Pharmacokinetic Study of IV Artesunate to Treat Children With Severe Malaria

• ClinicalTrials.gov Identifier: NCT05750459
• Recruitment Status: Recruiting
• First Posted: March 1, 2023
• Last Update Posted: March 22, 2024
• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Information provided by (Responsible Party): National Institute of Allergy and Infectious Diseases (NIAID)

Tracking Information

• First Submitted Date: February 20, 2023
• First Posted Date: March 1, 2023
• Last Update Posted Date: March 22, 2024
• Actual Study Start Date: November 29, 2023
• Estimated Primary Completion Date: November 15, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 13, 2023)

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

Original Primary Outcome Measures (submitted: February 20, 2023)

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

Current Secondary Outcome Measures (submitted: October 13, 2023)

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

Original Secondary Outcome Measures (submitted: February 20, 2023)

• Time to Hospital Discharge [ Time Frame: Up to the day of hospital discharge (an average of 3 days) ]
  The duration of hospitalization will be evaluated in days.
• Parasite Clearance Half-Life [ Time Frame: Up to Day 5 ]
  Samples to assess parasitemia will be collected at hours 0, 6, 12, 24, 36, and 48, then every 24 hours until parasite clearance. The half-life (t1/2) of parasite clearance will be determined.
• Parasite Clearance by Day 2 [ Time Frame: Up to Day 2 ]
  Samples to assess parasitemia will be collected at hours 0, 6, 12, 24, 36, and 48, then every 24 hours until parasite clearance. The percentage of parasitemia clearance by 48 hours post-dose will be determined.
• Time to 90% Reduction in Parasitemia [ Time Frame: Up to Day 5 ]
  Samples to assess parasitemia will be collected at hours 0, 6, 12, 24, 36, and 48, then every 24 hours until parasite clearance. The number of hours it takes for 90% reduction in parasitemia will be determined.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Pharmacokinetic Study of IV Artesunate to Treat Children With Severe Malaria
• Official Title: Exposure-Response Evaluation of IV Artesunate in Children With Severe Malaria
• Brief Summary: This clinical study is a phase 4, single-site, open-label pharmacokinetic (PK) study of IV artesunate in up to 100 Ugandan children 6 months-14 years of age who are diagnosed with severe malaria according to standardized World Health Organization (WHO) criteria (any P. falciparum parasitemia and the presence of danger signs). Participants will receive the standard of care IV artesunate for initial treatment of severe malaria per WHO guidelines: children weighing <20 kg should receive 3.0 mg/kg/dose compared to children weighing =20 kg who should receive 2.4 mg/kg/dose, at times 0, 12, 24, 48 and 72 hours (WHO 2015). Parenteral treatment will be administered for a minimum of 24 hours (irrespective of the patient's ability to tolerate oral medication earlier), after which patients will be evaluated clinically and assessed for ability for oral intake of antimalarials. Children who are able to transition to oral antimalarial therapy will initiate a 3-day course of artemisinin-combination oral therapy per national guidelines. The primary objective of the study is to determine the relationship between DHA exposures following IV artesunate dosing and markers of physiologic dysfunction associated with severe malaria in Ugandan children.
• Detailed Description: This clinical study is a phase 4, single-site, open-label pharmacokinetic (PK) study of IV artesunate in up to 100 Ugandan children 6 months-14 years of age who are diagnosed with severe malaria according to standardized World Health Organization (WHO) criteria (any P. falciparum parasitemia and the presence of danger signs). Participants will receive the standard of care IV artesunate for initial treatment of severe malaria per WHO guidelines: children weighing <20 kg should receive 3.0 mg/kg/dose compared to children weighing =20 kg who should receive 2.4 mg/kg/dose, at times 0, 12, 24, 48 and 72 hours (WHO 2015). Parenteral treatment will be administered for a minimum of 24 hours (irrespective of the patient's ability to tolerate oral medication earlier), after which patients will be evaluated clinically and assessed for ability for oral intake of antimalarials. Children who are able to transition to oral antimalarial therapy will initiate a 3-day course of artemisinin-combination oral therapy per national guidelines. Biomarkers of physiologic dysfunction will be quantified at regular intervals, including serum lactate, serum glucose, total and direct bilirubin, bicarbonate levels, Blantyre Coma Score (BCS), creatinine and hemoglobin. These biomarkers will be considered both independently and together as a weighted score to relate to the PK of the active metabolite of IV artesunate, DHA and to efficacy markers that more accurately reflect clinical outcomes. We will also quantify P. falciparum parasitemia using standardized thick blood smear and relate this outcome to DHA dose and exposure for comparison with historical studies. Children 6 months to 14 years of age living in or near Tororo District, Uganda, who are diagnosed with severe malaria and who meet inclusion and exclusion criteria will be enrolled.
• Study Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Plasmodium Falciparum Infection

Intervention

Drug: Artesunate

Artesunate is a succinic ester of artemether.

Study Arms

Experimental: Arm 1

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

Intervention: Drug: Artesunate

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: February 20, 2023): 100
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 30, 2024
• Estimated Primary Completion Date: November 15, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

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

Exclusion Criteria:

1. Receipt of > 24 hours of artemisinin therapy

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 6 Months to 14 Years (Child)
• Accepts Healthy Volunteers: No

Contacts

Contact: Matthew Laurens; 14107065328; mlaurens@som.umaryland.edu

• Listed Location Countries: Uganda
• Removed Location Countries: United States

Administrative Information

• NCT Number: NCT05750459
• Other Study ID Numbers: 19-0007; 5UM1AI148689-05 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

• IPD Sharing Statement: Not Provided
• Current Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• Original Responsible Party: Matthew B Laurens, MD, MPH, University of Maryland, Baltimore, Professor
• Current Study Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Original Study Sponsor: Emory University
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: National Institute of Allergy and Infectious Diseases (NIAID)
• Verification Date: October 17, 2023