Clinical trial NCT05750459: Pharmacokinetic Study of IV Artesunate to Treat Children With Severe Malaria
Official title: Exposure-Response Evaluation of IV Artesunate in Children With Severe Malaria
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Plasmodium Falciparum Infection
Keywords: Artesunate
Children
IV
P. falciparum
Severe Malaria
Uganda
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2023-03-01
Enrollment: 90
Sex: ALL
Minimum age (years): 6
Maximum age (years): 14
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Change from baseline bicarbonate levels
timeFrame: Day 1 through Day 183
measure: Change from baseline blood pressure
timeFrame: Day 1 through Day 183
measure: Change from baseline creatinine.
timeFrame: Day 1 through Day 183
measure: Change from baseline in acidosis.
timeFrame: Day 1 through Day 183
measure: Change from baseline in bilirubin
timeFrame: Day 1 through Day 183
measure: Change from baseline in Blantyre Coma Score (BCS).
timeFrame: Day 1 through Day 183
measure: Change from baseline in concentration of Dihydroartemisinin (DHA)
timeFrame: Day 1
measure: Change from baseline in hemoglobin
timeFrame: Day 1 through Day 183
measure: Change from baseline in serum glucose
timeFrame: Day 1 through Day 183
measure: Change from baseline in temperature.
timeFrame: Day 1 through Day 183
measure: Change from baseline in venous serum lactate.
timeFrame: Day 1 through Day 183
Secondary outcomes:
measure: Parasite (P. falciparum) density in thick blood smear.
timeFrame: Day 1 through Day 5
measure: Time to hospital discharge.
timeFrame: Day 1 through 183
Other outcomes:
Locations:
city: Kampala
country: Uganda
facility: Makerere University - Infectious Diseases Institute
Study officials:
References: