Heart Arteries and Sickle Cell Disease / Coeur Artères DREpanocytose (CADRE)

Heart, Arteries and Sikle Cell Disease, a Multicentric Cohort of Cardiovascular Complications in Subsaharan Africa

The CADRE study is a multinational observational cohort of patients with sickle-cell disease (SCD) in five west and central sub-Saharan African countries. The aim of this project is to describe the incidence and assess the predictive factors of SCD-related micro- and macro-vascular complications in sub-Saharan Africa.

Study Overview

• Status: Unknown
• Conditions: Sickle Cell Disease; Sickle Cell Anemia

Detailed Description

Sickle cell disease (SCD), one of the lost common genetic diseases worldwide, is caused by a mutation in the β globin gene. Most patients with this disease are homozygous for the βS allele (SS), whereas others have inherited a βS allele with another mutation in the β globin gene. In addition to repeated acute ischemic insults due to the red blood cells sickling in the microcirculation, a chronic vasculopathy leads to organ injuries, such as kidney disease, stroke, pulmonary hypertension, retinopathy, bone infarcts, and leg ulcers.

CADRE is a multinational prospective observational study undertaken in five countries in sub-Saharan Africa. Patients with SCD will be recruited through outpatients' clinics in public, university and private hospitals and research centers in five countries. The CADRE protocol was approved by the relevant national ethics committee in each of the participating countries.

Primary endpoint is to measure the prevalence and the incidence of the main vascular complications in the main types of SCD: glomerulopathy, nephropathy, cardiopathy, pulmonary hypertension, retinopathy, strokes, osteonecrosis and leg ulcers.

Secondary endpoints are:

• to define the clinical and biological predictors of SCD vasculopathy in Africa
• to search for genetic risk factors for the SCD-related cardiovascular complications, in particular alpha thalassemia, persistence of foetal hemoglobin and other candidate genetic polymorphisms
• to search for functional risk factors (pulse wave velocity, capillary vasodilatation, blood visosity) for the SCD-related cardiovascular complications
• to search for new biological determinant of SCD-related cardiovascular complications, in particular alternative markers of hemolysis (microparticules, free heme) and inflammation (cytokines, leucocytes phenotyping, NET (neutrophile extracellular traps))

• Study Type: Observational
• Enrollment (Anticipated): 4500

Contacts and Locations

• Study Contact: Name: Brigitte Ranque, MD PhD; Email: brigitte.ranque@aphp.fr
• Study Contact Backup: Name: Louise Boyer-Chatenet, MS; Phone Number: +33156093656; Email: louise.boyer-chatenet-ext@aphp.fr

Study Locations

• Cameroon
  • Yaounde, Cameroon
    • Recruiting
    • Central Hospital of Yaounde
    • Contact: Françoise Ngo Sacks, MD
    • Principal Investigator: Samuel Kingue, MD
    • Sub-Investigator: Françoise Ngo Sacks, MD
  • Yaounde, Cameroon
    • Recruiting
    • Centre mère et enfant / fondation Chantal Biya
    • Contact: David Chelo, MD
    • Principal Investigator: David Chelo, MD
    • Sub-Investigator: Anasthasie Alima, MD
  • Yaounde, Cameroon
    • Recruiting
    • Centre Pasteur du Cameroun
    • Contact: Suzanne Belinga, MD
    • Principal Investigator: Suzanne Belinga, MD
  • Yaounde, Cameroon
    • Recruiting
    • Pediatrics unit, Centre Hospitalier d'Essos
    • Contact: guillaume Wamba, MD
    • Principal Investigator: Guillaume Wamba, MD
• Congo, The Democratic Republic of the
  • Kinshasa, Congo, The Democratic Republic of the
    • Recruiting
    • Centre Hospitalier Monkole
    • Principal Investigator: Leon Tshilolo, MD
• Côte D'Ivoire
  • Abidjan, Côte D'Ivoire
    • Recruiting
    • Hematology Unit, CHU Yopougon
    • Contact: Aissata Tolo, MD
    • Principal Investigator: Aissata Tolo, MD
    • Sub-Investigator: Kouakou Boidy, MD
  • Abidjan, Côte D'Ivoire
    • Active, not recruiting
    • Institut de Cardiologie
• Gabon
  • Libreville, Gabon
    • Completed
    • CIRMF
• Mali
  • Bamako, Mali
    • Active, not recruiting
    • Cardiology Unit, Centre gyneco-obstretrique
  • Bamako, Mali
    • Recruiting
    • Centre de Recherche et de Lutte contre la Drepanocytose
    • Contact: Dapa Diallo, MD
    • Principal Investigator: Dapa Diallo, MD
    • Sub-Investigator: Karim Dembele, MD
• Senegal
  • Dakar, Senegal
    • Recruiting
    • Centre hospitalier d'enfants Albert Royer
    • Contact: Ibrahima Diagne, MD
    • Principal Investigator: Ibrahima Diagne, MD
    • Sub-Investigator: Indou Deme-Ly, MD
  • Dakar, Senegal
    • Recruiting
    • Centre hospitalo-universotaire de Fann, Cardiology department
    • Contact: Bara Diop, MD
    • Principal Investigator: Bara Diop, MD
  • Dakar, Senegal
    • Recruiting
    • Centre National de Transfusion Sanguine
    • Contact: Saliou Diop, MD
    • Principal Investigator: Saliou Diop, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 years and older (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Children and adult patients with the sickle cell disease living in subSaharan Africa

