A Phase 4 interventional study of Artesunate in Plasmodium Falciparum Infection, sponsored by National Institute of Allergy and Infectious Diseases (NIAID). Completed at 1 site in Uganda. Open to participants aged 6 Months to 14 Years. Per ClinicalTrials.gov, last updated 2026-06-18.
Sponsored by National Institute of Allergy and Infectious Diseases (NIAID) · Phase 4, Interventional, and Treatment
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.
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.
1,299 studies on the registry are indexed under Malaria; 86 are open to participants now.
This study's enrollment of 90 is below the median of 220 across 1,027 interventional studies indexed under Malaria.
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Exclusion Criteria:
1. Receipt of > 24 hours of artemisinin therapy
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.
Maximum Concentration (Cmax) of Dihydroartemisinin (DHA)
Population Pharmacokinetic (PK) modeling was conducted to derive Cmax from the concentration of DHA. The final model fit was a 1-compartment disposition of DHA with covariates for age and baseline bilirubin.
Time frame: Day 1(Sampling windows were defined as 0 (pre-dose), 0-1 hour, 1 - 2.5, 2.5-4, 4-6 and 6-24 hours post first on-study dose of IV artesunate)
Area Under the Curve Over 0-12 Hours (AUC0-12) of DHA
Population PK modeling was conducted to derive AUC0-12 from the concentration of DHA. The final model fit was a 1-compartment disposition of DHA with covariates for age and baseline bilirubin. Day 1 (Sampling windows were defined as 0 (pre-dose), 0-1 hour, 1 - 2.5, 2.5-4, 4-6 and 6-24 hours post first on-study dose of IV artesunate)
Time frame: Day 1(Sampling windows were defined as 0 (pre-dose), 0-1 hour, 1 - 2.5, 2.5-4, 4-6 and 6-24 hours post first on-study dose of IV artesunate)
Half-life (t1/2) of DHA
Population PK modeling was conducted to derive t1/2 from the concentration of DHA. The final model fit was a 1-compartment disposition of DHA with covariates for age and baseline bilirubin.
Time frame: Day 1 (Sampling windows were defined as 0 (pre-dose), 0-1 hour, 1 - 2.5, 2.5-4, 4-6 and 6-24 hours post first on-study dose of IV artesunate)
Time to Cmax (Tmax) of DHA
Population Pharmacokinetic (PK) modeling was conducted to derive PK parameters from the concentration of DHA. The final model fit was a 1-compartment disposition of DHA with covariates for age and baseline bilirubin. From the simulation, the Tmax was assumed to be 0 as the simulation replicates artesunate administered as an IV bolus directly into the central compartment.
Time frame: Day 1(Sampling windows were defined as 0 (pre-dose), 0-1 hour, 1 - 2.5, 2.5-4, 4-6 and 6-24 hours post first on-study dose of IV artesunate)
Change From Baseline in Temperature in the Primary Analysis Population
Temperature was recorded approximately every 6 hours until 6 hours post-parasite clearance and at least daily until discharge along with scheduled follow-up visits. Change from baseline in temperature was reported at pre-defined timepoints: 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Primary exposure-response analyses were performed to assess the relationship between DHA PK Parameters (AUC0-12, Cmax, and t1/2) and temperature. Many participants did not have unique measurements collected for each of the four timepoints defined, therefore these participants were using the same values at multiple timepoints. To meet the independence assumption of the Benjamini-Hochberg procedure, only 24-hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time to first hospital discharge had models fit and were assessed for significance for temperature.
Time frame: Baseline, 24 hours post-first IV Artesunate dose, 48 hours post-first IV Artesunate dose, Time of completion of planned IV Artesunate dosing (72 hours post-first IV Artesunate dose), and Time of first hospital discharge (up to day 9)
Change From Baseline in Temperature in the Subset Who Did Not Receive Any IV Artesunate or Other Artemisinin-based Therapy Before Enrollment
Temperature was recorded approximately every 6 hours until 6 hours post-parasite clearance and at least daily until discharge along with scheduled follow-up visits. Change from baseline in temperature was reported at pre-defined timepoints: 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Primary exposure-response analyses were performed to assess the relationship between DHA PK parameters (AUC0-12, Cmax, and t1/2) and temperature. Many participants did not have unique measurements collected for each of the four timepoints defined, therefore these participants were using the same values at multiple timepoints. To meet the independence assumption of the Benjamini-Hochberg procedure, only 24-hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time to first hospital discharge had models fit and were assessed for significance for temperature.
Time frame: Baseline, 24 hours post-first IV Artesunate dose, 48 hours post-first IV Artesunate dose, Time of completion of planned IV Artesunate dosing (72 hours post-first IV Artesunate dose), and Time of first hospital discharge (up to day 9)
Change From Baseline Systolic Blood Pressure (BP) in the Primary Analysis Population
Systolic BP was recorded approximately every 6 hours until 6 hours post-parasite clearance and at least daily until discharge along with scheduled follow-up visits. Change from baseline in systolic BP was reported at pre-defined timepoints: 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Primary exposure-response analyses were performed to assess the relationship between DHA PK parameters (AUC0-12, Cmax, and t1/2) and systolic BP. Many participants did not have unique measurements collected for each of the four timepoints defined, thus these participants were using the same values at multiple timepoints. To meet the independence assumption of the Benjamini-Hochberg procedure, only 24-hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time to first hospital discharge had models fit and were assessed for significance for systolic BP.
Time frame: Baseline, 24 hours post-first IV Artesunate dose, 48 hours post-first IV Artesunate dose, Time of completion of planned IV Artesunate dosing (72 hours post-first IV Artesunate dose), and Time of first hospital discharge (up to day 9)
Change From Baseline Systolic BP in the Subset Who Did Not Receive Any IV Artesunate or Other Artemisinin-based Therapy Before Enrollment
Systolic BP was recorded approximately every 6 hours until 6 hours post-parasite clearance and at least daily until discharge along with scheduled follow-up visits. Change from baseline in systolic BP was reported at pre-defined timepoints: 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Primary exposure-response analyses were performed to assess the relationship between DHA PK parameters (AUC0-12, Cmax, and t1/2) and systolic BP. Many participants did not have unique measurements collected for each of the four timepoints defined, thus these participants were using the same values at multiple timepoints. To meet the independence assumption of the Benjamini-Hochberg procedure, only 24-hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time to first hospital discharge had models fit and were assessed for significance for systolic BP.
Time frame: Baseline, 24 hours post-first IV Artesunate dose, 48 hours post-first IV Artesunate dose, Time of completion of planned IV Artesunate dosing (72 hours post-first IV Artesunate dose), and Time of first hospital discharge (up to day 9)
Change From Baseline Diastolic BP in the Primary Analysis Population
Diastolic BP was recorded approximately every 6 hours until 6 hours post-parasite clearance and at least daily until discharge along with scheduled follow-up visits. Change from baseline in diastolic BP was reported at pre-defined timepoints: 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Primary exposure-response analyses were performed to assess the relationship between DHA PK parameters (AUC0-12, Cmax, t1/2) and diastolic BP. Many participants did not have unique measurements collected for each of the four timepoints defined, therefore these participants were using the same values at multiple timepoints. To meet the independence assumption of the Benjamini-Hochberg procedure, only 24-hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time to first hospital discharge had models fit and were assessed for significance for diastolic BP.
Time frame: Baseline, 24 hours post-first IV Artesunate dose, 48 hours post-first IV Artesunate dose, Time of completion of planned IV Artesunate dosing (72 hours post-first IV Artesunate dose), and Time of first hospital discharge (up to day 9)
Change From Baseline Diastolic BP in the Subset Who Did Not Receive Any IV Artesunate or Other Artemisinin-based Therapy Before Enrollment
Diastolic BP was recorded approximately every 6 hours until 6 hours post-parasite clearance and at least daily until discharge along with scheduled follow-up visits. Change from baseline in diastolic BP was reported at pre-defined timepoints: 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Primary exposure-response analyses were performed to assess the relationship between DHA PK parameters (AUC0-12, Cmax, and t1/2) and diastolic BP. Many participants did not have unique measurements collected for each of the four timepoints defined, thus these participants were using the same values at multiple timepoints. To meet the independence assumption of the Benjamini-Hochberg procedure, only 24-hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time to first hospital discharge had models fit and were assessed for significance for diastolic BP.
Time frame: Baseline, 24 hours post-first IV Artesunate dose, 48 hours post-first IV Artesunate dose, Time of completion of planned IV Artesunate dosing (72 hours post-first IV Artesunate dose), and Time of first hospital discharge (up to day 9)
Change From in Venous Serum Lactate in the Primary Analysis Population
Serum lactate was recorded daily until discharge along with scheduled follow-up visits. Change from baseline in serum lactate was reported at pre-defined timepoints: 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Primary exposure-response analyses were performed to assess the relationship between DHA PK parameters (AUC0-12, Cmax, t1/2) and serum lactate. Many participants did not have unique measurements collected for each of the four timepoints defined, therefore these participants were using the same values at multiple timepoints. To meet the independence assumption of the Benjamini-Hochberg procedure, only 24-hours post-first IV artesunate and time of completion of planned IV artesunate dosing had models fit and were assessed for significance for serum lactate.
Time frame: Baseline, 24 hours post-first IV Artesunate dose, 48 hours post-first IV Artesunate dose, Time of completion of planned IV Artesunate dosing (72 hours post-first IV Artesunate dose), and Time of first hospital discharge (up to day 9)
Change From in Venous Serum Lactate in the Subset Who Did Not Receive Any IV Artesunate or Other Artemisinin-based Therapy Before Enrollment
Serum lactate was recorded daily until discharge along with scheduled follow-up visits. Change from baseline in serum lactate was reported at pre-defined timepoints: 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Primary exposure-response analyses were performed to assess the relationship between DHA PK parameters (AUC0-12, Cmax, t1/2) and serum lactate. Many participants did not have unique measurements collected for each of the four timepoints defined, therefore these participants were using the same values at multiple timepoints. To meet the independence assumption of the Benjamini-Hochberg procedure, only 24-hours post-first IV artesunate and time of completion of planned IV artesunate dosing had models fit and were assessed for significance for serum lactate.
Time frame: Baseline, 24 hours post-first IV Artesunate dose, 48 hours post-first IV Artesunate dose, Time of completion of planned IV Artesunate dosing (72 hours post-first IV Artesunate dose), and Time of first hospital discharge (up to day 9)
Change From Baseline in Serum Bicarbonate in the Primary Analysis Population
Serum bicarbonate was recorded daily until discharge along with scheduled follow-up visits. Change from baseline in serum bicarbonate was reported at pre-defined timepoints: 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Primary exposure-response analyses were performed to assess the relationship between DHA PK parameters (AUC0-12, Cmax, t1/2) and serum bicarbonate. Many participants did not have unique measurements collected for each of the four timepoints defined, therefore these participants were using the same values at multiple timepoints. To meet the independence assumption of the Benjamini-Hochberg procedure, only 24-hours post-first IV artesunate and time of completion of planned IV artesunate dosing had models fit and were assessed for significance for serum bicarbonate.
