Pharmacokinetic Study of IV Artesunate to Treat Children With Severe Malaria

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

This clinical study is a phase 4, single-site, open-label pharmacokinetic (PK) study of IV artesunate in up to 100 Ugandan children 6 months-14 years of age who are diagnosed with severe malaria according to standardized World Health Organization (WHO) criteria (any P. falciparum parasitemia and the presence of danger signs). Participants will receive the standard of care IV artesunate for initial treatment of severe malaria per WHO guidelines: children weighing <20 kg should receive 3.0 mg/kg/dose compared to children weighing =20 kg who should receive 2.4 mg/kg/dose, at times 0, 12, 24, 48 and 72 hours (WHO 2015). Parenteral treatment will be administered for a minimum of 24 hours (irrespective of the patient's ability to tolerate oral medication earlier), after which patients will be evaluated clinically and assessed for ability for oral intake of antimalarials. Children who are able to transition to oral antimalarial therapy will initiate a 3-day course of artemisinin-combination oral therapy per national guidelines. The primary objective of the study is to determine the relationship between DHA exposures following IV artesunate dosing and markers of physiologic dysfunction associated with severe malaria in Ugandan children.

Study Overview

• Status: Recruiting
• Conditions: Plasmodium Falciparum Infection
• Intervention / Treatment: Drug: Artesunate

Detailed Description

This clinical study is a phase 4, single-site, open-label pharmacokinetic (PK) study of IV artesunate in up to 100 Ugandan children 6 months-14 years of age who are diagnosed with severe malaria according to standardized World Health Organization (WHO) criteria (any P. falciparum parasitemia and the presence of danger signs). Participants will receive the standard of care IV artesunate for initial treatment of severe malaria per WHO guidelines: children weighing <20 kg should receive 3.0 mg/kg/dose compared to children weighing =20 kg who should receive 2.4 mg/kg/dose, at times 0, 12, 24, 48 and 72 hours (WHO 2015). Parenteral treatment will be administered for a minimum of 24 hours (irrespective of the patient's ability to tolerate oral medication earlier), after which patients will be evaluated clinically and assessed for ability for oral intake of antimalarials. Children who are able to transition to oral antimalarial therapy will initiate a 3-day course of artemisinin-combination oral therapy per national guidelines. Biomarkers of physiologic dysfunction will be quantified at regular intervals, including serum lactate, serum glucose, total and direct bilirubin, bicarbonate levels, Blantyre Coma Score (BCS), creatinine and hemoglobin. These biomarkers will be considered both independently and together as a weighted score to relate to the PK of the active metabolite of IV artesunate, DHA and to efficacy markers that more accurately reflect clinical outcomes. We will also quantify P. falciparum parasitemia using standardized thick blood smear and relate this outcome to DHA dose and exposure for comparison with historical studies. Children 6 months to 14 years of age living in or near Tororo District, Uganda, who are diagnosed with severe malaria and who meet inclusion and exclusion criteria will be enrolled.

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Matthew Laurens; Phone Number: 14107065328; Email: mlaurens@som.umaryland.edu

Study Locations

• Uganda
  • Kampala, Uganda
    • Recruiting
    • Makerere University - Infectious Diseases Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 14 years (Child)
• Accepts Healthy Volunteers: No

Study Population

This study is enrolling Ugandan children 6 months to 14 years of age who are diagnosed with severe malaria according to standardized World Health Organization (WHO) criteria (any P. falciparum parasitemia and the presence of danger signs).

Description

Inclusion Criteria:

1. Children ages 6 months-14 years at the time of severe malaria diagnosis, inclusive
2. Meet the case definition for severe malaria, per WHO standardized guidelines
3. Parent/guardian willing to provide informed consent
4. Assent for children between 8 and 14 years who are conscious and otherwise able to provide assent, inclusive

Exclusion Criteria:

1. Receipt of > 24 hours of artemisinin therapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Arm 1; Participants will receive the standard of care with IV artesunate for treatment of severe malaria. Each 60-mg vial of artesunic acid will be dissolved in 1 mL of 5% sodium bicarbonate to form sodium artesunate and then mixed with 5 mL of 5% dextrose. This will be injected as a bolus into an indwelling IV cannula. Children weighing <20 kg will receive IV artesunate at a dose of 3.0 mg/kg/dose compared to older children weighing >/= 20kg who will receive 2.4 mg/kg/dose, at times 0, 12, 24. If unable to take oral medication, IV artesunate will continue at 48 and 72 hours. Children who recover and are able to transition to oral antimalarial therapy after a minimum of 24 hours, will initiate a 3-day course of oral artemisinin-combination therapy per national guidelines. N = 100

Drug: Artesunate; Artesunate is a succinic ester of artemether.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline bicarbonate levels		Day 1 through Day 183
Change from baseline blood pressure		Day 1 through Day 183
Change from baseline creatinine.		Day 1 through Day 183
Change from baseline in acidosis.		Day 1 through Day 183
Change from baseline in bilirubin	Includes total and direct bilirubin	Day 1 through Day 183
Change from baseline in Blantyre Coma Score (BCS).		Day 1 through Day 183
Change from baseline in concentration of Dihydroartemisinin (DHA)	Pharmacokinetic parameters that will be derived from the concentration of Dihydroartemisinin (DHA) include maximum concentration (C max), area under the curve over hours 0-12 (AUC 0-12) and half-life (t 1/2) and time to C max (T max).	Day 1
Change from baseline in hemoglobin		Day 1 through Day 183
Change from baseline in serum glucose		Day 1 through Day 183
Change from baseline in temperature.		Day 1 through Day 183
Change from baseline in venous serum lactate.		Day 1 through Day 183

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Parasite (P. falciparum) density in thick blood smear.	Parasite clearance as calculated from parasite density over time, as measured by thick blood smear such as parasite clearance half-life, total parasite clearance by Day 2, and time to 90% reduction in parasitemia.	Day 1 through Day 5
Time to hospital discharge.		Day 1 through 183

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: University of Maryland, Baltimore; Makerere University
• Investigators: Principal Investigator: Matthew B Laurens, MD, MPH, University of Maryland School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): November 29, 2023
• Primary Completion (Estimated): November 15, 2024
• Study Completion (Estimated): December 30, 2024

Study Registration Dates

• First Submitted: February 20, 2023
• First Submitted That Met QC Criteria: February 20, 2023
• First Posted (Actual): March 1, 2023

Study Record Updates

• Last Update Posted (Actual): March 22, 2024
• Last Update Submitted That Met QC Criteria: March 21, 2024
• Last Verified: October 17, 2023

More Information

Terms related to this study

• Keywords: Children; Uganda; P. falciparum; Artesunate; IV; Severe Malaria
• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Mosquito-Borne Diseases; Malaria; Anti-Infective Agents; Antiviral Agents; Antineoplastic Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Anthelmintics; Schistosomicides; Antiplatyhelmintic Agents; Artesunate
• Other Study ID Numbers: 19-0007; 5UM1AI148689-05 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• IPD Plan Description: De-identified individual participant data related to the primary analysis will be made available for sharing with other researchers.
• IPD Sharing Time Frame: Data will be made available for sharing upon publication of primary study results, with no end date.
• IPD Sharing 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.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes