Inflammatory Response to Hydroxyurea Therapy in Sickle Cell Disease

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier:
NCT00784082
First received: October 27, 2008
Last updated: January 30, 2013
Last verified: January 2013
  Purpose

In sickle cell disease (SCD), polymerisation of haemoglobin S and the resulting shape change of the red blood cells (RBC) lead to vascular occlusion and severe painful crises. Permanent inflammatory state and abnormal RBC adhesion to the endothelium trigger these phenomenon. Hydroxyurea (HU) is the only drug that has been shown to reduce clinical severity of SCD, and this was initially attributed to the stimulation of foetal haemoglobin (HbF). However, the clinical response does not correlate consistently with the degree and time of HbF increment, suggesting that HU clinical benefits may involve other mechanisms such as the induction of natural anti-inflammatory response via the hypothalami-pituitary-adrenal axis.


Condition Intervention
Sickle Cell Disease
Drug: Hydroxycarbamide, Hydroxyurea (drug)

Study Type: Observational
Official Title: Inflammatory Response to Hydroxyurea Therapy in Sickle Cell Disease

Resource links provided by NLM:


Further study details as provided by Assistance Publique - Hôpitaux de Paris:

Primary Outcome Measures:
  • Determination of plasma inflammatory markers [ Time Frame: Day 1 ] [ Designated as safety issue: No ]
    Determination of plasma inflammatory markers (RANTES, IL-6, IL-8, MCP-1, IL-1A, IL-1B, ET-1, IL-4, IL-10, TNF a,, IFN g) of hormones of the pituitary-adrenal (cortisol, ACTH) and hypothalamic peptides (AVP, CRH).


Secondary Outcome Measures:
  • Clinical data [ Time Frame: Day 1 ] [ Designated as safety issue: No ]
    Clinical data (age, sex of the patient and his parent or siblings, frequency of painful crises requiring hospitalization, measured / year in the three years prior to the study, frequency and causes acute anemic episodes, whether or not a hepatosplenomegaly)

  • Hematological at baseline [ Time Frame: Day 1 ] [ Designated as safety issue: No ]
    Hematological at baseline (Hb, reticulocytes, MCV, platelets, leukocytes, PN and monocytes, lymphocytes, erythroblasts, iron status)

  • Determination of HbF [ Time Frame: Day 1 ] [ Designated as safety issue: No ]
    Determination of HbF

  • Determination of markers of the "acute phase" [ Time Frame: Day 1 ] [ Designated as safety issue: No ]
    Determination of markers of the "acute phase": CRP and orosomucoid

  • Plasma concentrations [ Time Frame: Day 1 ] [ Designated as safety issue: No ]
    Plasma concentrations of HU just before taking HU (residual) and H2 after dosing.


Biospecimen Retention:   Samples With DNA

Sample with DNA


Enrollment: 62
Study Start Date: May 2009
Study Completion Date: November 2012
Primary Completion Date: October 2012 (Final data collection date for primary outcome measure)
Groups/Cohorts Assigned Interventions
Homozygous SS sickle cell children

Hydroxycarbamide, Hydroxyurea (drug):

  1. Homozygous SS sickle cell children, aged > 3 years, of sub-Saharian Africa extraction, in a steady-state of disease , taken no drug except penicillin-V, folate or iron supplementation, hydroxyurea, divided into three groups :

    • children treated with hydroxyurea 20-25 mg/kg/day since at least 3 months with clinical efficacy on vaso-occlusive events
    • untreated children with major vaso-occlusive events
    • children > 5 year-old without a history of vaso-occlusive events
  2. Controls : heterozygous AS parents or siblings of the patients, and AA siblings or healthy African unrelated subjects, aged > 3 years, taken no drug on the day of blood sampling.
Drug: Hydroxycarbamide, Hydroxyurea (drug)
hydroxyurea 20-25 mg/kg/day since at least 3 months
Other Name: Hydroxycarbamide, Hydroxyurea (drug)
Homozygous SS children