Description

Inclusion Criteria:

• age: five-year-old or more
• signature of informed consent Patients : major sickle cell syndrome confirmed by hemoglobin phenotyping: SS, SC, SBeta+ or Sbeta0 Controls : healthy parents or siblings of the patients, hospital staff or their children, matched on age+/- 3 years and country (1 control for 4 patients)

Exclusion Criteria:

unstable clinical status such as:

• vaso-occlusive crisis in the previous 15 days
• fever or infectious disease in the previous 15 days
• transfusion in the previous 2 months

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
sickle cell patients; age: five-year-old or more; major sickle cell syndrome confirmed by hemoglobin phenotype: SS, SC, SBeta+ or Sbeta0; steady state defined as the absence of vaso-occlusive crisis for the previous 15 days, absence of fever or infectious disease for the previous 8 days and absence of transfusion for the previous 2 months
control patients; volunteer parents or siblings of sickle cell patients; hospital staff or their children matched on country and age +/- 3 ans with the patients

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Prevalence and 10 year-incidence of SCD-related vascular complications in different phenotypes of SCD: glomerulopathy	urinary albumin/creatinin ratio (mg/g)	10 years
Prevalence and 10 year-incidence of SCD-related vascular complications in different phenotypes of SCD: cardiopathy	left ventricular ejection fraction < 60 %	10 years
Prevalence and 10 year-incidence of SCD-related vascular complications in different phenotypes of SCD: pulmonary hypertension	tricuspid regurgitation jet velocity (m/s)	10 years
Prevalence and incidence and the 10 year-incidence of the main SCD-related vascular complications in different phenotypes of SCD: retinopathy	retinal examination	10 years
Prevalence and 10 year-incidence of SCD-related vascular complications in different phenotypes of SCD:stroke	clinical diagnosis	10 years
Prevalence and 10 year-incidence of SCD-related vascular complications in different phenotypes of SCD:osteonecrosis	standard radiography	10 years
Prevalence and 10 year-incidence of SCD-related vascular complications in different phenotypes of SCD: leg ulcers	clinical diagnosis	10 years
Prevalence and 10 year-incidence of SCD-related vascular complications in different phenotypes of SCD: priapism	clinical diagnosis	10 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Potential biological risk marker measured at baseline and follow up visits: carotid-femoral pulse wave velocity	measured by Pulsepen, m/s)	10 years
Potential biological risk marker measured at baseline and follow up visits: complete blood count		10 years
Potential biological risk marker measured at baseline and follow up visits: LDH level		10 years
Potential biological risk marker measured at baseline and follow up visits: bilirubin level		10 years
Potential biological risk marker measured at baseline and follow up visits: microparticules measure		10 years
Potential biological risk marker measured at baseline and follow up visits: free heme level		10 years
Potential biological risk marker measured at baseline and follow up visits: inflammatory cytokines		10 years
Potential biological risk marker measured at baseline and follow up visits: neutrophil extracellular traps		10 years

