Study of the Safety of Intravenous Artesunate

• Sponsor: U.S. Army Medical Research and Development Command (U.S. Fed)
• Overall Status: Completed
• CT.gov ID: NCT00292942
• Collaborator: Walter Reed Army Institute of Research (WRAIR) (U.S. Fed)
• Enrollment: 26
• Location: 1
• Arms: 4
• Actual Duration (Months): 18.7
• Patients Per Site Per Month: 1.4

Study Details

Study Description

Brief Summary

The purpose of this study is to establish the safety, tolerability, and pharmacokinetics of a multiple dose of the antimalarial drug artesunate.

Condition or Disease	Intervention/Treatment	Phase
Malaria; Malaria, Cerebral	Drug: Intravenous Artesunate; Drug: Placebo	Phase 1

Detailed Description

This study was a Phase 1b, randomized, double-blind, placebo-controlled trial using multiple ascending doses of intravenous artensunate (AS) to determine it's safety, tolerability, and PK in healthy subjects. Subjects were screened within 21 days of dosing. At the screening visit, subject underwent baseline assessments: vital signs were recorded; a physical examination, urinalysis, urine drug screen, and urine pregnancy test were performed; a complete blood cell count (CBC) with differential and indices, reticulocyte count, coagulation markers, and blood chemistry assessments were performed and medical and medication history was collected. Eligible subjects were scheduled for a 6-hour pre-dose electrocardiogram (ECG) and vital sign assessment with measurements taken at approx. the same times as Day 1 (dosing day). On Day 0, subjects were admitted to the clinical pharmacology unit to begin the inpatient phase of the study. Subjects had a brief physical examination and all procedures for the inpatient stay were reviewed. On Day 1, pre-dose vital signs and ECG were performed. Subjects then received study drug or placebo by IV bolus infusion. Subjects were closely monitored by evaluating hemodynamic measurements, periodic ECGs, and assessment of spontaneously reported AEs. Blood was drawn for blood count and chemistry analysis 6h and 24h after each dose. PK blood samples were drawn pre-dose and approx. 5min, 20min, 40min, 1h, 2h, 4h, 6h, and 24h after each dose. On Days 2 and 3 subjects received their second and third doses, respectively, of study drug or placebo with the same monitoring and laboratory measurements as for the first dose. Subjects were discharged 24 hours after the 3rd dose of drug or placebo and were followed as outpatients on Days 7, 10, and 15.

Study Design

• Study Type: Interventional
• Actual Enrollment: 26 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 1 Double-Blind, Placebo-Controlled, Randomized Multiple Dose Escalation Study to Evaluate the Safety, Tolerance, and Pharmacokinetics/Pharmacodynamics of a New GMP Formulation of Intravenous Artesunate if Healthy Subjects
• Actual Study Start Date: Jun 12, 2006
• Actual Primary Completion Date: Jan 17, 2007
• Actual Study Completion Date: Jan 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 2 mg/kg Intravenous Artesunate 2 mg/kg of Intravenous artesunate	Drug: Intravenous Artesunate; Three doses of Intravenous Artesunate drug at 2, 4, or 8 mg/kg in diluent Phosphate Buffer (0.3 M, pH 8.1); Other Names: IV AS
Experimental: 4 mg/kg Intravenous Artesunate 4 mg/kg of Intravenous artesunate	Drug: Intravenous Artesunate; Three doses of Intravenous Artesunate drug at 2, 4, or 8 mg/kg in diluent Phosphate Buffer (0.3 M, pH 8.1); Other Names: IV AS
Experimental: 8 mg/kg Intravenous Artesunate 8 mg/kg of Intravenous artesunate	Drug: Intravenous Artesunate; Three doses of Intravenous Artesunate drug at 2, 4, or 8 mg/kg in diluent Phosphate Buffer (0.3 M, pH 8.1); Other Names: IV AS
Placebo Comparator: Placebo Mannitol (200 mg/vial) diluted in phosphate buffer and delivered in an equivalent volume by subject's weight as artesunate.	Drug: Placebo; Mannitol (200 mg/vial) diluted in Phosphate Buffer and given IV in equivalent volume by subject's weight.; Other Names: Mannitol

Outcome Measures

Primary Outcome Measures

1. Number of Participants With AEs [up to 21 days]

   The general strategy of the safety analysis was to examine the clinical tolerability and laboratory safety parameter data and determine if there were any trends amongst the dose levels concerning all AEs and drug related AEs.