Time frame: Baseline, 24 hours post-first IV Artesunate dose, 48 hours post-first IV Artesunate dose, Time of completion of planned IV Artesunate dosing (72 hours post-first IV Artesunate dose), and Time of first hospital discharge (up to day 9)
Change From Baseline in Serum Bicarbonate in the Subset Who Did Not Receive Any IV Artesunate or Other Artemisinin-based Therapy Before Enrollment
Serum bicarbonate was recorded daily until discharge along with scheduled follow-up visits. Change from baseline in serum bicarbonate was reported at pre-defined timepoints: 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Primary exposure-response analyses were performed to assess the relationship between DHA PK parameters (AUC0-12, Cmax, t1/2) and serum bicarbonate. Many participants did not have unique measurements collected for each of the four timepoints defined, therefore these participants were using the same values at multiple timepoints. To meet the independence assumption of the Benjamini-Hochberg procedure, only 24-hours post-first IV artesunate and time of completion of planned IV artesunate dosing had models fit and were assessed for significance for serum bicarbonate.
Time frame: Baseline, 24 hours post-first IV Artesunate dose, 48 hours post-first IV Artesunate dose, Time of completion of planned IV Artesunate dosing (72 hours post-first IV Artesunate dose), and Time of first hospital discharge (up to day 9)
Change From Baseline in Serum Glucose in the Primary Analysis Population
Serum glucose was recorded daily until discharge along with scheduled follow-up visits. Change from baseline in serum glucose was reported at pre-defined timepoints: 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Primary exposure-response analyses were performed to assess the relationship between DHA PK parameters (AUC0-12, Cmax, t1/2) and serum glucose. Many participants did not have unique measurements collected for each of the four timepoints defined, therefore these participants were using the same values at multiple timepoints. To meet the independence assumption of the Benjamini-Hochberg procedure, only 24-hours post-first IV artesunate and time of completion of planned IV artesunate dosing had models fit and were assessed for significance for serum glucose.
Time frame: 24 hours post-first IV Artesunate dose, 48 hours post-first IV Artesunate dose, Time of completion of planned IV Artesunate dosing (72 hours post-first IV Artesunate dose), and Time of first hospital discharge (up to day 9)
Change From Baseline in Serum Glucose in the Subset Who Did Not Receive Any IV Artesunate or Other Artemisinin-based Therapy Before Enrollment
Serum glucose was recorded daily until discharge along with scheduled follow-up visits. Change from baseline in serum glucose was reported at pre-defined timepoints: 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Primary exposure-response analyses were performed to assess the relationship between DHA PK parameters (AUC0-12, Cmax, t1/2) and serum glucose. Many participants did not have unique measurements collected for each of the four timepoints defined, therefore these participants were using the same values at multiple timepoints. To meet the independence assumption of the Benjamini-Hochberg procedure, only 24-hours post-first IV artesunate and time of completion of planned IV artesunate dosing had models fit and were assessed for significance for serum glucose.
Time frame: Baseline, 24 hours post-first IV Artesunate dose, 48 hours post-first IV Artesunate dose, Time of completion of planned IV Artesunate dosing (72 hours post-first IV Artesunate dose), and Time of first hospital discharge (up to day 9)
Change From Baseline in Total Bilirubin in the Primary Analysis Population
Total bilirubin was recorded daily until discharge along with scheduled follow-up visits. Change from baseline in total bilirubin was reported at pre-defined timepoints: 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Primary exposure-response analyses were performed to assess the relationship between DHA PK parameters (AUC0-12, Cmax, t1/2) and total bilirubin. Many participants did not have unique measurements collected for each of the four timepoints defined, therefore these participants were using the same values at multiple timepoints. To meet the independence assumption of the Benjamini-Hochberg procedure, only 24-hours post-first IV artesunate and time of completion of planned IV artesunate dosing had models fit and were assessed for significance for total bilirubin.
Time frame: Baseline, 24 hours post-first IV Artesunate dose, 48 hours post-first IV Artesunate dose, Time of completion of planned IV Artesunate dosing (72 hours post-first IV Artesunate dose), and Time of first hospital discharge (up to day 9)
Change From Baseline in Total Bilirubin in the Subset Who Did Not Receive Any IV Artesunate or Other Artemisinin-based Therapy Before Enrollment
Total bilirubin was recorded daily until discharge along with scheduled follow-up visits. Change from baseline in total bilirubin was reported at pre-defined timepoints: 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Primary exposure-response analyses were performed to assess the relationship between DHA PK parameters (AUC0-12, Cmax, t1/2) and total bilirubin. Many participants did not have unique measurements collected for each of the four timepoints defined, therefore these participants were using the same values at multiple timepoints. To meet the independence assumption of the Benjamini-Hochberg procedure, only 24-hours post-first IV artesunate and time of completion of planned IV artesunate dosing had models fit and were assessed for significance for total bilirubin.
Time frame: Baseline, 24 hours post-first IV Artesunate dose, 48 hours post-first IV Artesunate dose, Time of completion of planned IV Artesunate dosing (72 hours post-first IV Artesunate dose), and Time of first hospital discharge (up to day 9)
Change From Baseline in Direct Bilirubin in the Primary Analysis Population
Direct bilirubin was recorded daily until discharge along with scheduled follow-up visits. Change from baseline in direct bilirubin was reported at pre-defined timepoints: 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Primary exposure-response analyses were performed to assess the relationship between DHA PK parameters (AUC0-12, Cmax, t1/2) and direct bilirubin. Many participants did not have unique measurements collected for each of the four timepoints defined, therefore these participants were using the same values at multiple timepoints. To meet the independence assumption of the Benjamini-Hochberg procedure, only 24-hours post-first IV artesunate and time of completion of planned IV artesunate dosing had models fit and were assessed for significance for direct bilirubin.
Time frame: Baseline, 24 hours post-first IV Artesunate dose, 48 hours post-first IV Artesunate dose, Time of completion of planned IV Artesunate dosing (72 hours post-first IV Artesunate dose), and Time of first hospital discharge (up to day 9)
Change From Baseline in Direct Bilirubin in the Subset Who Did Not Receive Any IV Artesunate or Other Artemisinin-based Therapy Before Enrollment
Direct bilirubin was recorded daily until discharge along with scheduled follow-up visits. Change from baseline in direct bilirubin was reported at pre-defined timepoints: 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Primary exposure-response analyses were performed to assess the relationship between DHA PK parameters (AUC0-12, Cmax, t1/2) and direct bilirubin. Many participants did not have unique measurements collected for each of the four timepoints defined, therefore these participants were using the same values at multiple timepoints. To meet the independence assumption of the Benjamini-Hochberg procedure, only 24-hours post-first IV artesunate and time of completion of planned IV artesunate dosing had models fit and were assessed for significance for direct bilirubin.
Time frame: Baseline, 24 hours post-first IV Artesunate dose, 48 hours post-first IV Artesunate dose, Time of completion of planned IV Artesunate dosing (72 hours post-first IV Artesunate dose), and Time of first hospital discharge (up to day 9)
Change From Baseline in Hemoglobin in the Primary Analysis Population
Hemoglobin was recorded daily until discharge along with scheduled follow-up visits. Change from baseline in hemoglobin was reported at pre-defined timepoints: 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Primary exposure-response analyses were performed to assess the relationship between DHA PK parameters (AUC0-12, Cmax, t1/2) and hemoglobin. Many participants did not have unique measurements collected for each of the four timepoints defined, therefore these participants were using the same values at multiple timepoints. To meet the independence assumption of the Benjamini-Hochberg procedure, only 24-hours post-first IV artesunate and time of completion of planned IV artesunate dosing had models fit and were assessed for significance for hemoglobin.
Time frame: Baseline, 24 hours post-first IV Artesunate dose, 48 hours post-first IV Artesunate dose, Time of completion of planned IV Artesunate dosing (72 hours post-first IV Artesunate dose), and Time of first hospital discharge (up to day 9)
Change From Baseline in Hemoglobin in the Subset Who Did Not Receive Any IV Artesunate or Other Artemisinin-based Therapy Before Enrollment
Hemoglobin was recorded daily until discharge along with scheduled follow-up visits. Change from baseline in hemoglobin was reported at pre-defined timepoints: 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Primary exposure-response analyses were performed to assess the relationship between DHA PK parameters (AUC0-12, Cmax, t1/2) and hemoglobin. Many participants did not have unique measurements collected for each of the four timepoints defined, therefore these participants were using the same values at multiple timepoints. To meet the independence assumption of the Benjamini-Hochberg procedure, only 24-hours post-first IV artesunate and time of completion of planned IV artesunate dosing had models fit and were assessed for significance for hemoglobin.
Time frame: Baseline, 24 hours post-first IV Artesunate dose, 48 hours post-first IV Artesunate dose, Time of completion of planned IV Artesunate dosing (72 hours post-first IV Artesunate dose), and Time of first hospital discharge (up to day 9)
Change From Baseline in Creatinine in the Primary Analysis Population
Creatinine was recorded daily until discharge along with scheduled follow-up visits. Change from baseline in creatinine was reported at pre-defined timepoints: 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Primary exposure-response analyses were performed to assess the relationship between DHA PK parameters (AUC0-12, Cmax, t1/2) and creatinine. Many participants did not have unique measurements collected for each of the four timepoints defined, therefore these participants were using the same values at multiple timepoints. To meet the independence assumption of the Benjamini-Hochberg procedure, only 24-hours post-first IV artesunate and time of completion of planned IV artesunate dosing had models fit and were assessed for significance for creatinine.
Time frame: Baseline, 24 hours post-first IV Artesunate dose, 48 hours post-first IV Artesunate dose, Time of completion of planned IV Artesunate dosing (72 hours post-first IV Artesunate dose), and Time of first hospital discharge (up to day 9)
Change From Baseline in Creatinine in the Subset Who Did Not Receive Any IV Artesunate or Other Artemisinin-based Therapy Before Enrollment
Creatinine was recorded daily until discharge along with scheduled follow-up visits. Change from baseline in creatinine was reported at pre-defined timepoints: 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Primary exposure-response analyses were performed to assess the relationship between DHA PK parameters (AUC0-12, Cmax, t1/2) and creatinine. Many participants did not have unique measurements collected for each of the four timepoints defined, therefore these participants were using the same values at multiple timepoints. To meet the independence assumption of the Benjamini-Hochberg procedure, only 24-hours post-first IV artesunate and time of completion of planned IV artesunate dosing had models fit and were assessed for significance for creatinine.