Hydroxycarbamide, Hydroxyurea (drug):

  1. Homozygous SS children, aged > 3 years, of sub-Saharian Africa extraction, in a steady-state of disease, taken no drug except penicillin-V, folate or iron supplementation, hydroxyurea, divided into three groups :

    • children treated with hydroxyurea 20-25 mg/kg/day since at least 3 months with clinical efficacy on vaso-occlusive events
    • untreated children with major vaso-occlusive events
    • children > 5 year-old without a history of vaso-occlusive events
  2. Controls : heterozygous AS parents or siblings of the patients, and AA siblings or healthy African unrelated subjects, aged > 3 years, taken no drug on the day of blood sampling.
Drug: Hydroxycarbamide, Hydroxyurea (drug)
hydroxyurea 20-25 mg/kg/day since at least 3 months
Other Name: Hydroxycarbamide, Hydroxyurea (drug)

Detailed Description:

Plasmatic proinflammatory molecules (C-reactive protein, orosomucoid, RANTES, IL-6, IL-8, MCP-1, IL-1A, IL-1B, ET-1, IL-4, IL-10, TNFalpha, IFNgamma), hormones from the hypothalami-pituitary-adrenal axis (cortisol, ACTH), and hypothalamic peptids (arginine vasopressin, corticotrophin-releasing hormone) will be measured from SCD children treated or not with HU (20 treated children, 20 untreated children with a history of vaso-occlusive events, 20 asymptomatic children, and 20 healthy African controls).

  Eligibility

Ages Eligible for Study:   3 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population

Homozygous SS sickle cell children, aged > 3 years, of sub-Saharian Africa heterozygous AS parents or siblings of the patients, and AA siblings or healthy African unrelated subjects, aged > 3 years

Criteria

INCLUSION CRITERIA:

  1. Homozygous SS sickle cell children, aged > 3 years, of sub-Saharian Africa extraction, in a steady-state of disease (free of any infectious or vaso-occlusive events for the 4 weeks prior to and 2 weeks after blood sampling, and transfusion-free for 4 months prior to blood sampling), taken no drug except penicillin-V, folate or iron supplementation, hydroxyurea, divided into three groups :

    • children treated with hydroxyurea 20-25 mg/kg/day since at least 3 months with clinical efficacy on vaso-occlusive events
    • untreated children with major vaso-occlusive events
    • children > 5 year-old without a history of vaso-occlusive events Signed informed consent obtained from the subjects (if possible) and their parents
  2. Controls : heterozygous AS parents or siblings of the patients, and AA siblings or healthy African unrelated subjects, aged > 3 years, taken no drug on the day of blood sampling.

Signed informed consent obtained from the subjects (if possible) and their parents

EXCLUSION CRITERIA:

  • Children in a acute-phase of the disease
  • Parent's or patient's refusal
  • Taking any drug except penicillin-V, folate or iron supplementation, hydroxyurea
  • Un-healthy control or taking drug
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00784082

Locations
France
Hopital Louis Mourier
Colombes, France, 92701
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Investigators
Principal Investigator: Marie-Hélène Odièvre, MD, PhD Assistance Publique - Hôpitaux de Paris
  More Information

No publications provided

Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT00784082     History of Changes
Other Study ID Numbers: P080102, 2008-005077-35
Study First Received: October 27, 2008
Last Updated: January 30, 2013
Health Authority: France: Ministry of Health

Keywords provided by Assistance Publique - Hôpitaux de Paris:
Sickle cell disease, hydroxyurea, inflammation

Additional relevant MeSH terms:
Anemia, Sickle Cell
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hematologic Diseases
Hemoglobinopathies
Genetic Diseases, Inborn
Hydroxyurea
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Antisickling Agents
Hematologic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Nucleic Acid Synthesis Inhibitors

ClinicalTrials.gov processed this record on July 20, 2014