2. Number of Participants With AEs Occurring in Greater Frequency in the 2.0 mg/kg IV AS Group Then in the Placebo Group to Access Safety and Tolerability of AS [up to 21 days]

   Comparison of number of participants with AEs reported for the placebo control and those treated with the 2.0 mg/kg of IV AS to access safety and tolerability

Secondary Outcome Measures

1. Cardiovascular Responses: Number of Participants With Changes in Blood Pressure and Heart Rate After Infusion [screening, on Day -1, on Days 1, 2, and 3, and at each follow-up visit]

   Cardiovascular Responses: Number of participants with changes in blood pressure and heart rate after infusion to determine change from baseline

2. Range of Pharmacokinetic Parameters for Artesunic Acid After Single 2.0, 4.0 and 8.0 mg/kg Dose of Artesunate Daily for 3 Days (ng*hr/mL) [Pre-dose, 5, 20, 40 minutes after infusion and 1, 2, 4, 8, 24 and 72 hours after infusion]

   For artesunic acid, AUC0-last was determine for each dose; as well as the total area under the curve (AUClastTOTAL), calculated as the sum of AUClast for each of the doses (ng*hr/mL)

3. Range of Pharmacokinetic Parameters for Artesunic Acid After Single 2.0, 4.0 and 8.0 mg/kg Dose of Artesunate Daily for 3 Days (ng/mL) [Pre-dose, 5, 20, 40 minutes after infusion and 1, 2, 4, 8, 24 and 72 hours after infusion]

   For the predicted concentration at the time of dose administration (C0) was determine for each dose (ng/mL)

4. Range of Pharmacokinetic Parameters for Dihydroartemisinin (DHA) After Single 2.0, 4.0 and 8.0 mg/kg Dose of Artesunate Daily for 3 Days (ng*hr/mL) [Pre-dose, 5, 20, 40 minutes after infution and 1, 2, 4, 8, 24 and 72 hours after infusion]

   For DHA, AUC24, and AUClast were calculated for each dose, as well as the total area under the curve extrapolated to infinite time (AUC∞TOTAL), calculated as the sum of AUC24 for each dose +C24/λz.

5. Cmax Assessment After Single 2.0, 4.0 and 8.0 mg/kg Dose of Artesunate Daily for 3 Days (ng/mL) [Pre-dose, 5, 20, 40 minutes after infution and 1, 2, 4, 8, 24 and 72 hours after infusion]

   Cmax was calculated after single 2.0, 4.0 and 8.0 mg/kg dose of Artesunate daily for 3 days (ng/mL)

6. Tmax Assessment After Single 2.0, 4.0 and 8.0 mg/kg Dose of Artesunate Daily for 3 Days (hr) [Pre-dose, 5, 20, 40 minutes after infution and 1, 2, 4, 8, 24 and 72 hours after infusion]

   Tmax was calculated after single 2.0, 4.0 and 8.0 mg/kg dose of Artesunate daily for 3 days (hr)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Healthy adult males and non-pregnant, non-lactating females

• Have a normal ECG that may include benign PAC's and PVC's, 1st degree AV block, 2nd degree AV block, Wenckebach

• Have a normal blood pressure (BP) and heart rate (HR). These will be measured after resting supine for about 3 minutes. Normal BP is defined as less than 140 mm Hg systolic and less than 90 mm Hg diastolic. Normal baseline HR is 50 to 90 bpm without symptoms.