Time frame: Baseline, 24 hours post-first IV Artesunate dose, 48 hours post-first IV Artesunate dose, Time of completion of planned IV Artesunate dosing (72 hours post-first IV Artesunate dose), and Time of first hospital discharge (up to day 9)
DHA AUC0-12 Summary Statistics for Participants With Blantyre Coma Score (BCS) of 1 in the Primary Analysis Population
Blantyre coma scale is an ordinal scale designed to assess malarial coma in children. Eye movement, best motor response, and best verbal response were assessed and scored. The total BCS score was then calculated as the sum of the scores for these three assessments with possible values of 0, 1, 2, 3, 4, or 5. Lower BCS values were indicative of impaired consciousness. BCS was recorded daily until discharge along with scheduled follow-up visits. The number of participants in each BCS were reported at pre-defined timepoints: baseline, 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Due to the lack of variability in BCS scores, proportional odds mixed effects models to assess the relationship between BCS scores and each PK exposure parameter were not conducted. Instead, summary statistics of DHA AUC0-12 for BCS score of 1 by timepoint are presented.
Time frame: Baseline, 24 hours post-first IV Artesunate dose, 48 hours post-first IV Artesunate dose, Time of completion of planned IV Artesunate dosing (72 hours post-first IV Artesunate dose), and Time of first hospital discharge (up to day 9)
DHA AUC0-12 Summary Statistics for Participants With BCS of 4 in the Primary Analysis Population
Blantyre coma scale is an ordinal scale designed to assess malarial coma in children. Eye movement, best motor response, and best verbal response were assessed and scored. The total BCS score was then calculated as the sum of the scores for these three assessments with possible values of 0, 1, 2, 3, 4, or 5. Lower BCS values were indicative of impaired consciousness. BCS was recorded daily until discharge along with scheduled follow-up visits. The number of participants in each BCS were reported at pre-defined timepoints: baseline, 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Due to the lack of variability in BCS scores, proportional odds mixed effects models to assess the relationship between BCS scores and each PK exposure parameter were not conducted. Instead, summary statistics of DHA AUC0-12 for BCS score of 4 by timepoint are presented.
Time frame: Baseline, 24 hours post-first IV Artesunate dose, 48 hours post-first IV Artesunate dose, Time of completion of planned IV Artesunate dosing (72 hours post-first IV Artesunate dose), and Time of first hospital discharge (up to day 9)
DHA AUC0-12 Summary Statistics for Participants With BCS of 5 in the Primary Analysis Population
Blantyre coma scale is an ordinal scale designed to assess malarial coma in children. Eye movement, best motor response, and best verbal response were assessed and scored. The total BCS score was then calculated as the sum of the scores for these three assessments with possible values of 0, 1, 2, 3, 4, or 5. Lower BCS values were indicative of impaired consciousness. BCS was recorded daily until discharge along with scheduled follow-up visits. The number of participants in each BCS were reported at pre-defined timepoints: baseline, 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Due to the lack of variability in BCS scores, proportional odds mixed effects models to assess the relationship between BCS scores and each PK exposure parameter were not conducted. Instead, summary statistics of DHA AUC0-12 for BCS score of 5 by timepoint are presented.
Time frame: Baseline, 24 hours post-first IV Artesunate dose, 48 hours post-first IV Artesunate dose, Time of completion of planned IV Artesunate dosing (72 hours post-first IV Artesunate dose), and Time of first hospital discharge (up to day 9)
DHA AUC0-12 Summary Statistics for Participants With BCS of 4 in the Subset Who Did Not Receive Any IV Artesunate or Other Artemisinin-based Therapy Before Enrollment
BCS is an ordinal scale designed to assess malarial coma in children. Eye movement, best motor response, and best verbal response were assessed and scored. The total BCS score was then calculated as the sum of the scores for these three assessments with possible values of 0, 1, 2, 3, 4, or 5. Lower BCS values were indicative of impaired consciousness. BCS was recorded daily until discharge along with scheduled follow-up visits. The number of participants in each BCS were reported at pre-defined timepoints: baseline, 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Due to the lack of variability in BCS scores, proportional odds mixed effects models to assess the relationship between BCS scores and each PK exposure parameter were not conducted. Instead, summary statistics of DHA AUC0-12 for BCS score of 4 by timepoint are presented. Only participants who were assessed a BCS of 4 are shown.
Time frame: Baseline, 24 hours post-first IV Artesunate dose, 48 hours post-first IV Artesunate dose, Time of completion of planned IV Artesunate dosing (72 hours post-first IV Artesunate dose), and Time of first hospital discharge (up to day 9)
DHA AUC0-12 Summary Statistics for Participants With BCS of 5 in the Subset Who Did Not Receive Any IV Artesunate or Other Artemisinin-based Therapy Before Enrollment
Blantyre coma scale is an ordinal scale designed to assess malarial coma in children. Eye movement, best motor response, and best verbal response were assessed and scored. The total BCS score was then calculated as the sum of the scores for these three assessments with possible values of 0, 1, 2, 3, 4, or 5. Lower BCS values were indicative of impaired consciousness. BCS was recorded daily until discharge along with scheduled follow-up visits. The number of participants in each BCS were reported at pre-defined timepoints: baseline, 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Due to the lack of variability in BCS scores, proportional odds mixed effects models to assess the relationship between BCS scores and each PK exposure parameter were not conducted. Instead, summary statistics of DHA AUC0-12 for BCS score of 5 by timepoint are presented.
Time frame: Baseline, 24 hours post-first IV Artesunate dose, 48 hours post-first IV Artesunate dose, Time of completion of planned IV Artesunate dosing (72 hours post-first IV Artesunate dose), and Time of first hospital discharge (up to day 9)
DHA Cmax Summary Statistics for Participants With BCS of 1 in the Primary Analysis Population
Blantyre coma scale is an ordinal scale designed to assess malarial coma in children. Eye movement, best motor response, and best verbal response were assessed and scored. The total BCS score was then calculated as the sum of the scores for these three assessments with possible values of 0, 1, 2, 3, 4, or 5. Lower BCS values were indicative of impaired consciousness. BCS was recorded daily until discharge along with scheduled follow-up visits. The number of participants in each BCS were reported at pre-defined timepoints: baseline, 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Due to the lack of variability in BCS scores, proportional odds mixed effects models to assess the relationship between BCS scores and each PK exposure parameter were not conducted. Instead, summary statistics of DHA Cmax for BCS score of 1 by timepoint are presented.
Time frame: Baseline, 24 hours post-first IV Artesunate dose, 48 hours post-first IV Artesunate dose, Time of completion of planned IV Artesunate dosing (72 hours post-first IV Artesunate dose), and Time of first hospital discharge (up to day 9)
DHA Cmax Summary Statistics for Participants With BCS of 4 in the Primary Analysis Population
Blantyre coma scale is an ordinal scale designed to assess malarial coma in children. Eye movement, best motor response, and best verbal response were assessed and scored. The total BCS score was then calculated as the sum of the scores for these three assessments with possible values of 0, 1, 2, 3, 4, or 5. Lower BCS values were indicative of impaired consciousness. BCS was recorded daily until discharge along with scheduled follow-up visits. The number of participants in each BCS were reported at pre-defined timepoints: baseline, 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Due to the lack of variability in BCS scores, proportional odds mixed effects models to assess the relationship between BCS scores and each PK exposure parameter were not conducted. Instead, summary statistics of DHA Cmax for BCS score of 4 by timepoint are presented.
Time frame: Baseline, 24 hours post-first IV Artesunate dose, 48 hours post-first IV Artesunate dose, Time of completion of planned IV Artesunate dosing (72 hours post-first IV Artesunate dose), and Time of first hospital discharge (up to day 9)
DHA Cmax Summary Statistics for Participants With BCS of 5 in the Primary Analysis Population
Blantyre coma scale is an ordinal scale designed to assess malarial coma in children. Eye movement, best motor response, and best verbal response were assessed and scored. The total BCS score was then calculated as the sum of the scores for these three assessments with possible values of 0, 1, 2, 3, 4, or 5. Lower BCS values were indicative of impaired consciousness. BCS was recorded daily until discharge along with scheduled follow-up visits. The number of participants in each BCS were reported at pre-defined timepoints: baseline, 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Due to the lack of variability in BCS scores, proportional odds mixed effects models to assess the relationship between BCS scores and each PK exposure parameter were not conducted. Instead, summary statistics of DHA Cmax for BCS score of 5 by timepoint are presented.
Time frame: Baseline, 24 hours post-first IV Artesunate dose, 48 hours post-first IV Artesunate dose, Time of completion of planned IV Artesunate dosing (72 hours post-first IV Artesunate dose), and Time of first hospital discharge (up to day 9)
DHA Cmax Summary Statistics for Participants With BCS of 4 in the Subset Who Did Not Receive Any IV Artesunate or Other Artemisinin-based Therapy Before Enrollment
Blantyre coma scale is an ordinal scale designed to assess malarial coma in children. Eye movement, best motor response, and best verbal response were assessed and scored. The total BCS score was then calculated as the sum of the scores for these three assessments with possible values of 0, 1, 2, 3, 4, or 5. Lower BCS values were indicative of impaired consciousness. BCS was recorded daily until discharge along with scheduled follow-up visits. The number of participants in each BCS were reported at pre-defined timepoints: baseline, 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Due to the lack of variability in BCS scores, proportional odds mixed effects models to assess the relationship between BCS scores and each PK exposure parameter were not conducted. Instead, summary statistics of DHA Cmax for BCS score of 4 by timepoint are presented. Only participants who were assessed a BCS of 4 are shown.
Time frame: Baseline, 24 hours post-first IV Artesunate dose, 48 hours post-first IV Artesunate dose, Time of completion of planned IV Artesunate dosing (72 hours post-first IV Artesunate dose), and Time of first hospital discharge (up to day 9)
DHA Cmax Summary Statistics for Participants With BCS of 5 in the Subset Who Did Not Receive Any IV Artesunate or Other Artemisinin-based Therapy Before Enrollment
Blantyre coma scale is an ordinal scale designed to assess malarial coma in children. Eye movement, best motor response, and best verbal response were assessed and scored. The total BCS score was then calculated as the sum of the scores for these three assessments with possible values of 0, 1, 2, 3, 4, or 5. Lower BCS values were indicative of impaired consciousness. BCS was recorded daily until discharge along with scheduled follow-up visits. The number of participants in each BCS were reported at pre-defined timepoints: baseline, 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Due to the lack of variability in BCS scores, proportional odds mixed effects models to assess the relationship between BCS scores and each PK exposure parameter were not conducted. Instead, summary statistics of DHA Cmax for BCS score of 5 by timepoint are presented.
