Network (INHERENT): An international initiative to study the role of genetic modifiers in hemoglobinopathies. Am J Hematol. 2021 Nov 1;96(11):E416-E420. doi: 10.1002/ajh.26323. Epub 2021 Aug 30. No abstract available. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Genetic modifiers in haemoglobinopathies through GWAS	Number of genetic variants (SNPs) associated with disease-specific phenotypes	5 years

External Links

•   Official INHERENT website