• Body mass index between 18 and 29 kg/m**2 or, if out of range, not clinically significant (within 15% of their ideal body weight).

• Be able to verbalize understanding of the consent form, provide written informed consent and verbalize willingness to complete study procedures

• Have a physical examination that demonstrates no clinically significant contraindication for participating in the study. This would include documentation of any abnormal movements suggesting neurological pathology and ECG tracings to document an abnormalities in cardiac conduction

• If female, have a negative serum pregnancy test at screening and urine pregnancy test on pre-admission and admission, or be postmenopausal, or have had a hysterectomy, or have been sterilized, AND, if still able to bear children, agree to practice effective contraception for the duration of the study and for a period of 12 weeks after stopping study drug.

• Active duty participants must be on leave during the inpatient phase of the study.

Exclusion Criteria:

• Have received any investigational drug or vaccine in the period 0 to 16 weeks before entry to the study.

• Have been on a liquid protein diet in the last year

• Have any clinically important physical findings, laboratory abnormalities, or histories of Rx or OTC drug use that may, in the judgement of a study investigator, impact study interpretation or affect subject safety

• Have used any prescription drugs within 14 days prior to admission or most non-prescription drugs including herbals or dietary supplements within 7 days prior to admission (at the investigator's discretion).

• Existence of any surgical or medical condition that, in the judgement of the clinical investigator, might interfere with the distribution, metabolism or excretion of the drug

• Presence of history of drug allergy requiring treatment. Hay fever is allowed unless it is active or has required treatment within the previous 2 months

• Donation or loss of greater than 400 ml of blood in the period 0 to 12 weeks before entry to the study.

• Serious adverse reaction or hypersensitivity to any drug, particularly artemisinin derivatives

• CAGE (screening test for alcoholism) postitive (2 out of 4 criteria) or has a history of recent alcohol abuse

• Use of illicit drugs

• Family history (in 1st degree relatives) of sudden cardiac death or prolonged QT/QTc syndrome

• History of seizure (excluding febrile seizures in childhood), episodes of unexplained syncope, or trouble with balance, undiagnosed hearing deficits, and other neurological disorder

• History of severe psychiatric disorder or hospitalization for severe psychiatric disorder

• Current job or personal habit of reversed sleep-wake cycle

• History of cardiac disease to include cardiomyopathy, valvular disease, arrhythmia, ischemia, or enlarged heart

• Presence of hepatitis B surface antigen (Hbs-Ag), hepatitis C antibody (antiHCV) or HIV type 1 at screening

• A finding or history of hematuria (excluding menses-related hematuria) during subject screening

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Uniformed Services University of the HEalth Sciences	Bethesda	Maryland	United States	20814-4799

Sponsors and Collaborators

• U.S. Army Medical Research and Development Command
• Walter Reed Army Institute of Research (WRAIR)

Investigators

• Study Director: Peter J Weina, MD, PhD, Walter Reed Army Institute of Research (WRAIR)

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: U.S. Army Medical Research and Development Command
• ClinicalTrials.gov Identifier: NCT00292942
• Other Study ID Numbers: WRAIR 1142; USUHS G183SP; A-13419
• First Posted: Feb 16, 2006
• Last Update Posted: Oct 25, 2018
• Last Verified: Feb 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by U.S. Army Medical Research and Development Command: artesunate; artemisinin; falciparum
• Additional relevant MeSH terms: Malaria; Malaria, Cerebral; Artesunate; Mannitol

Study Results

Participant Flow

Recruitment Details	A total of 47 subjects were screened over the 3 dose escalation cohorts of the study. Twenty-six subjects were enrolled and received IV AS at the USUHS, Clinical Pharmacology Unit (CPU), Bethesda, MD