Time frame: Baseline, 24 hours post-first IV Artesunate dose, 48 hours post-first IV Artesunate dose, Time of completion of planned IV Artesunate dosing (72 hours post-first IV Artesunate dose), and Time of first hospital discharge (up to day 9)
DHA t1/2 Summary Statistics for Participants With BCS of 1 in the Primary Analysis Population
Blantyre coma scale is an ordinal scale designed to assess malarial coma in children. Eye movement, best motor response, and best verbal response were assessed and scored. The total BCS score was then calculated as the sum of the scores for these three assessments with possible values of 0, 1, 2, 3, 4, or 5. Lower BCS values were indicative of impaired consciousness. BCS was recorded daily until discharge along with scheduled follow-up visits. The number of participants in each BCS were reported at pre-defined timepoints: baseline, 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Due to the lack of variability in BCS scores, proportional odds mixed effects models to assess the relationship between BCS scores and each PK exposure parameter were not conducted. Instead, summary statistics of DHA t1/2 for BCS score of 1 by timepoint are presented.
Time frame: Baseline, 24 hours post-first IV Artesunate dose, 48 hours post-first IV Artesunate dose, Time of completion of planned IV Artesunate dosing (72 hours post-first IV Artesunate dose), and Time of first hospital discharge (up to day 9)
DHA t1/2 Summary Statistics for Participants With BCS of 4 in the Primary Analysis Population
Blantyre coma scale is an ordinal scale designed to assess malarial coma in children. Eye movement, best motor response, and best verbal response were assessed and scored. The total BCS score was then calculated as the sum of the scores for these three assessments with possible values of 0, 1, 2, 3, 4, or 5. Lower BCS values were indicative of impaired consciousness. BCS was recorded daily until discharge along with scheduled follow-up visits. The number of participants in each BCS were reported at pre-defined timepoints: baseline, 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Due to the lack of variability in BCS scores, proportional odds mixed effects models to assess the relationship between BCS scores and each PK exposure parameter were not conducted. Instead, summary statistics of DHA t1/2 for BCS score of 4 by timepoint are presented.
Time frame: Baseline, 24 hours post-first IV Artesunate dose, 48 hours post-first IV Artesunate dose, Time of completion of planned IV Artesunate dosing (72 hours post-first IV Artesunate dose), and Time of first hospital discharge (up to day 9)
DHA t1/2 Summary Statistics for Participants With BCS of 5 in the Primary Analysis Population
Blantyre coma scale is an ordinal scale designed to assess malarial coma in children. Eye movement, best motor response, and best verbal response were assessed and scored. The total BCS score was then calculated as the sum of the scores for these three assessments with possible values of 0, 1, 2, 3, 4, or 5. Lower BCS values were indicative of impaired consciousness. BCS was recorded daily until discharge along with scheduled follow-up visits. The number of participants in each BCS were reported at pre-defined timepoints: baseline, 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Due to the lack of variability in BCS scores, proportional odds mixed effects models to assess the relationship between BCS scores and each PK exposure parameter were not conducted. Instead, summary statistics of DHA t1/2 for BCS score of 5 by timepoint are presented.
Time frame: Baseline, 24 hours post-first IV Artesunate dose, 48 hours post-first IV Artesunate dose, Time of completion of planned IV Artesunate dosing (72 hours post-first IV Artesunate dose), and Time of first hospital discharge (up to day 9)
DHA t1/2 Summary Statistics for Participants With BCS of 4 in the Subset Who Did Not Receive Any IV Artesunate or Other Artemisinin-based Therapy Before Enrollment
Blantyre coma scale is an ordinal scale designed to assess malarial coma in children. Eye movement, best motor response, and best verbal response were assessed and scored. The total BCS score was then calculated as the sum of the scores for these three assessments with possible values of 0, 1, 2, 3, 4, or 5. Lower BCS values were indicative of impaired consciousness. BCS was recorded daily until discharge along with scheduled follow-up visits. The number of participants in each BCS were reported at pre-defined timepoints: baseline, 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Due to the lack of variability in BCS scores, proportional odds mixed effects models to assess the relationship between BCS scores and each PK exposure parameter were not conducted. Instead, summary statistics of DHA t1/2 for BCS score of 4 by timepoint are presented. Only participants who were assessed a BCS of 4 are shown.
Time frame: Baseline, 24 hours post-first IV Artesunate dose, 48 hours post-first IV Artesunate dose, Time of completion of planned IV Artesunate dosing (72 hours post-first IV Artesunate dose), and Time of first hospital discharge (up to day 9)
DHA t1/2 Summary Statistics for Participants With BCS of 5 in the Subset Who Did Not Receive Any IV Artesunate or Other Artemisinin-based Therapy Before Enrollment
Blantyre coma scale is an ordinal scale designed to assess malarial coma in children. Eye movement, best motor response, and best verbal response were assessed and scored. The total BCS score was then calculated as the sum of the scores for these three assessments with possible values of 0, 1, 2, 3, 4, or 5. Lower BCS values were indicative of impaired consciousness. BCS was recorded daily until discharge along with scheduled follow-up visits. The number of participants in each BCS were reported at pre-defined timepoints: baseline, 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Due to the lack of variability in BCS scores, proportional odds mixed effects models to assess the relationship between BCS scores and each PK exposure parameter were not conducted. Instead, summary statistics of DHA t1/2 for BCS score of 5 by timepoint are presented.
Time frame: Baseline, 24 hours post-first IV Artesunate dose, 48 hours post-first IV Artesunate dose, Time of completion of planned IV Artesunate dosing (72 hours post-first IV Artesunate dose), and Time of first hospital discharge (up to day 9)
Time to Hospital Discharge in the Primary Analysis Population
Dates and times of hospital admittance and discharge for each participant were collected for calculation of time to hospital discharge. Time to hospital discharge was defined as the time in days from initial participant admission to the time of first discharge. Time to hospital discharge was calculated using the actual dates and times of initial participant admission and first discharge and was rounded to the nearest tenths place.
Time frame: Day 1 through Day 9
Time to Hospital Discharge in the Subset Who Did Not Receive Any IV Artesunate or Other Artemisinin-based Therapy Before Enrollment
Dates and times of hospital admittance and discharge for each participant were collected for calculation of time to hospital discharge. Time to hospital discharge was defined as the time in days from initial participant admission to the time of first discharge. Time to hospital discharge was calculated using the actual dates and times of initial participant admission and first discharge and was rounded to the nearest tenths place.
Time frame: Day 1 through Day 9
Parasite (Plasmodium Falciparum) Density in Thick Blood Smear in the Primary Analysis Population
Parasite clearance as calculated from parasite density over time, as measured by thick blood smear. Parasite density is defined as the number of parasites per 200 white blood cells (WBCs). Parasite clearance half-life (PCT50) and parasite clearance time to 90% reduction (PCT90) were estimated using the WorldWide Antimalarial Resistance Network (WWARN) parasite clearance estimator (PCE) algorithm.
Time frame: Day 1 through Day 7 (Samples were collected according to the following schedule post-first on-study dose of IV artesunate in hours: 0, 6, 12, 24, 36, and 48 hours, and at least every 24 hours until clearance.)
Parasite (P. Falciparum) Density in Thick Blood Smear in the Subset Who Did Not Receive Any IV Artesunate or Other Artemisinin-based Therapy Before Enrollment
Parasite clearance as calculated from parasite density over time, as measured by thick blood smear. Parasite density is defined as the number of parasites per 200 white blood cells (WBCs). Parasite clearance half-life (PCT50) and parasite clearance time to 90% reduction (PCT90) were estimated using the WorldWide Antimalarial Resistance Network (WWARN) parasite clearance estimator (PCE) algorithm.
Time frame: Day 1 through Day 7 (Samples were collected according to the following schedule post-first on-study dose of IV artesunate in hours: 0, 6, 12, 24, 36, and 48 hours, and at least every 24 hours until clearance.)
Number of Participants With Parasite (P. Falciparum) Clearance in the Primary Analysis Population
Total parasite clearance was defined as the first negative thick blood smear (i.e., a thick blood smear for which there were no detectable P. falciparum parasites per 200 WBC) after a participant's last positive blood smear for P. falciparum. The date and time of total parasite clearance was defined as the collection date and time of the first thick blood smear to meet the definition of parasite clearance. Total parasite clearance by Day 2 was defined as a binary variable indicating whether total parasite clearance occurred within the first 50 hours post-first on-study dose of IV artesunate.
Time frame: Day 1 through Day 7 (Samples were collected according to the following schedule post-first on-study dose of IV artesunate in hours: 0, 6, 12, 24, 36, and 48 hours, and at least every 24 hours until clearance.)
Number of Participants With Parasite (P. Falciparum) Clearance in the Subset Who Did Not Receive Any IV Artesunate or Other Artemisinin-based Therapy Before Enrollment
Total parasite clearance was defined as the first negative thick blood smear (i.e., a thick blood smear for which there were no detectable P. falciparum parasites per 200 WBC) after a participant's last positive blood smear for P. falciparum. The date and time of total parasite clearance was defined as the collection date and time of the first thick blood smear to meet the definition of parasite clearance. Total parasite clearance by Day 2 was defined as a binary variable indicating whether total parasite clearance occurred within the first 50 hours post-first on-study dose of IV artesunate.
Time frame: Day 1 through Day 7 (Samples were collected according to the following schedule post-first on-study dose of IV artesunate in hours: 0, 6, 12, 24, 36, and 48 hours, and at least every 24 hours until clearance.)
The study population included participants aged 6 months through 14 years old residing in Tororo District, Uganda, who met all eligibility criteria, including a diagnosis of severe malaria. Ninety participants were enrolled between 29 November 2023 and 13 October 2024.
| Milestone | Standard of Care IV Artesunate |
|---|---|
| Started | 90 |
| Completed | 83 |
| Not completed | 7 |
| Withdrew: Death | 1 |
| Withdrew: Withdrawal by subject | 4 |
| Withdrew: Failure to meet enrollment criteria | 2 |
Population Pharmacokinetic (PK) modeling was conducted to derive Cmax from the concentration of DHA. The final model fit was a 1-compartment disposition of DHA with covariates for age and baseline bilirubin.
| ug/L | Standard of Care IV Artesunate |
|---|---|
| Maximum Concentration (Cmax) of Dihydroartemisinin (DHA) | 4,361.09 (3,488.88 to 4,368.38) |
Population PK modeling was conducted to derive AUC0-12 from the concentration of DHA. The final model fit was a 1-compartment disposition of DHA with covariates for age and baseline bilirubin. Day 1 (Sampling windows were defined as 0 (pre-dose), 0-1 hour, 1 - 2.5, 2.5-4, 4-6 and 6-24 hours post first on-study dose of IV artesunate)
| ug*h/L | Standard of Care IV Artesunate |
|---|---|
| Area Under the Curve Over 0-12 Hours (AUC0-12) of DHA | 4,417.88 (1,966.87 to 9,390.38) |
Population PK modeling was conducted to derive t1/2 from the concentration of DHA. The final model fit was a 1-compartment disposition of DHA with covariates for age and baseline bilirubin.
| h | Standard of Care IV Artesunate |
|---|---|
| Half-life (t1/2) of DHA | 0.74 (0.39 to 1.50) |
Population Pharmacokinetic (PK) modeling was conducted to derive PK parameters from the concentration of DHA. The final model fit was a 1-compartment disposition of DHA with covariates for age and baseline bilirubin. From the simulation, the Tmax was assumed to be 0 as the simulation replicates artesunate administered as an IV bolus directly into the central compartment.