Collaborators and Investigators

• Sponsor: Cardiologie et Développement
• Collaborators: Institut National de la Santé Et de la Recherche Médicale, France; University of Paris 5 - Rene Descartes; laboratory of excellence GR-Ex
• Investigators: Principal Investigator: Xavier Jouven, MD PhD, Cardiologie et Developpement

Publications and helpful links

General Publications

• Kato GJ, Gladwin MT, Steinberg MH. Deconstructing sickle cell disease: reappraisal of the role of hemolysis in the development of clinical subphenotypes. Blood Rev. 2007 Jan;21(1):37-47. doi: 10.1016/j.blre.2006.07.001. Epub 2006 Nov 7.
• Hebbel RP. Reconstructing sickle cell disease: a data-based analysis of the "hyperhemolysis paradigm" for pulmonary hypertension from the perspective of evidence-based medicine. Am J Hematol. 2011 Feb;86(2):123-54. doi: 10.1002/ajh.21952.
• Nouraie M, Lee JS, Zhang Y, Kanias T, Zhao X, Xiong Z, Oriss TB, Zeng Q, Kato GJ, Gibbs JS, Hildesheim ME, Sachdev V, Barst RJ, Machado RF, Hassell KL, Little JA, Schraufnagel DE, Krishnamurti L, Novelli E, Girgis RE, Morris CR, Rosenzweig EB, Badesch DB, Lanzkron S, Castro OL, Goldsmith JC, Gordeuk VR, Gladwin MT; Walk-PHASST Investigators and Patients. The relationship between the severity of hemolysis, clinical manifestations and risk of death in 415 patients with sickle cell anemia in the US and Europe. Haematologica. 2013 Mar;98(3):464-72. doi: 10.3324/haematol.2012.068965. Epub 2012 Sep 14.
• Gordeuk VR, Minniti CP, Nouraie M, Campbell AD, Rana SR, Luchtman-Jones L, Sable C, Dham N, Ensing G, Prchal JT, Kato GJ, Gladwin MT, Castro OL. Elevated tricuspid regurgitation velocity and decline in exercise capacity over 22 months of follow up in children and adolescents with sickle cell anemia. Haematologica. 2011 Jan;96(1):33-40. doi: 10.3324/haematol.2010.030767. Epub 2010 Sep 30.
• Maier-Redelsperger M, Levy P, Lionnet F, Stankovic K, Haymann JP, Lefevre G, Avellino V, Perol JP, Girot R, Elion J. Strong association between a new marker of hemolysis and glomerulopathy in sickle cell anemia. Blood Cells Mol Dis. 2010 Dec 15;45(4):289-92. doi: 10.1016/j.bcmd.2010.08.001. Epub 2010 Sep 15.
• Taylor JG 6th, Nolan VG, Mendelsohn L, Kato GJ, Gladwin MT, Steinberg MH. Chronic hyper-hemolysis in sickle cell anemia: association of vascular complications and mortality with less frequent vasoocclusive pain. PLoS One. 2008 May 7;3(5):e2095. doi: 10.1371/journal.pone.0002095.
• Gladwin MT, Sachdev V, Jison ML, Shizukuda Y, Plehn JF, Minter K, Brown B, Coles WA, Nichols JS, Ernst I, Hunter LA, Blackwelder WC, Schechter AN, Rodgers GP, Castro O, Ognibene FP. Pulmonary hypertension as a risk factor for death in patients with sickle cell disease. N Engl J Med. 2004 Feb 26;350(9):886-95. doi: 10.1056/NEJMoa035477.
• Kato GJ, McGowan V, Machado RF, Little JA, Taylor J 6th, Morris CR, Nichols JS, Wang X, Poljakovic M, Morris SM Jr, Gladwin MT. Lactate dehydrogenase as a biomarker of hemolysis-associated nitric oxide resistance, priapism, leg ulceration, pulmonary hypertension, and death in patients with sickle cell disease. Blood. 2006 Mar 15;107(6):2279-85. doi: 10.1182/blood-2005-06-2373. Epub 2005 Nov 15.
