Clinical trial NCT03352986: Substudy of CADRE: for People With Extreme Phenotype: BIOCADRE
Official title: A Substudy of the CADRE Study: Determination of Clinical Markers in Patients With Extreme Sickle Cell Disease Phenotype
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Sickle Cell Disease
Keywords: Sickle cell disease
anemia
Africa
Lead sponsor: Cardiologie et Développement
Sponsor class: OTHER
Collaborators: name: Institut National de la Santé Et de la Recherche Médicale, France
First posted: 2017-11-24
Enrollment: 300
Sex: ALL
Minimum age (years): 10
Standard ages: CHILD
ADULT
OLDER_ADULT
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: The study population is sickle cell patients with extreme phenotypes (SS-hemoglobin) with a steady state.

Brief summary: BIOCADRE is a CADRE substudy and aims to characterize more precisely the sickle cell patients with extreme phenotype.

Detailed description: Sickle cell disease (SCD) is the most frequent monogenic disease in the world, due to a unique mutation on the β-globin gene. Most affected individuals live in sub-Saharan Africa, yet, the natural history of the disease in Africa remains largely unknown. SCD usually presents in childhood and is characterized by the association of a chronic hemolytic anemia with episodes of acute vaso-occlusive events and progressive vascular organ damage. SCD is now widely recognized as a vascular disease with marked endothelial dysfunction. Hemolysis probably plays a key role by reducing NO bioavailability, but other involved mechanisms are not fully understood.

The project aims at better understanding SCD chronic vascular complications and in particular to explore extensively the different mechanisms associated with hemolysis. This will be addressed through both an epidemiological approach and a hypotheses-driven pathophysiological approach. On the one hand, a descriptive and analytic epidemiological study will isolate clusters of clinical, functional and usual biological phenotypes in SCD patients and look for new mechanistic and biological markers predictive of chronic vascular complications in SCD with SS phenotype. Investigators will specifically investigate i) microcirculation functions using peripheral arterial tonometry, ii) blood and plasma viscosities, iii) level of plasma blood cell derived microparticles, free hemoglobin, and the free heme content of erythrocytes-derived microparticles and expression of Duffy erythrocyte antigen, the unique erythroid receptor for chemokines. One the other hand, investigators will test novel markers and modifiers of hemolysis and heme metabolism and assess their relationship with inflammation and vascular phenotypes.These different biomarkers will be compared between the selected subgroups of patients with extreme vascular phenotype.

Methods: The project involves a transversal case control study, nested in the CADRE cohort, recently built up by Partner 1 and African collaborators. CADRE is the largest ongoing epidemiological cohort, including 4,300 SCD patients and 1,000 controls in five west and central African countries, in which various chronic complications of SCD have already been registered. The present second phase study will be conducted in the centres of Dakar and Bamako. Patients' selection will be performed in the existing database to obtain 6 subgroups of 40 SS patients with one of the main vascular chronic complications or none of them, for a total of 240 patients. Selected patients will be recalled during one year in parallel in the 2 recruiting centres. Clinical phenotyping, usual biology, functional microvascular functions (peripheral arterial tonometry), and blood/plasma viscosities analyses will be performed in the African recruiting centres after training of technicians, PhD and MD students by the French partners. Plasma samples, microparticles and extracellular DNA, will be prepared and frozen for further analyses in the partner's laboratories. DNA will be collected for each subject. A principal component analysis will isolate clusters of clinical complications, functional and biological markers and a multivariate logistic regression will quantify the effect of these markers on the risk of vasculopathy, with adjustment on all known SCD modifying factors.

Expected results: 1) The identification of high risk SCD patients for chronic vascular complications using new biomarkers, 2) A better understanding of chronic vascular disease process at the mechanistic and biological (viscosity, hemolysis, erythrocyte derived microparticles, inflammatory cytokines and receptors) levels, 3) The identification of endophenotypes and constitution of DNA bank for further genetic studies.

Eligibility criteria: Inclusion Criteria:

* sickle cell patients with extreme phenotypes: SS-hemoglobin

Exclusion Criteria:

* transfusion in the previous 2 months
* vaso-occlusive crisis in the previous 15 days
* infection in the previous 8 days

Primary outcomes:
measure: Description of microcirculation by peripheral arterial tonometry
timeFrame: 1 year
Secondary outcomes:
measure: Measure of blood viscosities
timeFrame: 1 year
measure: Dosage of microparticles
timeFrame: 1 year
measure: Determination of free hemoglobin
timeFrame: 1 year
measure: Measurement of neutrophil extracellular trap (NET)
timeFrame: 1 year
measure: Measurement of proinflammatory cytokines by ELISA
timeFrame: 1 year
measure: Genotyping of the alpha-globin gene associated with persistence of fetal hemoglobin
timeFrame: 1 year
measure: Genotyping of the polymorphisms associated with persistence of fetal hemoglobin
timeFrame: 1 year
Other outcomes:
Locations:
city: Bamako
country: Mali
facility: Centre de Recherches er de Lutte contre la Drépanocytose
city: Dakar
country: Senegal
facility: Centre National de Transfusion Sanguine
Study officials:
affiliation: Institut National de la Santé Et de la Recherche Médicale, France
name: Brigitte Ranque, MD
role: PRINCIPAL_INVESTIGATOR
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