Arm/Group Title	Placebo	2 mg/kg Intravenous Artesunate	4 mg/kg Intravenous Artesunate	8 mg/kg Intravenous Artesunate
Arm/Group Description	Mannitol (200 mg/vial) diluted in phosphate buffer and delivered in an equivalent volume by subject's weight as artesunate. Placebo: Mannitol (200 mg/vial) diluted in Phosphate Buffer and given IV in equivalent volume by subject's weight.	2 mg/kg of Intravenous artesunate Intravenous Artesunate: Three doses of Intravenous Artesunate drug at 2, 4, or 8 mg/kg in diluent Phosphate Buffer (0.3 M, pH 8.1)	4 mg/kg of Intravenous artesunate Intravenous Artesunate: Three doses of Intravenous Artesunate drug at 2, 4, or 8 mg/kg in diluent Phosphate Buffer (0.3 M, pH 8.1)	8 mg/kg of Intravenous artesunate Intravenous Artesunate: Three doses of Intravenous Artesunate drug at 2, 4, or 8 mg/kg in diluent Phosphate Buffer (0.3 M, pH 8.1)
Period Title: Overall Study
STARTED	6	6	7	7
COMPLETED	6	6	6	6
NOT COMPLETED	0	0	1	1

Baseline Characteristics

Arm/Group Title	Placebo	2 mg/kg Intravenous Artesunate	4 mg/kg Intravenous Artesunate	8 mg/kg Intravenous Artesunate	Total
Arm/Group Description	Mannitol (200 mg/vial) diluted in phosphate buffer and delivered in an equivalent volume by subject's weight as artesunate. Placebo: Mannitol (200 mg/vial) diluted in Phosphate Buffer and given IV in equivalent volume by subject's weight.	2 mg/kg of Intravenous artesunate Intravenous Artesunate: Three doses of Intravenous Artesunate drug at 2, 4, or 8 mg/kg in diluent Phosphate Buffer (0.3 M, pH 8.1)	4 mg/kg of Intravenous artesunate Intravenous Artesunate: Three doses of Intravenous Artesunate drug at 2, 4, or 8 mg/kg in diluent Phosphate Buffer (0.3 M, pH 8.1)	8 mg/kg of Intravenous artesunate Intravenous Artesunate: Three doses of Intravenous Artesunate drug at 2, 4, or 8 mg/kg in diluent Phosphate Buffer (0.3 M, pH 8.1)	Total of all reporting groups
Overall Participants	6	6	7	7	26
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	36.0 (10.41)	43.2 (12.02)	35.3 (9.96)	35.0 (11.86)	37.2 (10.95)
Sex: Female, Male (Count of Participants)
Female	1 16.7%	0 0%	1 14.3%	0 0%	2 7.7%
Male	5 83.3%	6 100%	6 85.7%	7 100%	24 92.3%
Race/Ethnicity, Customized (Count of Participants)
White	2 33.3%	4 66.7%	3 42.9%	3 42.9%	12 46.2%
Black or African American	4 66.7%	0 0%	2 28.6%	3 42.9%	9 34.6%
American Indian or Alaska Native	0 0%	0 0%	0 0%	1 14.3%	1 3.8%
Hispanic or Latino	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	1 14.3%	0 0%	1 3.8%
Native Hawaiian or Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Other	0 0%	0 0%	0 0%	0 0%	0 0%
Subjects with >1 race	0 0%	2 33.3%	1 14.3%	0 0%	3 11.5%
Region of Enrollment (Count of Participants)
United States	6 100%	6 100%	7 100%	7 100%	26 100%
Height (cm) (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	173.68 (7.598)	172.97 (3.634)	173.14 (12.472)	175.34 (2.519)	173.82 (7.348)
Weight (kg) (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	80.33 (8.390)	76.53 (11.114)	81.03 (12.681)	77.80 (5.912)	78.96 (9.445)
Body Mass Index (kg/m^2) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	26.68 (2.917)	25.50 (2.828)	26.89 (2.270)	25.30 (1.628)	26.09 (2.386)

