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

Optimizing Hydroxyurea Therapy in Children With Sickle Cell Anemia In Malaria Endemic Areas: The NOHARM Maximum Tolerated Dose (MTD) Study

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.

Study Overview

• Status: Completed
• Conditions: Malaria; Sickle Cell Disease; Sickle Cell Anemia
• Intervention / Treatment: Drug: Hydroxyurea

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.

• Study Type: Interventional
• Enrollment (Actual): 187
• Phase: Phase 3

Contacts and Locations

Study Locations

• Uganda
  • Kampala, Uganda
    • Mulago Hospital Sickle Cell Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 6 years (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / 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: Hydroxycarbamide; Siklos
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: Hydroxycarbamide; Siklos

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Over 24 month period on study drug

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Over 24 month period on study drug
Vaso-occlusive crises	SCA-related adverse events defined as: Pain event; Dactylitis; Acute chest syndrome	Over 24 month period on study drug
Incidence of severe adverse events (SAE)	Death, hospitalization >7 days, life-threatening event	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	Over 24 month period on study drug
Cerebrovascular function	Transcranial Doppler blood vessel velocity to determine cerebrovascular function	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	Over 24 month period on study drug
Change in cystatin C	Changes in cystatin C level as a measure of renal function	Over 24 month period on study drug
Change in splenic function	Quantitative micronuclei [Howell Jolly bodies] measured by flow cytometry	Over 24 month period on study drug
Change in height-for-age z-score	Change in height-for-age z-score	Over 24 month period on study drug
Change in weight-for-age z-score	Change in weight-for-age z-score	Over 24 month period on study drug
Change in weight-for-height z-score	Change in weight-for-height z-score	Over 24 month period on study drug

Collaborators and Investigators

• Sponsor: Indiana University
• Collaborators: Children's Hospital Medical Center, Cincinnati; Makerere University; Doris Duke Charitable Foundation; Mulago Hospital, Uganda
• Investigators: Principal Investigator: Chandy C John, M.D., Indiana University

Publications and helpful links

General Publications

• John CC, Opoka RO, Latham TS, Hume HA, Nabaggala C, Kasirye P, Ndugwa CM, Lane A, Ware RE. Hydroxyurea Dose Escalation for Sickle Cell Anemia in Sub-Saharan Africa. N Engl J Med. 2020 Jun 25;382(26):2524-2533. doi: 10.1056/NEJMoa2000146.

Study record dates

Study Major Dates

• Study Start (ACTUAL): July 26, 2017
• Primary Completion (ACTUAL): April 7, 2019
• Study Completion (ACTUAL): January 28, 2020

Study Registration Dates

• First Submitted: March 22, 2017
• First Submitted That Met QC Criteria: April 20, 2017
• First Posted (ACTUAL): April 25, 2017

Study Record Updates

• Last Update Posted (ACTUAL): February 20, 2020
• Last Update Submitted That Met QC Criteria: February 19, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Keywords: Hydroxyurea
• Additional Relevant MeSH Terms: Infections; Hematologic Diseases; Genetic Diseases, Inborn; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Malaria; Anemia; Anemia, Sickle Cell; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antineoplastic Agents; Antisickling Agents; Hydroxyurea
• Other Study ID Numbers: 00456728

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