History of Changes for Study: NCT05750459

Exposure-Response Evaluation of IV Artesunate in Children With Severe Malaria

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Study Record Versions

Version	Submitted Date	Changes
1	February 20, 2023	None (earliest Version on record)
2	April 12, 2023	Study Design, Study Status, Eligibility, Arms and Interventions and Study Description
3	August 15, 2023	Study Status, Outcome Measures and Study Description
4	September 29, 2023	Sponsor/Collaborators, Study Identification and Study Status
5	October 13, 2023	Contacts/Locations, Study Design, Outcome Measures, Study Status, Study Identification, Eligibility, Arms and Interventions, Conditions, Study Description, IPDSharing, Oversight and Sponsor/Collaborators
6	October 19, 2023	Oversight, Study Description, Study Status and Contacts/Locations
7	October 26, 2023	Oversight, Study Description and Study Status
8	November 2, 2023	Study Status
9	November 9, 2023	Oversight and Study Status
10	November 16, 2023	Study Status
11	November 30, 2023	Recruitment Status, Study Status, Contacts/Locations and Study Identification
12	December 7, 2023	Study Status and Study Identification
13	March 21, 2024	Conditions, Study Status and Study Identification

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Study Identification


Unique Protocol ID:	EUCC-DMID-19-0007
Brief Title:	Exposure-Response Evaluation of IV Artesunate in Children With Severe Malaria
Official Title:	Exposure-Response Evaluation of IV Artesunate in Children With Severe Malaria
Secondary IDs:	UM1AI148689 [U.S. NIH Grant/Contract]

Study Status


Record Verification:	February 2023
Overall Status:	Not yet recruiting
Study Start:	March 2023
Primary Completion:	August 2024 [Anticipated]
Study Completion:	August 2024 [Anticipated]

First Submitted:	February 20, 2023
First Submitted that Met QC Criteria:	February 20, 2023
First Posted:	March 1, 2023 [Actual]

Last Update Submitted that Met QC Criteria:	February 20, 2023
Last Update Posted:	March 1, 2023 [Actual]

Sponsor/Collaborators


Sponsor:	Emory University
Responsible Party:	Principal Investigator Investigator: Matthew B Laurens, MD, MPH Official Title: Professor Affiliation: University of Maryland, Baltimore
Collaborators:	University of Maryland, Baltimore National Institute of Allergy and Infectious Diseases (NIAID) Makerere University

Oversight


U.S. FDA-regulated Drug:	No
U.S. FDA-regulated Device:	No
Data Monitoring:	No

Study Description

Brief Summary:

In this study, Ugandan children who are diagnosed with severe malaria will receive intravenous (IV) artesunate per World Health Organization (WHO) guidelines.

Detailed Description:

Despite recent advances in malaria control, Plasmodium falciparum continues to kill almost half a million persons annually, most of whom are children living in sub-Saharan Africa. Plasmodium falciparum is the most prevalent malaria parasite specie and the cause of the most severe form of disease and death. It accounted for 99.7% of all malaria cases in the World Health Organization (WHO) African Region in 2018. Children younger than 5 years of age and pregnant women are most at risk of malaria and death, accounting for 67% of the estimated 405,000 malaria deaths worldwide, with 94% of these in the African Region. Although there was an overall reduction in malaria deaths in 2018 compared with 2010, the malaria mortality reduction rate slowed since 2016 and this has malaria researchers questioning if current malaria treatment regimens are optimal and based on sound scientific evidence.

Severe malaria is a medical emergency which if not immediately treated results in 100% mortality. It is fundamental that plasma concentrations of a highly effective antimalarial drug are achieved as rapidly as possible. Artesunate is a water soluble hemisuccinate artemisinin derivative, available as sodium hemisuccinate salt for injection. Artesunate's excellent antimalarial property demonstrated by rapid parasite clearance, is enhanced by its high initial maximum concentration (Cmax) and rapid hydrolysis to its active metabolite dihydroartemisinin (DHA).

Current dosing regimens for IV artesunate are based on time to parasite clearance and not clinical endpoints related to physiologic changes that occur with parasitemia. Other measures of physiologic dysfunction can be used as study endpoints for a malaria treatment outcome analysis of current regimens for IV artesunate for severe malaria treatment. Improved dosing regimens will lead to fewer complications and likely fewer deaths. Such a strategy is needed to further reduce public health gains against malaria mortality that seem to have recently stalled.

