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Optimizing Hydroxyurea Therapy in Children With SCA In Malaria Endemic Areas (NOHARM-MTD)

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ClinicalTrials.gov Identifier: NCT03128515
Recruitment Status : Completed
First Posted : April 25, 2017
Last Update Posted : February 20, 2020
Sponsor:
Collaborators:
Doris Duke Charitable Foundation
Makerere University
Mulago Hospital, Uganda
Children's Hospital Medical Center, Cincinnati
Information provided by (Responsible Party):
Chandy John, Indiana University

Brief Summary:

The Novel use Of Hydroxyurea in an African Region with Malaria (NOHARM) study is the first placebo-controlled randomized clinical trial of hydroxyurea treatment in a malaria endemic region. NOHARM has now achieved full enrollment; all children have completed the blinded portion of the protocol and are in the open-label study treatment portion.

This extension study of maximum tolerated dose (MTD), addresses the next critical set of questions about the optimal dosing and monitoring of hydroxyurea treatment for children with SCA in low-resource settings. By providing guidance about optimal hydroxyurea treatment, the NOHARM MTD Study will directly inform policies that can transform the health of African children living with SCA.


Condition or disease Intervention/treatment Phase
Sickle Cell Anemia Sickle Cell Disease Malaria Drug: Hydroxyurea Phase 3

Detailed Description:

All children enrolled in NOHARM received hydroxyurea treatment at a fixed daily dose of 20 mg/kg/day. This dose was selected as a likely safe dose, but does not escalate hydroxyurea to MTD as is commonly done in the US. Without this information, we cannot know whether hydroxyurea treatment at the MTD would be feasible (since it requires closer monitoring to avoid hematological toxicities), safe (since adverse events may be greater with MTD, risk of malaria may be altered by MTD, and risk of infections as a result of neutropenia could also be greater with MTD) or beneficial (MTD is associated with higher hemoglobin and fetal hemoglobin concentration).

In this extension MTD study of open-label hydroxyurea for children in NOHARM who complete the initial study, consented children will be randomized to either fixed-dose or MTD hydroxyurea treatment for a minimum of 24 months. If hydroxyurea treatment continues to prove safe and effective in this low-resource malaria endemic area, and an optimal dosing scheme is determined, then the long-term goal is for all study children to transition to hydroxyurea treatment provided through the Ugandan Ministry of Health. To provide for a smooth transition, we will continue all children at either MTD or fixed dose hydroxyurea until a common end date (November 2019), at which time all study participants will have received a minimum of 24 months of additional hydroxyurea (either MTD or fixed dose). Addmedica, the Paris-based pharmaceutical company that provides the current active drug and placebo for the NOHARM trial, has agreed to provide additional hydroxyurea for this MTD study at no cost to the study or the participants.

The Specific Aims of the NOHARM MTD proposal include two initiatives for participants who are currently enrolled in NOHARM:

Aim 1. To determine the safety and efficacy of maximum tolerated dose (MTD) vs. fixed dose (20 mg/kg/day) hydroxyurea treatment in children with SCA in a low-resource, malaria endemic setting. For safety, we will compare adverse events and severe adverse events, including hematologic toxicities. For efficacy, we will assess hemoglobin level, fetal hemoglobin percentage (% HbF), and incidence of vaso-occlusive events such as pain crisis and acute chest syndrome.

Aim 2. To compare the clinical outcomes of MTD vs. fixed dose hydroxyurea treatment in children with SCA in a low-resource, malaria endemic setting. Clinical outcomes assessed will include growth and malaria incidence over a 24-month follow-up period, and differences in renal, splenic, and cerebrovascular function between study entry and 24-month follow-up.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 187 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Optimizing Hydroxyurea Therapy in Children With Sickle Cell Anemia In Malaria Endemic Areas: The NOHARM Maximum Tolerated Dose (MTD) Study
Actual Study Start Date : July 26, 2017
Actual Primary Completion Date : April 7, 2019
Actual Study Completion Date : January 28, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Anemia Malaria
Drug Information available for: Hydroxyurea

Arm Intervention/treatment
Experimental: MTD Dose Escalation
Maximum tolerated dose of Hydroxyurea, 25-30 mg/kg/day
Drug: Hydroxyurea
Administered once a day in tablet form (100mg or scored 1000mg) for 24 months
Other Names:
  • Siklos
  • Hydroxycarbamide