| h | Standard of Care IV Artesunate |
|---|---|
| Time to Cmax (Tmax) of DHA | 0 (0 to 0) |
Temperature was recorded approximately every 6 hours until 6 hours post-parasite clearance and at least daily until discharge along with scheduled follow-up visits. Change from baseline in temperature was reported at pre-defined timepoints: 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Primary exposure-response analyses were performed to assess the relationship between DHA PK Parameters (AUC0-12, Cmax, and t1/2) and temperature. Many participants did not have unique measurements collected for each of the four timepoints defined, therefore these participants were using the same values at multiple timepoints. To meet the independence assumption of the Benjamini-Hochberg procedure, only 24-hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time to first hospital discharge had models fit and were assessed for significance for temperature.
| degrees C | Standard of Care IV Artesunate |
|---|---|
| 24 hours post-first IV Artesunate dose | -1.30 (-4.3 to 2.3) |
| 48 hours post-first IV Artesunate dose | -1.80 (-4.6 to 0.5) |
| Time of completion of planned IV Artesunate dosing | -1.30 (-4.3 to 1.5) |
| Time of first hospital discharge | -1.9 (-4.3 to 0.4) |
Temperature was recorded approximately every 6 hours until 6 hours post-parasite clearance and at least daily until discharge along with scheduled follow-up visits. Change from baseline in temperature was reported at pre-defined timepoints: 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Primary exposure-response analyses were performed to assess the relationship between DHA PK parameters (AUC0-12, Cmax, and t1/2) and temperature. Many participants did not have unique measurements collected for each of the four timepoints defined, therefore these participants were using the same values at multiple timepoints. To meet the independence assumption of the Benjamini-Hochberg procedure, only 24-hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time to first hospital discharge had models fit and were assessed for significance for temperature.
| degrees C | Standard of Care IV Artesunate |
|---|---|
| 24 hours post-first IV Artesunate dose | -1.10 (-4.3 to 2.3) |
| 48 hours post-first IV Artesunate dose | -1.70 (-4.3 to 0.4) |
| Time of completion of planned IV Artesunate dosing | -1.05 (-4.3 to 1.5) |
| Time of first hospital discharge | -2.10 (-4.3 to 0.4) |
Systolic BP was recorded approximately every 6 hours until 6 hours post-parasite clearance and at least daily until discharge along with scheduled follow-up visits. Change from baseline in systolic BP was reported at pre-defined timepoints: 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Primary exposure-response analyses were performed to assess the relationship between DHA PK parameters (AUC0-12, Cmax, and t1/2) and systolic BP. Many participants did not have unique measurements collected for each of the four timepoints defined, thus these participants were using the same values at multiple timepoints. To meet the independence assumption of the Benjamini-Hochberg procedure, only 24-hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time to first hospital discharge had models fit and were assessed for significance for systolic BP.
| mmHg | Standard of Care IV Artesunate |
|---|---|
| 24 hours post-first IV Artesunate dose | -1.0 (-43 to 59) |
| 48 hours post-first IV Artesunate dose | 0.0 (-31 to 23) |
| Time of completion of planned IV Artesunate dosing | -1.0 (-39 to 20) |
| Time of first hospital discharge | -3.0 (-41 to 27) |
Systolic BP was recorded approximately every 6 hours until 6 hours post-parasite clearance and at least daily until discharge along with scheduled follow-up visits. Change from baseline in systolic BP was reported at pre-defined timepoints: 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Primary exposure-response analyses were performed to assess the relationship between DHA PK parameters (AUC0-12, Cmax, and t1/2) and systolic BP. Many participants did not have unique measurements collected for each of the four timepoints defined, thus these participants were using the same values at multiple timepoints. To meet the independence assumption of the Benjamini-Hochberg procedure, only 24-hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time to first hospital discharge had models fit and were assessed for significance for systolic BP.
| mmHg | Standard of Care IV Artesunate |
|---|---|
| 24 hours post-first IV Artesunate dose | -2.5 (-33 to 59) |
| 48 hours post-first IV Artesunate dose | 0.0 (-31 to 23) |
| Time of completion of planned IV Artesunate dosing | -1.0 (-19 to 20) |
| Time of first hospital discharge | 0.0 (-41 to 27) |
Diastolic BP was recorded approximately every 6 hours until 6 hours post-parasite clearance and at least daily until discharge along with scheduled follow-up visits. Change from baseline in diastolic BP was reported at pre-defined timepoints: 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Primary exposure-response analyses were performed to assess the relationship between DHA PK parameters (AUC0-12, Cmax, t1/2) and diastolic BP. Many participants did not have unique measurements collected for each of the four timepoints defined, therefore these participants were using the same values at multiple timepoints. To meet the independence assumption of the Benjamini-Hochberg procedure, only 24-hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time to first hospital discharge had models fit and were assessed for significance for diastolic BP.
| mmHg | Standard of Care IV Artesunate |
|---|---|
| 24 hours post-first IV Artesunate dose | -0.5 (-42 to 39) |
| 48 hours post-first IV Artesunate dose | -2.0 (-35 to 26) |
| Time of completion of planned IV Artesunate dosing | -1.5 (-24 to 29) |
| Time of first hospital discharge | -2.0 (-38 to 31) |
Diastolic BP was recorded approximately every 6 hours until 6 hours post-parasite clearance and at least daily until discharge along with scheduled follow-up visits. Change from baseline in diastolic BP was reported at pre-defined timepoints: 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Primary exposure-response analyses were performed to assess the relationship between DHA PK parameters (AUC0-12, Cmax, and t1/2) and diastolic BP. Many participants did not have unique measurements collected for each of the four timepoints defined, thus these participants were using the same values at multiple timepoints. To meet the independence assumption of the Benjamini-Hochberg procedure, only 24-hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time to first hospital discharge had models fit and were assessed for significance for diastolic BP.
| mmHg | Standard of Care IV Artesunate |
|---|---|
| 24 hours post-first IV Artesunate dose | -1.5 (-42 to 39) |
| 48 hours post-first IV Artesunate dose | -1.0 (-35 to 26) |
| Time of completion of planned IV Artesunate dosing | -1.5 (-24 to 29) |
| Time of first hospital discharge | -2.5 (-38 to 27) |
Serum lactate was recorded daily until discharge along with scheduled follow-up visits. Change from baseline in serum lactate was reported at pre-defined timepoints: 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Primary exposure-response analyses were performed to assess the relationship between DHA PK parameters (AUC0-12, Cmax, t1/2) and serum lactate. Many participants did not have unique measurements collected for each of the four timepoints defined, therefore these participants were using the same values at multiple timepoints. To meet the independence assumption of the Benjamini-Hochberg procedure, only 24-hours post-first IV artesunate and time of completion of planned IV artesunate dosing had models fit and were assessed for significance for serum lactate.
| mmol/L | Standard of Care IV Artesunate |
|---|---|
| 24 hours post-first IV Artesunate dose | 0.000 (-8.30 to 9.41) |
| 48 hours post-first IV Artesunate dose | -0.700 (-7.29 to 8.47) |
| Time of completion of planned IV Artesunate dosing | -0.760 (-7.29 to 8.47) |
| Time of first hospital discharge | -0.430 (-8.30 to 8.19) |
Serum lactate was recorded daily until discharge along with scheduled follow-up visits. Change from baseline in serum lactate was reported at pre-defined timepoints: 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Primary exposure-response analyses were performed to assess the relationship between DHA PK parameters (AUC0-12, Cmax, t1/2) and serum lactate. Many participants did not have unique measurements collected for each of the four timepoints defined, therefore these participants were using the same values at multiple timepoints. To meet the independence assumption of the Benjamini-Hochberg procedure, only 24-hours post-first IV artesunate and time of completion of planned IV artesunate dosing had models fit and were assessed for significance for serum lactate.
| mmol/L | Standard of Care IV Artesunate |
|---|---|
| 24 hours post-first IV Artesunate dose | -0.090 (-8.30 to 9.41) |
| 48 hours post-first IV Artesunate dose | -0.865 (-7.29 to 8.47) |
| Time of completion of planned IV Artesunate dosing | -0.865 (-7.29 to 8.47) |
| Time of first hospital discharge | -0.445 (-8.30 to 8.19) |
Serum bicarbonate was recorded daily until discharge along with scheduled follow-up visits. Change from baseline in serum bicarbonate was reported at pre-defined timepoints: 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Primary exposure-response analyses were performed to assess the relationship between DHA PK parameters (AUC0-12, Cmax, t1/2) and serum bicarbonate. Many participants did not have unique measurements collected for each of the four timepoints defined, therefore these participants were using the same values at multiple timepoints. To meet the independence assumption of the Benjamini-Hochberg procedure, only 24-hours post-first IV artesunate and time of completion of planned IV artesunate dosing had models fit and were assessed for significance for serum bicarbonate.
| mmol/L | Standard of Care IV Artesunate |
|---|---|
| 24 hours post-first IV Artesunate dose | 1.0 (-6 to 24) |
| 48 hours post-first IV Artesunate dose | 2.0 (-10 to 13) |
| Time of completion of planned IV Artesunate dosing | 2.0 (-8 to 13) |
| Time of first hospital discharge | 1.0 (-10 to 13) |
Serum bicarbonate was recorded daily until discharge along with scheduled follow-up visits. Change from baseline in serum bicarbonate was reported at pre-defined timepoints: 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Primary exposure-response analyses were performed to assess the relationship between DHA PK parameters (AUC0-12, Cmax, t1/2) and serum bicarbonate. Many participants did not have unique measurements collected for each of the four timepoints defined, therefore these participants were using the same values at multiple timepoints. To meet the independence assumption of the Benjamini-Hochberg procedure, only 24-hours post-first IV artesunate and time of completion of planned IV artesunate dosing had models fit and were assessed for significance for serum bicarbonate.
| mmol/L | Standard of Care IV Artesunate |
|---|---|
| 24 hours post-first IV Artesunate dose | 1.0 (-6 to 24) |
| 48 hours post-first IV Artesunate dose | 2.0 (-8 to 13) |
| Time of completion of planned IV Artesunate dosing | 2.0 (-8 to 13) |
| Time of first hospital discharge | 1.0 (-6 to 13) |
Serum glucose was recorded daily until discharge along with scheduled follow-up visits. Change from baseline in serum glucose was reported at pre-defined timepoints: 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Primary exposure-response analyses were performed to assess the relationship between DHA PK parameters (AUC0-12, Cmax, t1/2) and serum glucose. Many participants did not have unique measurements collected for each of the four timepoints defined, therefore these participants were using the same values at multiple timepoints. To meet the independence assumption of the Benjamini-Hochberg procedure, only 24-hours post-first IV artesunate and time of completion of planned IV artesunate dosing had models fit and were assessed for significance for serum glucose.
