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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
187
Administered once a day in tablet form (100mg or scored 1000mg) for 24 months
Mulago Hospital Sickle Cell Clinic
Kampala, Uganda
Proportion of children with average hemoglobin ≥9.0 g/dL or average HbF ≥20%
Proportion of children who achieve either an average hemoglobin ≥9.0 g/dL or an average HbF ≥20% after 24 months on study drug
Time frame: Over 24 month period on study drug
Clinical malaria incidence
Clinical malaria is defined as a history of fever or measured axillary temperature ≥37.5 degrees, plus Plasmodium species on blood smear.
Time frame: Over 24 month period on study drug
Vaso-occlusive crises
SCA-related adverse events defined as: * Pain event * Dactylitis * Acute chest syndrome
Time frame: Over 24 month period on study drug
Incidence of severe adverse events (SAE)
Death, hospitalization \>7 days, life-threatening event
Time frame: Over 24 month period on study drug
Incidence of hematologic toxicities
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
Time frame: Over 24 month period on study drug
Cerebrovascular function
Transcranial Doppler blood vessel velocity to determine cerebrovascular function
Time frame: At study treatment initiation then at 12 months and 24 months after study initiation
Change in creatinine levels
Changes in creatinine level as a measure of renal function
Time frame: Over 24 month period on study drug
Change in cystatin C
Changes in cystatin C level as a measure of renal function
Time frame: Over 24 month period on study drug
Change in splenic function
Quantitative micronuclei \[Howell Jolly bodies\] measured by flow cytometry
Time frame: Over 24 month period on study drug
Change in height-for-age z-score
Change in height-for-age z-score
Time frame: Over 24 month period on study drug
Change in weight-for-age z-score
Change in weight-for-age z-score
Time frame: Over 24 month period on study drug
Change in weight-for-height z-score
Change in weight-for-height z-score
Time frame: Over 24 month period on study drug
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