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Substudy of CADRE: for People With Extreme Phenotype: BIOCADRE (BIOCADRE)

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ClinicalTrials.gov Identifier: NCT03352986
Recruitment Status : Recruiting
First Posted : November 24, 2017
Last Update Posted : November 24, 2017
Sponsor:
Collaborator:
Institut National de la Santé Et de la Recherche Médicale, France
Information provided by (Responsible Party):
Cardiologie et Développement

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

Condition or disease Intervention/treatment
Sickle Cell Disease Biological: biological analysis Other: peripheral arterial tonometry

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.


Study Type : Observational
Estimated Enrollment : 300 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: A Substudy of the CADRE Study: Determination of Clinical Markers in Patients With Extreme Sickle Cell Disease Phenotype
Actual Study Start Date : May 15, 2017
Estimated Primary Completion Date : June 2019
Estimated Study Completion Date : December 2019

Resource links provided by the National Library of Medicine


Group/Cohort Intervention/treatment
osteonecrosis
Sickle cell patients with osteonecrosis as a vascular main complication
Biological: biological analysis
biological analysis will be performed in the 6 groups of patients

Other: peripheral arterial tonometry
peripheral arterial tonometry will be performed in the 6 groups of patients

leg ulcer
Sickle cell patients with leg ulcer as a vascular main complication
Biological: biological analysis
biological analysis will be performed in the 6 groups of patients

Other: peripheral arterial tonometry
peripheral arterial tonometry will be performed in the 6 groups of patients

microalbuminuria
Sickle cell patients with microalbuminuria as a vascular main complication
Biological: biological analysis
biological analysis will be performed in the 6 groups of patients

Other: peripheral arterial tonometry
peripheral arterial tonometry will be performed in the 6 groups of patients

pulmonary hypertension
Sickle cell patients with pulmonary hypertension as a vascular main complication
Biological: biological analysis
biological analysis will be performed in the 6 groups of patients

Other: peripheral arterial tonometry
peripheral arterial tonometry will be performed in the 6 groups of patients

stroke
Sickle cell patients with strocke as a vascular main complication
Biological: biological analysis
biological analysis will be performed in the 6 groups of patients

Other: peripheral arterial tonometry
peripheral arterial tonometry will be performed in the 6 groups of patients

priapism
Sickle cell patients with priapism as a vascular main complication
Biological: biological analysis
biological analysis will be performed in the 6 groups of patients

Other: peripheral arterial tonometry
peripheral arterial tonometry will be performed in the 6 groups of patients




Primary Outcome Measures :
  1. Description of microcirculation by peripheral arterial tonometry [ Time Frame: 1 year ]
    EndoPAT2000®, Itamar Medical Ltd,


Secondary Outcome Measures :
  1. Measure of blood viscosities [ Time Frame: 1 year ]
    In whole blood by viscosimeter

  2. Dosage of microparticles [ Time Frame: 1 year ]
    In plasma: microparticles of erythrocytic, platelet, monocytic, neutrophilic and endothelial origin by flow cytometry

  3. Determination of free hemoglobin [ Time Frame: 1 year ]
    In plasma

  4. Measurement of neutrophil extracellular trap (NET) [ Time Frame: 1 year ]
    In plasma

  5. Measurement of proinflammatory cytokines by ELISA [ Time Frame: 1 year ]
    In plasma by ELISA

  6. Genotyping of the alpha-globin gene associated with persistence of fetal hemoglobin [ Time Frame: 1 year ]
    In saliva DNA

  7. Genotyping of the polymorphisms associated with persistence of fetal hemoglobin [ Time Frame: 1 year ]
    In saliva DNA


Biospecimen Retention:   Samples With DNA
3 ml of saliva for DNA extraction (sample with DNA) and 2 ml of plasma (sample with no DNA) are taken.


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Ages Eligible for Study:   10 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Sampling Method:   Non-Probability Sample
Study Population
The study population is sickle cell patients with extreme phenotypes (SS-hemoglobin) with a steady state.
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03352986


Contacts
Contact: Brigitte Ranque, MD 0156092772 brigitte.ranque@aphp.fr

Locations
Mali
Centre de Recherches er de Lutte contre la Drépanocytose Recruiting
Bamako, Mali
Contact: Dapa Diallo, MD    0022320223898    da.diallo@laposte.net   
Principal Investigator: Dapa Diallo, MD         
Senegal
Centre National de Transfusion Sanguine Recruiting
Dakar, Senegal
Contact: Saliou Diop, MD    (221) 33 869 86 60    saliou.diop@ucad.edu.sn   
Principal Investigator: Saliou Diop, MD         
Sponsors and Collaborators
Cardiologie et Développement
Institut National de la Santé Et de la Recherche Médicale, France
Investigators
Principal Investigator: Brigitte Ranque, MD Institut National de la Santé Et de la Recherche Médicale, France

Publications:

Responsible Party: Cardiologie et Développement
ClinicalTrials.gov Identifier: NCT03352986     History of Changes
Other Study ID Numbers: 003
First Posted: November 24, 2017    Key Record Dates
Last Update Posted: November 24, 2017
Last Verified: November 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Cardiologie et Développement:
Sickle cell disease
anemia
Africa

Additional relevant MeSH terms:
Anemia, Sickle Cell
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hematologic Diseases
Hemoglobinopathies
Genetic Diseases, Inborn