| mmol/L | Standard of Care IV Artesunate |
|---|---|
| 24 hours post-first IV Artesunate dose | 0.15 (-4.7 to 7.6) |
| 48 hours post-first IV Artesunate dose | -0.50 (-5.7 to 1.8) |
| Time of completion of planned IV Artesunate dosing | -0.50 (-5.7 to 1.8) |
| Time of first hospital discharge | -0.10 (-4.4 to 7.6) |
Serum glucose was recorded daily until discharge along with scheduled follow-up visits. Change from baseline in serum glucose was reported at pre-defined timepoints: 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Primary exposure-response analyses were performed to assess the relationship between DHA PK parameters (AUC0-12, Cmax, t1/2) and serum glucose. Many participants did not have unique measurements collected for each of the four timepoints defined, therefore these participants were using the same values at multiple timepoints. To meet the independence assumption of the Benjamini-Hochberg procedure, only 24-hours post-first IV artesunate and time of completion of planned IV artesunate dosing had models fit and were assessed for significance for serum glucose.
| mmol/L | Standard of Care IV Artesunate |
|---|---|
| 24 hours post-first IV Artesunate dose | 0.10 (-4.7 to 7.6) |
| 48 hours post-first IV Artesunate dose | -0.55 (-5.7 to 1.8) |
| Time of completion of planned IV Artesunate dosing | -0.55 (-5.7 to 1.8) |
| Time of first hospital discharge | -0.10 (-4.4 to 7.6) |
Total bilirubin was recorded daily until discharge along with scheduled follow-up visits. Change from baseline in total bilirubin was reported at pre-defined timepoints: 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Primary exposure-response analyses were performed to assess the relationship between DHA PK parameters (AUC0-12, Cmax, t1/2) and total bilirubin. Many participants did not have unique measurements collected for each of the four timepoints defined, therefore these participants were using the same values at multiple timepoints. To meet the independence assumption of the Benjamini-Hochberg procedure, only 24-hours post-first IV artesunate and time of completion of planned IV artesunate dosing had models fit and were assessed for significance for total bilirubin.
| umol/L | Standard of Care IV Artesunate |
|---|---|
| 24 hours post-first IV Artesunate dose | -4.0 (-35 to 20) |
| 48 hours post-first IV Artesunate dose | -11.0 (-95 to 45) |
| Time of completion of planned IV Artesunate dosing | -11.0 (-95 to 5) |
| Time of first hospital discharge | -6.0 (-95 to 20) |
Total bilirubin was recorded daily until discharge along with scheduled follow-up visits. Change from baseline in total bilirubin was reported at pre-defined timepoints: 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Primary exposure-response analyses were performed to assess the relationship between DHA PK parameters (AUC0-12, Cmax, t1/2) and total bilirubin. Many participants did not have unique measurements collected for each of the four timepoints defined, therefore these participants were using the same values at multiple timepoints. To meet the independence assumption of the Benjamini-Hochberg procedure, only 24-hours post-first IV artesunate and time of completion of planned IV artesunate dosing had models fit and were assessed for significance for total bilirubin.
| umol/L | Standard of Care IV Artesunate |
|---|---|
| 24 hours post-first IV Artesunate dose | -3.5 (-35 to 20) |
| 48 hours post-first IV Artesunate dose | -11.0 (-65 to 5) |
| Time of completion of planned IV Artesunate dosing | -11.0 (-65 to 5) |
| Time of first hospital discharge | -5.0 (-39 to 20) |
Direct bilirubin was recorded daily until discharge along with scheduled follow-up visits. Change from baseline in direct bilirubin was reported at pre-defined timepoints: 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Primary exposure-response analyses were performed to assess the relationship between DHA PK parameters (AUC0-12, Cmax, t1/2) and direct bilirubin. Many participants did not have unique measurements collected for each of the four timepoints defined, therefore these participants were using the same values at multiple timepoints. To meet the independence assumption of the Benjamini-Hochberg procedure, only 24-hours post-first IV artesunate and time of completion of planned IV artesunate dosing had models fit and were assessed for significance for direct bilirubin.
| umol/L | Standard of Care IV Artesunate |
|---|---|
| 24 hours post-first IV Artesunate dose | -1.0 (-26 to 7) |
| 48 hours post-first IV Artesunate dose | -3.0 (-69 to 40) |
| Time of completion of planned IV Artesunate dosing | -3.0 (-69 to 3) |
| Time of first hospital discharge | -2.0 (-26 to 7) |
Direct bilirubin was recorded daily until discharge along with scheduled follow-up visits. Change from baseline in direct bilirubin was reported at pre-defined timepoints: 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Primary exposure-response analyses were performed to assess the relationship between DHA PK parameters (AUC0-12, Cmax, t1/2) and direct bilirubin. Many participants did not have unique measurements collected for each of the four timepoints defined, therefore these participants were using the same values at multiple timepoints. To meet the independence assumption of the Benjamini-Hochberg procedure, only 24-hours post-first IV artesunate and time of completion of planned IV artesunate dosing had models fit and were assessed for significance for direct bilirubin.
| umol/L | Standard of Care IV Artesunate |
|---|---|
| 24 hours post-first IV Artesunate dose | -1.0 (-26 to 7) |
| 48 hours post-first IV Artesunate dose | -4.0 (-69 to 3) |
| Time of completion of planned IV Artesunate dosing | -4.0 (-69 to 3) |
| Time of first hospital discharge | -2.0 (-26 to 7) |
Hemoglobin was recorded daily until discharge along with scheduled follow-up visits. Change from baseline in hemoglobin was reported at pre-defined timepoints: 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Primary exposure-response analyses were performed to assess the relationship between DHA PK parameters (AUC0-12, Cmax, t1/2) and hemoglobin. Many participants did not have unique measurements collected for each of the four timepoints defined, therefore these participants were using the same values at multiple timepoints. To meet the independence assumption of the Benjamini-Hochberg procedure, only 24-hours post-first IV artesunate and time of completion of planned IV artesunate dosing had models fit and were assessed for significance for hemoglobin.
| g/dL | Standard of Care IV Artesunate |
|---|---|
| 24 hours post-first IV Artesunate dose | -0.70 (-15.1 to 9.7) |
| 48 hours post-first IV Artesunate dose | -0.80 (-15.2 to 8.7) |
| Time of completion of planned IV Artesunate dosing | -0.80 (-15.2 to 8.7) |
| Time of first hospital discharge | -0.70 (-15.1 to 8.7) |
Hemoglobin was recorded daily until discharge along with scheduled follow-up visits. Change from baseline in hemoglobin was reported at pre-defined timepoints: 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Primary exposure-response analyses were performed to assess the relationship between DHA PK parameters (AUC0-12, Cmax, t1/2) and hemoglobin. Many participants did not have unique measurements collected for each of the four timepoints defined, therefore these participants were using the same values at multiple timepoints. To meet the independence assumption of the Benjamini-Hochberg procedure, only 24-hours post-first IV artesunate and time of completion of planned IV artesunate dosing had models fit and were assessed for significance for hemoglobin.
| g/dL | Standard of Care IV Artesunate |
|---|---|
| 24 hours post-first IV Artesunate dose | -0.70 (-15.1 to 9.7) |
| 48 hours post-first IV Artesunate dose | -0.80 (-15.2 to 8.7) |
| Time of completion of planned IV Artesunate dosing | -0.80 (-15.2 to 8.7) |
| Time of first hospital discharge | -0.70 (-15.1 to 8.7) |
Creatinine was recorded daily until discharge along with scheduled follow-up visits. Change from baseline in creatinine was reported at pre-defined timepoints: 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Primary exposure-response analyses were performed to assess the relationship between DHA PK parameters (AUC0-12, Cmax, t1/2) and creatinine. Many participants did not have unique measurements collected for each of the four timepoints defined, therefore these participants were using the same values at multiple timepoints. To meet the independence assumption of the Benjamini-Hochberg procedure, only 24-hours post-first IV artesunate and time of completion of planned IV artesunate dosing had models fit and were assessed for significance for creatinine.
| umol/L | Standard of Care IV Artesunate |
|---|---|
| 24 hours post-first IV Artesunate dose | -4.0 (-22 to 21) |
| 48 hours post-first IV Artesunate dose | -5.0 (-41 to 15) |
| Time of completion of planned IV Artesunate dosing | -5.0 (-41 to 15) |
| Time of first hospital discharge | -3.0 (-39 to 21) |
Creatinine was recorded daily until discharge along with scheduled follow-up visits. Change from baseline in creatinine was reported at pre-defined timepoints: 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Primary exposure-response analyses were performed to assess the relationship between DHA PK parameters (AUC0-12, Cmax, t1/2) and creatinine. Many participants did not have unique measurements collected for each of the four timepoints defined, therefore these participants were using the same values at multiple timepoints. To meet the independence assumption of the Benjamini-Hochberg procedure, only 24-hours post-first IV artesunate and time of completion of planned IV artesunate dosing had models fit and were assessed for significance for creatinine.
| g/dL | Standard of Care IV Artesunate |
|---|---|
| 24 hours post-first IV Artesunate dose | -4.0 (-22 to 21) |
| 48 hours post-first IV Artesunate dose | -5.0 (-24 to 11) |
| Time of completion of planned IV Artesunate dosing | -5.0 (-24 to 11) |
| Time of first hospital discharge | -3.0 (-24 to 21) |
Blantyre coma scale is an ordinal scale designed to assess malarial coma in children. Eye movement, best motor response, and best verbal response were assessed and scored. The total BCS score was then calculated as the sum of the scores for these three assessments with possible values of 0, 1, 2, 3, 4, or 5. Lower BCS values were indicative of impaired consciousness. BCS was recorded daily until discharge along with scheduled follow-up visits. The number of participants in each BCS were reported at pre-defined timepoints: baseline, 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Due to the lack of variability in BCS scores, proportional odds mixed effects models to assess the relationship between BCS scores and each PK exposure parameter were not conducted. Instead, summary statistics of DHA AUC0-12 for BCS score of 1 by timepoint are presented.
| ng*h/mL | Standard of Care IV Artesunate |
|---|---|
| Baseline | 5357.830 (5357.83 to 5357.83) |
| 24 hours post-first IV Artesunate dose | 5357.830 (5357.830 to 5357.830) |
| 48 hours post-first IV Artesunate dose | 5357.830 (5357.830 to 5357.830) |
Blantyre coma scale is an ordinal scale designed to assess malarial coma in children. Eye movement, best motor response, and best verbal response were assessed and scored. The total BCS score was then calculated as the sum of the scores for these three assessments with possible values of 0, 1, 2, 3, 4, or 5. Lower BCS values were indicative of impaired consciousness. BCS was recorded daily until discharge along with scheduled follow-up visits. The number of participants in each BCS were reported at pre-defined timepoints: baseline, 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Due to the lack of variability in BCS scores, proportional odds mixed effects models to assess the relationship between BCS scores and each PK exposure parameter were not conducted. Instead, summary statistics of DHA AUC0-12 for BCS score of 4 by timepoint are presented.