For pediatric patients, IV artesunate dosing is weight-based to adjust for artesunate clearance and has been developed based on time to parasitemia clearance times, which may not completely reflect clinical cure. P. falciparum parasites are known for their capacity to infect red blood cells that then display variant surface antigens that adhere to endothelial vasculature in target organs. For this reason, measurement of parasite clearance in the peripheral blood may not reflect physiologic effects of severe malaria that result from end organ damage, whether through direct impairment of blood flow and decreased delivery of oxygen, a local inflammatory response directed against infected red blood cells attached to vascular endothelium, or rosetting of infected and uninfected red blood cells at the vasculature. Other measures of physiologic dysfunction when quantified alone or in an algorithmic fashion such as a score, may more accurately reflect successful treatment, including serum lactate, serum glucose, bicarbonate levels, BCS, creatinine and hemoglobin. These measures, compared to the standard parasite clearance times from peripheral blood, may be more important to quantify and relate to pharmacologic dosing of antimalarial therapy.

This study aims to develop an improved IV artesunate dosing regimen for treatment of severe malaria in children.

Conditions


Conditions:	Malaria Severe Malaria
Keywords:	Plasmodium falciparum

Study Design


Study Type:	Interventional
Primary Purpose:	Treatment
Study Phase:	Phase 4
Interventional Study Model:	Single Group Assignment
Number of Arms:	1
Masking:	None (Open Label)
Allocation:	N/A
Enrollment:	100 [Anticipated]

Arms and Interventions

Arms	Assigned Interventions
Experimental: Artesunate Children with severe malaria will be treated with artesunate	Drug: Artesunate Participants will receive intravenous (IV) artesunate for severe malaria according to national guidelines. After a minimum of 24 hours and when they can tolerate oral therapy, they will transition to oral artemisinin combination therapy (ACT), also per national guidelines.

