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Pharmacokinetic Study of IV Artesunate to Treat Children With Severe Malaria

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

Study Description
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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.

Condition or disease Intervention/treatment Phase
Plasmodium Falciparum Infection Drug: Artesunate Phase 4

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 Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Exposure-Response Evaluation of IV Artesunate in Children With Severe Malaria
Actual Study Start Date : November 29, 2023
Estimated Primary Completion Date : November 15, 2024
Estimated Study Completion Date : December 30, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Malaria

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


Outcome Measures
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Primary Outcome Measures :
  1. Change from baseline bicarbonate levels [ Time Frame: Day 1 through Day 183 ]
  2. Change from baseline blood pressure [ Time Frame: Day 1 through Day 183 ]
  3. Change from baseline creatinine. [ Time Frame: Day 1 through Day 183 ]
  4. Change from baseline in acidosis. [ Time Frame: Day 1 through Day 183 ]
  5. Change from baseline in bilirubin [ Time Frame: Day 1 through Day 183 ]
    Includes total and direct bilirubin

  6. Change from baseline in Blantyre Coma Score (BCS). [ Time Frame: Day 1 through Day 183 ]
  7. 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).

  8. Change from baseline in hemoglobin [ Time Frame: Day 1 through Day 183 ]
  9. Change from baseline in serum glucose [ Time Frame: Day 1 through Day 183 ]
  10. Change from baseline in temperature. [ Time Frame: Day 1 through Day 183 ]
  11. Change from baseline in venous serum lactate. [ Time Frame: Day 1 through Day 183 ]

Secondary Outcome Measures :
  1. 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.

  2. Time to hospital discharge. [ Time Frame: Day 1 through 183 ]

Eligibility Criteria
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Ages Eligible for Study:   6 Months to 14 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05750459


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

Locations
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Uganda
Makerere University - Infectious Diseases Institute Recruiting
Kampala, Uganda
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
More Information
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Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT05750459    
Other Study ID Numbers: 19-0007
5UM1AI148689-05 ( U.S. NIH Grant/Contract )
First Posted: March 1, 2023    Key Record Dates
Last Update Posted: March 22, 2024
Last Verified: October 17, 2023

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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
Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
Artesunate
Children
IV
 P. falciparum
Severe Malaria
Uganda
Additional relevant MeSH terms:
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Malaria
Protozoan Infections
Parasitic Diseases
Infections
Mosquito-Borne Diseases
Vector Borne Diseases
Artesunate
Antimalarials
 Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Antineoplastic Agents
Antiviral Agents
Schistosomicides
Antiplatyhelmintic Agents
Anthelmintics