Optimizing Hydroxyurea Therapy in Children With SCA In Malaria Endemic Areas

Malaria Clinical Trial

— NOHARM-MTD  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03128515
• Other study ID #: 00456728
• Status: Completed
• Phase: Phase 3
• Start date: July 26, 2017
• Est. completion date: January 28, 2020

Study information

• Verified date: February 2020
• Source: Indiana University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 187
• Est. completion date: January 28, 2020
• Est. primary completion date: April 7, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 24 Months to 72 Months

Eligibility

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

Related Conditions & MeSH terms

• Anemia
• Anemia, Sickle Cell
• Malaria
• Sickle Cell Anemia
• Sickle Cell Disease

Intervention

Drug:
• Hydroxyurea
Administered once a day in tablet form (100mg or scored 1000mg) for 24 months

Locations

Country	Name	City	State
Uganda	Mulago Hospital Sickle Cell Clinic	Kampala

Sponsors (5)

Lead Sponsor	Collaborator
Indiana University	Children's Hospital Medical Center, Cincinnati, Doris Duke Charitable Foundation, Makerere University, Mulago Hospital, Uganda

Country where clinical trial is conducted

Uganda, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	Vaso-occlusive crises	SCA-related adverse events defined as: Pain event; Dactylitis; Acute chest syndrome	Over 24 month period on study drug
Secondary	Incidence of severe adverse events (SAE)	Death, hospitalization >7 days, life-threatening event	Over 24 month period on study drug
Secondary	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
Secondary	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
Secondary	Change in creatinine levels	Changes in creatinine level as a measure of renal function	Over 24 month period on study drug
Secondary	Change in cystatin C	Changes in cystatin C level as a measure of renal function	Over 24 month period on study drug
Secondary	Change in splenic function	Quantitative micronuclei [Howell Jolly bodies] measured by flow cytometry	Over 24 month period on study drug
Secondary	Change in height-for-age z-score	Change in height-for-age z-score	Over 24 month period on study drug
Secondary	Change in weight-for-age z-score	Change in weight-for-age z-score	Over 24 month period on study drug
Secondary	Change in weight-for-height z-score	Change in weight-for-height z-score	Over 24 month period on study drug