Outcome Measures


Primary Outcome Measures:
1.	Dihydroartemisinin (DHA) Maximum Concentration (Cmax) [ Time Frame: Up to 12 hours after first dose ] Dihydroartemisinin (DHA), the active metabolite of artesunate, pharmacokinetics will be examined. Venous blood for pharmacokinetic analyses will be collected from the arm that was not used for drug administration predosing, 0 - 1 hours post-dose, 1 - 2.5 hours post-dose, 2.5 - 4 hours post-dose, 4 - 6 hours post-dose, and 6 - 24 hours post dose.
2.	Area Under the Curve Over Hours 0-12 (AUC0-12) [ Time Frame: Up to 12 hours after first dose ] Dihydroartemisinin (DHA), the active metabolite of artesunate, pharmacokinetics will be examined. Venous blood for pharmacokinetic analyses will be collected from the arm that was not used for drug administration predosing, 0 - 1 hours post-dose, 1 - 2.5 hours post-dose, 2.5 - 4 hours post-dose, 4 - 6 hours post-dose, and 6 - 24 hours post dose.
3.	Half-Life of DHA (t1/2) [ Time Frame: Up to 12 hours after first dose ] Dihydroartemisinin (DHA), the active metabolite of artesunate, pharmacokinetics will be examined. Venous blood for pharmacokinetic analyses will be collected from the arm that was not used for drug administration predosing, 0 - 1 hours post-dose, 1 - 2.5 hours post-dose, 2.5 - 4 hours post-dose, 4 - 6 hours post-dose, and 6 - 24 hours post dose.
4.	Time to Cmax (Tmax) [ Time Frame: Up to 12 hours after first dose ] Dihydroartemisinin (DHA), the active metabolite of artesunate, pharmacokinetics will be examined. Venous blood for pharmacokinetic analyses will be collected from the arm that was not used for drug administration predosing, 0 - 1 hours post-dose, 1 - 2.5 hours post-dose, 2.5 - 4 hours post-dose, 4 - 6 hours post-dose, and 6 - 24 hours post dose. The time, in hours, it takes to reach the maximum concentration of artesunate will be assessed.
5.	Change in Body Temperature [ Time Frame: Days 1, 2, 3, 4, 5, 6, 7, 14, 28, 183 ] Axillary body temperature is assessed in degrees Celsius.
6.	Change in Systolic Blood Pressure [ Time Frame: Days 1, 2, 3, 4, 5, 6, 7, 14, 28, 183 ] The normal range of systolic blood pressure in children varies by age, size, and sex. In pediatric patients with severe malaria, low systolic blood pressure (<50 millimeters of mercury (mm Hg)) indicates a risk of circulatory collapse or shock.
7.	Change in Diastolic Blood Pressure [ Time Frame: Days 1, 2, 3, 4, 5, 6, 7, 14, 28, 183 ] The normal range of diastolic blood pressure in children varies by age, size, and sex.
8.	Change in Venous Plasma Lactate [ Time Frame: Days 1, 2, 3, 4, 5, 6, 7 ] Venous plasma lactate will be assessed as a biomarker of physiologic dysfunction.
9.	Change in Venous Bicarbonate Levels [ Time Frame: Days 1, 2, 3, 4, 5, 6, 7, 14 ] Venous bicarbonate will be assessed as a biomarker of physiologic dysfunction.
10.	Change in Serum Glucose [ Time Frame: Days 1, 2, 3, 4, 5, 6, 7 ] Serum glucose levels can be reduced during severe malaria with hypoglycemia levels of < 3 millimoles per liter (mmol/L) indicating high risk of death.
11.	Change in Blantyre Coma Score (BCS) [ Time Frame: Days 1, 2, 3, 4, 5, 6, 7, 14, 28, 183 ] The Blantyre Coma Score (BCS) includes 8 items assessing eye movement, motor response, and verbal response. Total scores range from 0 to 5 where participants scoring 0 show no response to pain and participants scoring 5 are fully conscious.
12.	Change in Total Bilirubin [ Time Frame: Days 1, 2, 3, 4, 5, 6, 7 ] Total bilirubin will be assessed as a biomarker of physiologic dysfunction.
13.	Change in Direct Bilirubin [ Time Frame: Days 1, 2, 3, 4, 5, 6, 7 ] Direct bilirubin will be assessed as a biomarker of physiologic dysfunction.
14.	Change in Hemoglobin [ Time Frame: Days 1, 2, 3, 4, 5, 6, 7, 14, 28, 183 ] Hemoglobin will be assessed as a biomarker of physiologic dysfunction.
15.	Change in Creatinine [ Time Frame: Days 1, 2, 3, 4, 5, 6, 7 ] Creatinine will be assessed as a biomarker of physiologic dysfunction.
Secondary Outcome Measures:
1.	Time to Hospital Discharge [ Time Frame: Up to the day of hospital discharge (an average of 3 days) ] The duration of hospitalization will be evaluated in days.
2.	Parasite Clearance Half-Life [ Time Frame: Up to Day 5 ] Samples to assess parasitemia will be collected at hours 0, 6, 12, 24, 36, and 48, then every 24 hours until parasite clearance. The half-life (t1/2) of parasite clearance will be determined.
3.	Parasite Clearance by Day 2 [ Time Frame: Up to Day 2 ] Samples to assess parasitemia will be collected at hours 0, 6, 12, 24, 36, and 48, then every 24 hours until parasite clearance. The percentage of parasitemia clearance by 48 hours post-dose will be determined.
4.	Time to 90% Reduction in Parasitemia [ Time Frame: Up to Day 5 ] Samples to assess parasitemia will be collected at hours 0, 6, 12, 24, 36, and 48, then every 24 hours until parasite clearance. The number of hours it takes for 90% reduction in parasitemia will be determined.

Eligibility


Minimum Age:	6 Months
Maximum Age:	14 Years
Sex:	All
Gender Based:
Accepts Healthy Volunteers:	No
Criteria:	Inclusion Criteria: Children ages 6 months to 14 years at the time of severe malaria diagnosis, inclusive Meet the case definition for severe malaria, per WHO standardized guidelines Parent/guardian willing to provide informed consent Assent for children between 8 and 14 years who are conscious and otherwise able to provide assent, inclusive Living in or near Tororo District, Uganda Exclusion Criteria: Receipt of >24 hours of artemisinin therapy

Contacts/Locations


Central Contact Person:	Matthew B Laurens, MD, MPH Telephone: 410-706-5328 Email: mlaurens@som.umaryland.edu
Study Officials:	Matthew B Laurens, MD, MPH Principal Investigator University of Maryland, Baltimore
Locations:	Uganda
	Tororo Hospital Tororo, Uganda Contact:Contact: Pauline Byakika-Kibwika, PhD, MMed (+256) 772 626885 pbyakika@gmail.com Contact:Principal Investigator: Pauline Byakika-Kibwika, PhD, MMed

IPDSharing


Plan to Share IPD:	Yes De-identified individual participant data related to the primary analysis will be made available for sharing with other researchers.
	Supporting Information: Study Protocol Statistical Analysis Plan (SAP)
	Time Frame: Data will be made available for sharing upon publication of primary study results, with no end date.
	Access Criteria: Data will be made available in an accessible database, in an online platform. Researchers will be able to access the data for analyses related to their proposed study objectives.
	URL:

References


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