Active Comparator: Fixed Dose
Fixed dose of Hydroxyurea, 20 mg/kg/day
Drug: Hydroxyurea
Administered once a day in tablet form (100mg or scored 1000mg) for 24 months
Other Names:
  • Siklos
  • Hydroxycarbamide




Primary Outcome Measures :
  1. Proportion of children with average hemoglobin ≥9.0 g/dL or average HbF ≥20% [ Time Frame: Over 24 month period on study drug ]
    Proportion of children who achieve either an average hemoglobin ≥9.0 g/dL or an average HbF ≥20% after 24 months on study drug


Secondary Outcome Measures :
  1. Clinical malaria incidence [ Time Frame: Over 24 month period on study drug ]
    Clinical malaria is defined as a history of fever or measured axillary temperature ≥37.5 degrees, plus Plasmodium species on blood smear.

  2. Vaso-occlusive crises [ Time Frame: Over 24 month period on study drug ]

    SCA-related adverse events defined as:

    • Pain event
    • Dactylitis
    • Acute chest syndrome

  3. Incidence of severe adverse events (SAE) [ Time Frame: Over 24 month period on study drug ]
    Death, hospitalization >7 days, life-threatening event

  4. Incidence of hematologic toxicities [ Time Frame: Over 24 month period on study drug ]

    Hematologic toxicities are defined as:

    • Hemoglobin (Hb) <4.0g/dL
    • Hb <6.0g/dL AND absolute reticulocyte count (ARC) <100 x 10E9/L
    • Hb <7.0g/dL AND ARC <80 x 10E9/L
    • Platelets <80 x 10E9/L
    • Absolute neutrophil count (ANC) <1.0 x 10E9/L

  5. Cerebrovascular function [ Time Frame: At study treatment initiation then at 12 months and 24 months after study initiation ]
    Transcranial Doppler blood vessel velocity to determine cerebrovascular function

  6. Change in creatinine levels [ Time Frame: Over 24 month period on study drug ]
    Changes in creatinine level as a measure of renal function

  7. Change in cystatin C [ Time Frame: Over 24 month period on study drug ]
    Changes in cystatin C level as a measure of renal function

  8. Change in splenic function [ Time Frame: Over 24 month period on study drug ]
    Quantitative micronuclei [Howell Jolly bodies] measured by flow cytometry

  9. Change in height-for-age z-score [ Time Frame: Over 24 month period on study drug ]
    Change in height-for-age z-score

  10. Change in weight-for-age z-score [ Time Frame: Over 24 month period on study drug ]
    Change in weight-for-age z-score

  11. Change in weight-for-height z-score [ Time Frame: Over 24 month period on study drug ]
    Change in weight-for-height z-score



Information from the National Library of Medicine

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Ages Eligible for Study:   24 Months to 72 Months   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Children with confirmed SCA who participated in the NOHARM study of hydroxyurea at the Mulago Hospital Sickle Cell Clinic (MHSCC), will be eligible for the MTD study after completing both 12-months of blinded study treatment and then an additional 12-months of open-label hydroxyurea for the second year of the study.
  • The age range for enrollment into NOHARM, which began in 2014, was 1-4 years. Therefore, the children who will be enrolled in the follow up MTD study will be 3-6 years of age.

Exclusion Criteria:

  • Not willing to come for all scheduled clinical visits or accept randomization

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): NCT03128515


Locations
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Uganda
Mulago Hospital Sickle Cell Clinic
Kampala, Uganda
Sponsors and Collaborators
Indiana University
Doris Duke Charitable Foundation
Makerere University
Mulago Hospital, Uganda
Children's Hospital Medical Center, Cincinnati
Investigators
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Principal Investigator: Chandy C John, M.D. Indiana University
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Chandy John, Professor of Pediatrics, Medicine, Microbiology and Immunology, Indiana University
ClinicalTrials.gov Identifier: NCT03128515    
Other Study ID Numbers: 00456728
First Posted: April 25, 2017    Key Record Dates
Last Update Posted: February 20, 2020
Last Verified: February 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Chandy John, Indiana University:
Hydroxyurea
Additional relevant MeSH terms:
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Malaria
Anemia
Anemia, Sickle Cell
Hematologic Diseases
Protozoan Infections
Parasitic Diseases
Infections
Vector Borne Diseases
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Hemoglobinopathies
Genetic Diseases, Inborn
Hydroxyurea
Antineoplastic Agents
Antisickling Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Nucleic Acid Synthesis Inhibitors