| ng*h/mL | Standard of Care IV Artesunate |
|---|---|
| Baseline | 5271.585 (4054.71 to 6488.46) |
| 24 hours post-first IV Artesunate dose | 6488.460 (6488.460 to 6488.460) |
| 48 hours post-first IV Artesunate dose | 6488.460 (6488.460 to 6488.460) |
| Time of completion of planned IV Artesunate dosing | 6488.460 (6488.460 to 6488.460) |
Blantyre coma scale is an ordinal scale designed to assess malarial coma in children. Eye movement, best motor response, and best verbal response were assessed and scored. The total BCS score was then calculated as the sum of the scores for these three assessments with possible values of 0, 1, 2, 3, 4, or 5. Lower BCS values were indicative of impaired consciousness. BCS was recorded daily until discharge along with scheduled follow-up visits. The number of participants in each BCS were reported at pre-defined timepoints: baseline, 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Due to the lack of variability in BCS scores, proportional odds mixed effects models to assess the relationship between BCS scores and each PK exposure parameter were not conducted. Instead, summary statistics of DHA AUC0-12 for BCS score of 5 by timepoint are presented.
| ng*h/mL | Standard of Care IV Artesunate |
|---|---|
| Baseline | 4377.195 (1966.87 to 9390.38) |
| 24 hours post-first IV Artesunate dose | 4374.420 (1966.87 to 9390.38) |
| 48 hours post-first IV Artesunate dose | 4374.420 (1966.87 to 9390.38) |
| Time of completion of planned IV Artesunate dosing | 4377.195 (1966.87 to 9390.38) |
| Time of first hospital discharge | 4377.195 (1966.87 to 9390.38) |
BCS is an ordinal scale designed to assess malarial coma in children. Eye movement, best motor response, and best verbal response were assessed and scored. The total BCS score was then calculated as the sum of the scores for these three assessments with possible values of 0, 1, 2, 3, 4, or 5. Lower BCS values were indicative of impaired consciousness. BCS was recorded daily until discharge along with scheduled follow-up visits. The number of participants in each BCS were reported at pre-defined timepoints: baseline, 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Due to the lack of variability in BCS scores, proportional odds mixed effects models to assess the relationship between BCS scores and each PK exposure parameter were not conducted. Instead, summary statistics of DHA AUC0-12 for BCS score of 4 by timepoint are presented. Only participants who were assessed a BCS of 4 are shown.
| ng*h/mL | Standard of Care IV Artesunate |
|---|---|
| Baseline | 4054.710 (4054.710 to 4054.710) |
Blantyre coma scale is an ordinal scale designed to assess malarial coma in children. Eye movement, best motor response, and best verbal response were assessed and scored. The total BCS score was then calculated as the sum of the scores for these three assessments with possible values of 0, 1, 2, 3, 4, or 5. Lower BCS values were indicative of impaired consciousness. BCS was recorded daily until discharge along with scheduled follow-up visits. The number of participants in each BCS were reported at pre-defined timepoints: baseline, 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Due to the lack of variability in BCS scores, proportional odds mixed effects models to assess the relationship between BCS scores and each PK exposure parameter were not conducted. Instead, summary statistics of DHA AUC0-12 for BCS score of 5 by timepoint are presented.
| ng*h/mL | Standard of Care IV Artesunate |
|---|---|
| Baseline | 4417.875 (1966.87 to 7070.97) |
| 24 hours post-first IV Artesunate dose | 4379.970 (1966.87 to 7070.97) |
| 48 hours post-first IV Artesunate dose | 4379.970 (1966.87 to 7070.97) |
| Time of completion of planned IV Artesunate dosing | 4379.970 (1966.87 to 7070.97) |
| Time of first hospital discharge | 4377.195 (1966.87 to 7070.97) |
Blantyre coma scale is an ordinal scale designed to assess malarial coma in children. Eye movement, best motor response, and best verbal response were assessed and scored. The total BCS score was then calculated as the sum of the scores for these three assessments with possible values of 0, 1, 2, 3, 4, or 5. Lower BCS values were indicative of impaired consciousness. BCS was recorded daily until discharge along with scheduled follow-up visits. The number of participants in each BCS were reported at pre-defined timepoints: baseline, 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Due to the lack of variability in BCS scores, proportional odds mixed effects models to assess the relationship between BCS scores and each PK exposure parameter were not conducted. Instead, summary statistics of DHA Cmax for BCS score of 1 by timepoint are presented.
| ng/mL | Standard of Care IV Artesunate |
|---|---|
| Baseline | 4361.170 (4361.170 to 4361.170) |
| 24 hours post-first IV Artesunate dose | 4361.170 (4361.170 to 4361.170) |
| 48 hours post-first IV Artesunate dose | 4361.170 (4361.170 to 4361.170) |
Blantyre coma scale is an ordinal scale designed to assess malarial coma in children. Eye movement, best motor response, and best verbal response were assessed and scored. The total BCS score was then calculated as the sum of the scores for these three assessments with possible values of 0, 1, 2, 3, 4, or 5. Lower BCS values were indicative of impaired consciousness. BCS was recorded daily until discharge along with scheduled follow-up visits. The number of participants in each BCS were reported at pre-defined timepoints: baseline, 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Due to the lack of variability in BCS scores, proportional odds mixed effects models to assess the relationship between BCS scores and each PK exposure parameter were not conducted. Instead, summary statistics of DHA Cmax for BCS score of 4 by timepoint are presented.
| ng/mL | Standard of Care IV Artesunate |
|---|---|
| Baseline | 4361.905 (4361.09 to 4362.72) |
| 24 hours post-first IV Artesunate dose | 4362.720 (4362.720 to 4362.720) |
| 48 hours post-first IV Artesunate dose | 4362.720 (4362.720 to 4362.720) |
| Time of completion of planned IV Artesunate dosing | 4362.720 (4362.720 to 4362.720) |
Blantyre coma scale is an ordinal scale designed to assess malarial coma in children. Eye movement, best motor response, and best verbal response were assessed and scored. The total BCS score was then calculated as the sum of the scores for these three assessments with possible values of 0, 1, 2, 3, 4, or 5. Lower BCS values were indicative of impaired consciousness. BCS was recorded daily until discharge along with scheduled follow-up visits. The number of participants in each BCS were reported at pre-defined timepoints: baseline, 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Due to the lack of variability in BCS scores, proportional odds mixed effects models to assess the relationship between BCS scores and each PK exposure parameter were not conducted. Instead, summary statistics of DHA Cmax for BCS score of 5 by timepoint are presented.
| ng/mL | Standard of Care IV Artesunate |
|---|---|
| Baseline | 4361.090 (3488.88 to 4368.38) |
| 24 hours post-first IV Artesunate dose | 4361.090 (3488.88 to 4368.38) |
| 48 hours post-first IV Artesunate dose | 4361.090 (3488.88 to 4368.38) |
| Time of completion of planned IV Artesunate dosing | 4361.090 (3488.88 to 4368.38) |
| Time of first hospital discharge | 4361.090 (3488.88 to 4368.38) |
Blantyre coma scale is an ordinal scale designed to assess malarial coma in children. Eye movement, best motor response, and best verbal response were assessed and scored. The total BCS score was then calculated as the sum of the scores for these three assessments with possible values of 0, 1, 2, 3, 4, or 5. Lower BCS values were indicative of impaired consciousness. BCS was recorded daily until discharge along with scheduled follow-up visits. The number of participants in each BCS were reported at pre-defined timepoints: baseline, 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Due to the lack of variability in BCS scores, proportional odds mixed effects models to assess the relationship between BCS scores and each PK exposure parameter were not conducted. Instead, summary statistics of DHA Cmax for BCS score of 4 by timepoint are presented. Only participants who were assessed a BCS of 4 are shown.
| ng/mL | Standard of Care IV Artesunate |
|---|---|
| Baseline | 4361.090 (4361.090 to 4361.090) |
Blantyre coma scale is an ordinal scale designed to assess malarial coma in children. Eye movement, best motor response, and best verbal response were assessed and scored. The total BCS score was then calculated as the sum of the scores for these three assessments with possible values of 0, 1, 2, 3, 4, or 5. Lower BCS values were indicative of impaired consciousness. BCS was recorded daily until discharge along with scheduled follow-up visits. The number of participants in each BCS were reported at pre-defined timepoints: baseline, 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Due to the lack of variability in BCS scores, proportional odds mixed effects models to assess the relationship between BCS scores and each PK exposure parameter were not conducted. Instead, summary statistics of DHA Cmax for BCS score of 5 by timepoint are presented.
| ng/mL | Standard of Care IV Artesunate |
|---|---|
| Baseline | 4361.090 (3488.88 to 4361.09) |
| 24 hours post-first IV Artesunate dose | 4361.090 (3488.88 to 4361.09) |
| 48 hours post-first IV Artesunate dose | 4361.090 (3488.88 to 4361.09) |
| Time of completion of planned IV Artesunate dosing | 4361.090 (3488.88 to 4361.09) |
| Time of first hospital discharge | 4361.090 (3488.88 to 4361.09) |
Blantyre coma scale is an ordinal scale designed to assess malarial coma in children. Eye movement, best motor response, and best verbal response were assessed and scored. The total BCS score was then calculated as the sum of the scores for these three assessments with possible values of 0, 1, 2, 3, 4, or 5. Lower BCS values were indicative of impaired consciousness. BCS was recorded daily until discharge along with scheduled follow-up visits. The number of participants in each BCS were reported at pre-defined timepoints: baseline, 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Due to the lack of variability in BCS scores, proportional odds mixed effects models to assess the relationship between BCS scores and each PK exposure parameter were not conducted. Instead, summary statistics of DHA t1/2 for BCS score of 1 by timepoint are presented.
| h | Standard of Care IV Artesunate |
|---|---|
| Baseline | 0.850 (0.85 to 0.85) |
| 24 hours post-first IV Artesunate dose | 0.850 (0.85 to 0.85) |
| 48 hours post-first IV Artesunate dose | 0.850 (0.85 to 0.85) |
Blantyre coma scale is an ordinal scale designed to assess malarial coma in children. Eye movement, best motor response, and best verbal response were assessed and scored. The total BCS score was then calculated as the sum of the scores for these three assessments with possible values of 0, 1, 2, 3, 4, or 5. Lower BCS values were indicative of impaired consciousness. BCS was recorded daily until discharge along with scheduled follow-up visits. The number of participants in each BCS were reported at pre-defined timepoints: baseline, 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Due to the lack of variability in BCS scores, proportional odds mixed effects models to assess the relationship between BCS scores and each PK exposure parameter were not conducted. Instead, summary statistics of DHA t1/2 for BCS score of 4 by timepoint are presented.