Outcome Measures

1. Primary Outcome

Title	Number of Participants With AEs
Description	The general strategy of the safety analysis was to examine the clinical tolerability and laboratory safety parameter data and determine if there were any trends amongst the dose levels concerning all AEs and drug related AEs.
Time Frame	up to 21 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	2 mg/kg Intravenous Artesunate	4 mg/kg Intravenous Artesunate	8 mg/kg Intravenous Artesunate
Arm/Group Description	Mannitol (200 mg/vial) diluted in phosphate buffer and delivered in an equivalent volume by subject's weight as artesunate. Placebo: Mannitol (200 mg/vial) diluted in Phosphate Buffer and given IV in equivalent volume by subject's weight.	2 mg/kg of Intravenous artesunate Intravenous Artesunate: Three doses of Intravenous Artesunate drug at 2, 4, or 8 mg/kg in diluent Phosphate Buffer (0.3 M, pH 8.1)	4 mg/kg of Intravenous artesunate Intravenous Artesunate: Three doses of Intravenous Artesunate drug at 2, 4, or 8 mg/kg in diluent Phosphate Buffer (0.3 M, pH 8.1)	8 mg/kg of Intravenous artesunate Intravenous Artesunate: Three doses of Intravenous Artesunate drug at 2, 4, or 8 mg/kg in diluent Phosphate Buffer (0.3 M, pH 8.1)
Measure Participants	6	6	7	7
No AEs	0 0%	0 0%	2 28.6%	0 0%
Subjects with 1 AE	3 50%	3 50%	0 0%	2 28.6%
Subjects with 2 AEs	3 50%	0 0%	1 14.3%	2 28.6%
Subjects with ≥3 AEs	0 0%	3 50%	4 57.1%	3 42.9%
No AEs	2 33.3%	0 0%	2 28.6%	1 14.3%
Subjects with 1 AE	2 33.3%	3 50%	1 14.3%	2 28.6%
Subjects with 2 AEs	2 33.3%	1 16.7%	1 14.3%	2 28.6%
Subjects with ≥3 AEs	0 0%	2 33.3%	3 42.9%	2 28.6%

2. Primary Outcome

Title	Number of Participants With AEs Occurring in Greater Frequency in the 2.0 mg/kg IV AS Group Then in the Placebo Group to Access Safety and Tolerability of AS
Description	Comparison of number of participants with AEs reported for the placebo control and those treated with the 2.0 mg/kg of IV AS to access safety and tolerability
Time Frame	up to 21 days

Outcome Measure Data

Analysis Population Description

As the intended, compassionate use dose of Intravenous Artesunate will be 2.4 mg/kg for the treatment of individuals with severe malaria, a comparison was performed between the frequency of AEs reported for the placebo control subjects and those treated with the 2.0 mg/kg dose of Intravenous Artesunate.

Arm/Group Title	Placebo	2 mg/kg Intravenous Artesunate
Arm/Group Description	Mannitol (200 mg/vial) diluted in phosphate buffer and delivered in an equivalent volume by subject's weight as artesunate. Placebo: Mannitol (200 mg/vial) diluted in Phosphate Buffer and given IV in equivalent volume by subject's weight.	2 mg/kg of Intravenous artesunate Intravenous Artesunate: Three doses of Intravenous Artesunate drug at 2, 4, or 8 mg/kg in diluent Phosphate Buffer (0.3 M, pH 8.1)
Measure Participants	6	6
Dysguesia	1 16.7%	4 66.7%
Dizziness	0 0%	1 16.7%
Headache	1 16.7%	3 50%
Parethesia	0 0%	1 16.7%
Parosmia	0 0%	1 16.7%
Erythema	0 0%	1 16.7%
Pruritus Generalized	0 0%	1 16.7%
Tenderness	0 0%	1 16.7%
Venipuncture Site Inflammation	0 0%	1 16.7%
Eye Pain	0 0%	1 16.7%
Back Pain	0 0%	1 16.7%
Muscle Strain	0 0%	1 16.7%