• Connes P, Lamarre Y, Hardy-Dessources MD, Lemonne N, Waltz X, Mougenel D, Mukisi-Mukaza M, Lalanne-Mistrih ML, Tarer V, Tressieres B, Etienne-Julan M, Romana M. Decreased hematocrit-to-viscosity ratio and increased lactate dehydrogenase level in patients with sickle cell anemia and recurrent leg ulcers. PLoS One. 2013 Nov 4;8(11):e79680. doi: 10.1371/journal.pone.0079680. eCollection 2013.
• Nolan VG, Wyszynski DF, Farrer LA, Steinberg MH. Hemolysis-associated priapism in sickle cell disease. Blood. 2005 Nov 1;106(9):3264-7. doi: 10.1182/blood-2005-04-1594. Epub 2005 Jun 28.
• Kato GJ, Hsieh M, Machado R, Taylor J 6th, Little J, Butman JA, Lehky T, Tisdale J, Gladwin MT. Cerebrovascular disease associated with sickle cell pulmonary hypertension. Am J Hematol. 2006 Jul;81(7):503-10. doi: 10.1002/ajh.20642.
• Steinberg MH, Sebastiani P. Genetic modifiers of sickle cell disease. Am J Hematol. 2012 Aug;87(8):795-803. doi: 10.1002/ajh.23232. Epub 2012 May 28.
• Ranque B, Menet A, Boutouyrie P, Diop IB, Kingue S, Diarra M, N'Guetta R, Diallo D, Diop S, Diagne I, Sanogo I, Tolo A, Chelo D, Wamba G, Gonzalez JP, Abough'elie C, Diakite CO, Traore Y, Legueun G, Deme-Ly I, Faye BF, Seck M, Kouakou B, Kamara I, Le Jeune S, Jouven X. Arterial Stiffness Impairment in Sickle Cell Disease Associated With Chronic Vascular Complications: The Multinational African CADRE Study. Circulation. 2016 Sep 27;134(13):923-33. doi: 10.1161/CIRCULATIONAHA.115.021015. Epub 2016 Aug 31.
• Ranque B, Menet A, Diop IB, Thiam MM, Diallo D, Diop S, Diagne I, Sanogo I, Kingue S, Chelo D, Wamba G, Diarra M, Anzouan JB, N'Guetta R, Diakite CO, Traore Y, Legueun G, Deme-Ly I, Belinga S, Boidy K, Kamara I, Tharaux PL, Jouven X. Early renal damage in patients with sickle cell disease in sub-Saharan Africa: a multinational, prospective, cross-sectional study. Lancet Haematol. 2014 Nov;1(2):e64-73. doi: 10.1016/S2352-3026(14)00007-6. Epub 2014 Oct 28.
• Dembele AK, Lapoumeroulie C, Diaw M, Tessougue O, Offredo L, Diallo DA, Diop S, Elion J, Colin-Aronovicz Y, Tharaux PL, Jouven X, Romana M, Ranque B, Le Van Kim C. Cell-derived microparticles and sickle cell disease chronic vasculopathy in sub-Saharan Africa: A multinational study. Br J Haematol. 2021 Feb;192(3):634-642. doi: 10.1111/bjh.17242. Epub 2020 Nov 29.

Study record dates

Study Major Dates

• Study Start (ACTUAL): March 1, 2012
• Primary Completion (ANTICIPATED): December 1, 2020
• Study Completion (ANTICIPATED): December 1, 2022

Study Registration Dates

• First Submitted: March 30, 2017
• First Submitted That Met QC Criteria: April 10, 2017
• First Posted (ACTUAL): April 14, 2017

Study Record Updates

• Last Update Posted (ACTUAL): May 25, 2018
• Last Update Submitted That Met QC Criteria: May 24, 2018
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Keywords: Pulmonary hypertension; Sickle Cell Disease; Sub-Saharan Africa; pulse wave velocity; hemolysis; Nephropathy; Vasculopathy; blood viscosity; cardiac disease
• Additional Relevant MeSH Terms: Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Anemia, Sickle Cell
• Other Study ID Numbers: 002 (University of CT Health Center)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No