Pharmacokinetic Study of IV Artesunate to Treat Children With Severe Malaria

Plasmodium Falciparum Infection Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05750459
• Other study ID #: 19-0007
• Secondary ID: 5UM1AI148689-05
• Status: Recruiting
• Phase: Phase 4
• Start date: November 29, 2023
• Est. completion date: December 30, 2024

Study information

• Verified date: October 17, 2023
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: Matthew Laurens
• Phone: 14107065328
• Email: mlaurens[@]som.umaryland.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 100
• Est. completion date: December 30, 2024
• Est. primary completion date: November 15, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Months to 14 Years

Eligibility

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

Related Conditions & MeSH terms

• Malaria
• Plasmodium Falciparum Infection

Intervention

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

Locations

Country	Name	City	State
Uganda	Makerere University - Infectious Diseases Institute	Kampala

Sponsors (1)

Lead Sponsor	Collaborator
National Institute of Allergy and Infectious Diseases (NIAID)

Country where clinical trial is conducted

Uganda, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change from baseline bicarbonate levels		Day 1 through Day 183
Primary	Change from baseline blood pressure		Day 1 through Day 183
Primary	Change from baseline creatinine.		Day 1 through Day 183
Primary	Change from baseline in acidosis.		Day 1 through Day 183
Primary	Change from baseline in bilirubin	Includes total and direct bilirubin	Day 1 through Day 183
Primary	Change from baseline in Blantyre Coma Score (BCS).		Day 1 through Day 183
Primary	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
Primary	Change from baseline in hemoglobin		Day 1 through Day 183
Primary	Change from baseline in serum glucose		Day 1 through Day 183
Primary	Change from baseline in temperature.		Day 1 through Day 183
Primary	Change from baseline in venous serum lactate.		Day 1 through Day 183
Secondary	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
Secondary	Time to hospital discharge.		Day 1 through 183