3. Secondary Outcome

Title	Cardiovascular Responses: Number of Participants With Changes in Blood Pressure and Heart Rate After Infusion
Description	Cardiovascular Responses: Number of participants with changes in blood pressure and heart rate after infusion to determine change from baseline
Time Frame	screening, on Day -1, on Days 1, 2, and 3, and at each follow-up visit

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	2 mg/kg Intravenous Artesunate	4 mg/kg Intravenous Artesunate	8 mg/kg Intravenous Artesunate
Arm/Group Description	Mannitol (200 mg/vial) diluted in phosphate buffer and delivered in an equivalent volume by subject's weight as artesunate. Placebo: Mannitol (200 mg/vial) diluted in Phosphate Buffer and given IV in equivalent volume by subject's weight.	2 mg/kg of Intravenous artesunate Intravenous Artesunate: Three doses of Intravenous Artesunate drug at 2, 4, or 8 mg/kg in diluent Phosphate Buffer (0.3 M, pH 8.1)	4 mg/kg of Intravenous artesunate Intravenous Artesunate: Three doses of Intravenous Artesunate drug at 2, 4, or 8 mg/kg in diluent Phosphate Buffer (0.3 M, pH 8.1)	8 mg/kg of Intravenous artesunate Intravenous Artesunate: Three doses of Intravenous Artesunate drug at 2, 4, or 8 mg/kg in diluent Phosphate Buffer (0.3 M, pH 8.1)
Measure Participants	6	6	7	7
Increase	1 16.7%	1 16.7%	1 14.3%	1 14.3%
Decrease	0 0%	0 0%	0 0%	0 0%
No significant change	5 83.3%	5 83.3%	6 85.7%	6 85.7%
Increase	4 66.7%	4 66.7%	6 85.7%	3 42.9%
Decrease	0 0%	0 0%	0 0%	0 0%
No significant change	2 33.3%	2 33.3%	1 14.3%	4 57.1%

4. Secondary Outcome

Title	Range of Pharmacokinetic Parameters for Artesunic Acid After Single 2.0, 4.0 and 8.0 mg/kg Dose of Artesunate Daily for 3 Days (ng*hr/mL)
Description	For artesunic acid, AUC0-last was determine for each dose; as well as the total area under the curve (AUClastTOTAL), calculated as the sum of AUClast for each of the doses (ng*hr/mL)
Time Frame	Pre-dose, 5, 20, 40 minutes after infusion and 1, 2, 4, 8, 24 and 72 hours after infusion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	2 mg/kg Intravenous Artesunate	4 mg/kg Intravenous Artesunate	8 mg/kg Intravenous Artesunate
Arm/Group Description	2 mg/kg of Intravenous artesunate Intravenous Artesunate: Three doses of Intravenous Artesunate drug at 2, 4, or 8 mg/kg in diluent Phosphate Buffer (0.3 M, pH 8.1)	4 mg/kg of Intravenous artesunate Intravenous Artesunate: Three doses of Intravenous Artesunate drug at 2, 4, or 8 mg/kg in diluent Phosphate Buffer (0.3 M, pH 8.1)	8 mg/kg of Intravenous artesunate Intravenous Artesunate: Three doses of Intravenous Artesunate drug at 2, 4, or 8 mg/kg in diluent Phosphate Buffer (0.3 M, pH 8.1)
Measure Participants	6	6	6
AUC24 1 (ng.hr/mL)	1368 (912)	2325 (721)	5766 (2121)
AUC24 2 (ng.hr/mL)	978 (648)	1746 (247)	5272 (2089)
AUC24 3 (ng.hr/mL)	935 (301)	1880 (795)	4379 (2361)
AUC last 1 (ng.hr/mL)	1162 (656)	2421 (755)	4631 (2402)
AUC last 2 (ng.hr/mL)	932 (524)	1636 (342)	5728 (1980)
AUC last 3 (ng.hr/mL)	933 (239)	1627 (957)	4374 (2362)
AUC last TOTAL (ng.hr/mL)	3027 (1158)	5683 (550)	14733 (5846)