| h | Standard of Care IV Artesunate |
|---|---|
| Baseline | 0.835 (0.64 to 1.03) |
| 24 hours post-first IV Artesunate dose | 1.030 (1.03 to 1.03) |
| 48 hours post-first IV Artesunate dose | 1.030 (1.03 to 1.03) |
| Time of completion of planned IV Artesunate dosing | 1.030 (1.03 to 1.03) |
Blantyre coma scale is an ordinal scale designed to assess malarial coma in children. Eye movement, best motor response, and best verbal response were assessed and scored. The total BCS score was then calculated as the sum of the scores for these three assessments with possible values of 0, 1, 2, 3, 4, or 5. Lower BCS values were indicative of impaired consciousness. BCS was recorded daily until discharge along with scheduled follow-up visits. The number of participants in each BCS were reported at pre-defined timepoints: baseline, 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Due to the lack of variability in BCS scores, proportional odds mixed effects models to assess the relationship between BCS scores and each PK exposure parameter were not conducted. Instead, summary statistics of DHA t1/2 for BCS score of 5 by timepoint are presented.
| h | Standard of Care IV Artesunate |
|---|---|
| Baseline | 0.740 (0.39 to 1.50) |
| 24 hours post-first IV Artesunate dose | 0.740 (0.39 to 1.50) |
| 48 hours post-first IV Artesunate dose | 0.740 (0.39 to 1.50) |
| Time of completion of planned IV Artesunate dosing | 0.740 (0.39 to 1.50) |
| Time of first hospital discharge | 0.740 (0.39 to 1.50) |
Blantyre coma scale is an ordinal scale designed to assess malarial coma in children. Eye movement, best motor response, and best verbal response were assessed and scored. The total BCS score was then calculated as the sum of the scores for these three assessments with possible values of 0, 1, 2, 3, 4, or 5. Lower BCS values were indicative of impaired consciousness. BCS was recorded daily until discharge along with scheduled follow-up visits. The number of participants in each BCS were reported at pre-defined timepoints: baseline, 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Due to the lack of variability in BCS scores, proportional odds mixed effects models to assess the relationship between BCS scores and each PK exposure parameter were not conducted. Instead, summary statistics of DHA t1/2 for BCS score of 4 by timepoint are presented. Only participants who were assessed a BCS of 4 are shown.
| h | Standard of Care IV Artesunate |
|---|---|
| Baseline | 0.640 (0.64 to 0.64) |
Blantyre coma scale is an ordinal scale designed to assess malarial coma in children. Eye movement, best motor response, and best verbal response were assessed and scored. The total BCS score was then calculated as the sum of the scores for these three assessments with possible values of 0, 1, 2, 3, 4, or 5. Lower BCS values were indicative of impaired consciousness. BCS was recorded daily until discharge along with scheduled follow-up visits. The number of participants in each BCS were reported at pre-defined timepoints: baseline, 24 and 48 hours post-first IV artesunate, time of completion of planned IV artesunate dosing, and time of first hospital discharge. Due to the lack of variability in BCS scores, proportional odds mixed effects models to assess the relationship between BCS scores and each PK exposure parameter were not conducted. Instead, summary statistics of DHA t1/2 for BCS score of 5 by timepoint are presented.
| h | Standard of Care IV Artesunate |
|---|---|
| Baseline | 0.740 (0.39 to 1.12) |
| 24 hours post-first IV Artesunate dose | 0.740 (0.39 to 1.12) |
| 48 hours post-first IV Artesunate dose | 0.740 (0.39 to 1.12) |
| Time of completion of planned IV Artesunate dosing | 0.740 (0.39 to 1.12) |
| Time of first hospital discharge | 0.740 (0.39 to 1.12) |
Dates and times of hospital admittance and discharge for each participant were collected for calculation of time to hospital discharge. Time to hospital discharge was defined as the time in days from initial participant admission to the time of first discharge. Time to hospital discharge was calculated using the actual dates and times of initial participant admission and first discharge and was rounded to the nearest tenths place.
| days | Standard of Care IV Artesunate |
|---|---|
| Time to Hospital Discharge in the Primary Analysis Population | 2.65 (1.9 to 8.3) |
Dates and times of hospital admittance and discharge for each participant were collected for calculation of time to hospital discharge. Time to hospital discharge was defined as the time in days from initial participant admission to the time of first discharge. Time to hospital discharge was calculated using the actual dates and times of initial participant admission and first discharge and was rounded to the nearest tenths place.
| days | Standard of Care IV Artesunate |
|---|---|
| Time to Hospital Discharge in the Subset Who Did Not Receive Any IV Artesunate or Other Artemisinin-based Therapy Before Enrollment | 2.20 (1.9 to 8.3) |
Parasite clearance as calculated from parasite density over time, as measured by thick blood smear. Parasite density is defined as the number of parasites per 200 white blood cells (WBCs). Parasite clearance half-life (PCT50) and parasite clearance time to 90% reduction (PCT90) were estimated using the WorldWide Antimalarial Resistance Network (WWARN) parasite clearance estimator (PCE) algorithm.
| parasites/200 WBCs | Standard of Care IV Artesunate |
|---|---|
| 0 (0-2)h | 620.5 (1 to 10800) |
| 6 (4-8) h | 352.0 (0 to 8080) |
| 12 (10-14) h | 168.0 (0 to 1844) |
| 24 (22-26) h | 6.0 (0 to 964) |
| 36 (34-38) h | 1.0 (0 to 460) |
| 48 (46-50) h | 1.0 (0 to 464) |
| Day 3 | 0.0 (0 to 28) |
| Day 4 | 0.5 (0 to 90) |
| Day 5 | 0.0 (0 to 5) |
| Day 6 | 0.0 (0 to 2) |
| Day 7 | 0.0 (0 to 0) |
Parasite clearance as calculated from parasite density over time, as measured by thick blood smear. Parasite density is defined as the number of parasites per 200 white blood cells (WBCs). Parasite clearance half-life (PCT50) and parasite clearance time to 90% reduction (PCT90) were estimated using the WorldWide Antimalarial Resistance Network (WWARN) parasite clearance estimator (PCE) algorithm.
| parasites/200 WBCs | Standard of Care IV Artesunate |
|---|---|
| 0 (0-2)h | 694.0 (1 to 10800) |
| 6 (4-8) h | 876.0 (0 to 8080) |
| 12 (10-14) h | 358.0 (0 to 1844) |
| 24 (22-26) h | 20.0 (0 to 964) |
| 36 (34-38) h | 2.0 (0 to 460) |
| 48 (46-50) h | 1.0 (0 to 464) |
| Day 3 | 0.0 (0 to 28) |
| Day 4 | 1.0 (0 to 90) |
| Day 5 | 0.0 (0 to 5) |
| Day 6 | 0.0 (0 to 2) |
| Day 7 | 0.0 (0 to 0) |
Total parasite clearance was defined as the first negative thick blood smear (i.e., a thick blood smear for which there were no detectable P. falciparum parasites per 200 WBC) after a participant's last positive blood smear for P. falciparum. The date and time of total parasite clearance was defined as the collection date and time of the first thick blood smear to meet the definition of parasite clearance. Total parasite clearance by Day 2 was defined as a binary variable indicating whether total parasite clearance occurred within the first 50 hours post-first on-study dose of IV artesunate.
| Participants | Standard of Care IV Artesunate |
|---|---|
| 0 (0-2)h | 0 |
| 6 (4-8) h | 1 |
| 12 (10-14) h | 3 |
| 24 (22-26) h | 12 |
| 36 (34-38) h | 32 |
| 48 (46-50) h | 48 |
| Day 3 | 48 |
| Day 4 | 59 |
| Day 5 | 76 |
| Day 6 | 81 |
| Day 7 | 83 |
Total parasite clearance was defined as the first negative thick blood smear (i.e., a thick blood smear for which there were no detectable P. falciparum parasites per 200 WBC) after a participant's last positive blood smear for P. falciparum. The date and time of total parasite clearance was defined as the collection date and time of the first thick blood smear to meet the definition of parasite clearance. Total parasite clearance by Day 2 was defined as a binary variable indicating whether total parasite clearance occurred within the first 50 hours post-first on-study dose of IV artesunate.
| Participants | Standard of Care IV Artesunate |
|---|---|
| 0 (0-2)h | 0 |
| 6 (4-8) h | 1 |
| 12 (10-14) h | 1 |
| 24 (22-26) h | 6 |
| 36 (34-38) h | 22 |
| 48 (46-50) h | 33 |
| Day 3 | 33 |
| Day 4 | 42 |
| Day 5 | 55 |
| Day 6 | 59 |
| Day 7 | 61 |
Collected over All AEs and SAEs were documented from time of study product administration (Day 1) through the time of the last assessment (Day 183).. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Standard of Care IV Artesunate | 2/90 (2.2%) | 4/90 (4.4%) | 35/90 (38.9%) |
| Event | Standard of Care IV Artesunate |
|---|---|
| AcidosisMetabolism and nutrition disorders | 1/90 |
| Complicated MalariaInfections and infestations | 1/90 |
| SeizureNervous system disorders | 1/90 |
| Cerebral malariaInfections and infestations | 1/90 |
| Event | Standard of Care IV Artesunate |
|---|---|
| Upper respiratory tract infectionInfections and infestations | 24/90 |
| MalariaInfections and infestations | 10/90 |
| BacteraemiaInfections and infestations | 5/90 |
| GastroenteritisInfections and infestations | 5/90 |
| Age, Categorical(Participants) | Standard of Care IV Artesunate |
|---|---|
| <=18 years | 90 |
| Between 18 and 65 years | 0 |
| >=65 years | 0 |
| Age, Continuous(years) | Standard of Care IV Artesunate |
|---|---|
| Mean | 5.65 ± 3.42 |
| Age, Customized(Participants) | Standard of Care IV Artesunate |
|---|---|
| 6-11 months | 5 |
| 1-2 years | 20 |
| 3-5 years | 23 |
| 6-11 years | 37 |
| 12-14 years | 5 |
| Sex: Female, Male(Participants) | Standard of Care IV Artesunate |
|---|---|
| Female | 46 |
| Male | 44 |
| Ethnicity (NIH/OMB)(Participants) | Standard of Care IV Artesunate |
|---|---|
| Hispanic or Latino | 0 |
| Not Hispanic or Latino | 90 |
| Unknown or Not Reported | 0 |
| Race (NIH/OMB)(Participants) | Standard of Care IV Artesunate |
|---|---|
| American Indian or Alaska Native | 0 |
| Asian | 0 |
| Native Hawaiian or Other Pacific Islander | 0 |
| Black or African American | 90 |
| White | 0 |
| More than one race | 0 |
| Unknown or Not Reported | 0 |
| Region of Enrollment(Participants) | Standard of Care IV Artesunate |
|---|---|
| Uganda | 90 |
| Weight-for-Age Z-score(z-score) | Standard of Care IV Artesunate |
|---|---|
| Mean | -0.711 ± 1.723 |
1 further baseline measures are reported on the registry.
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