5. Secondary Outcome

Title	Range of Pharmacokinetic Parameters for Artesunic Acid After Single 2.0, 4.0 and 8.0 mg/kg Dose of Artesunate Daily for 3 Days (ng/mL)
Description	For the predicted concentration at the time of dose administration (C0) was determine for each dose (ng/mL)
Time Frame	Pre-dose, 5, 20, 40 minutes after infusion and 1, 2, 4, 8, 24 and 72 hours after infusion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	2 mg/kg Intravenous Artesunate	4 mg/kg Intravenous Artesunate	8 mg/kg Intravenous Artesunate
Arm/Group Description	2 mg/kg of Intravenous artesunate Intravenous Artesunate: Three doses of Intravenous Artesunate drug at 2, 4, or 8 mg/kg in diluent Phosphate Buffer (0.3 M, pH 8.1)	4 mg/kg of Intravenous artesunate Intravenous Artesunate: Three doses of Intravenous Artesunate drug at 2, 4, or 8 mg/kg in diluent Phosphate Buffer (0.3 M, pH 8.1)	8 mg/kg of Intravenous artesunate Intravenous Artesunate: Three doses of Intravenous Artesunate drug at 2, 4, or 8 mg/kg in diluent Phosphate Buffer (0.3 M, pH 8.1)
Measure Participants	6	6	6
C0 1	14840 (10902)	29056 (12850)	53503 (33017)
C0 2	11992 (8311)	17265 (3590)	66380 (32973)
C0 3	10408 (1851)	23417 (10200)	54674 (43261)

6. Secondary Outcome

Title	Range of Pharmacokinetic Parameters for Dihydroartemisinin (DHA) After Single 2.0, 4.0 and 8.0 mg/kg Dose of Artesunate Daily for 3 Days (ng*hr/mL)
Description	For DHA, AUC24, and AUClast were calculated for each dose, as well as the total area under the curve extrapolated to infinite time (AUC∞TOTAL), calculated as the sum of AUC24 for each dose +C24/λz.
Time Frame	Pre-dose, 5, 20, 40 minutes after infution and 1, 2, 4, 8, 24 and 72 hours after infusion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	2 mg/kg Intravenous Artesunate	4 mg/kg Intravenous Artesunate	8 mg/kg Intravenous Artesunate
Arm/Group Description	2 mg/kg of Intravenous artesunate Intravenous Artesunate: Three doses of Intravenous Artesunate drug at 2, 4, or 8 mg/kg in diluent Phosphate Buffer (0.3 M, pH 8.1)	4 mg/kg of Intravenous artesunate Intravenous Artesunate: Three doses of Intravenous Artesunate drug at 2, 4, or 8 mg/kg in diluent Phosphate Buffer (0.3 M, pH 8.1)	8 mg/kg of Intravenous artesunate Intravenous Artesunate: Three doses of Intravenous Artesunate drug at 2, 4, or 8 mg/kg in diluent Phosphate Buffer (0.3 M, pH 8.1)
Measure Participants	6	6	6
AUC24 1	1982 (377)	4122 (809)	8992 (3355)
AUC24 2	1865 (512)	3509 (970)	8122 (2750)
AUC24 3	2204 (524)	3748 (646)	8571 (2817)
AUC last 1	1954 (367)	4065 (771)	8842 (3265)
AUC last 2	1847 (516)	3394 (974)	8011 (2780)
AUC last 3	2171 (519)	3701 (647)	8405 (2715)
AUC oo TOTAL	6051 (1074)	11379 (2128)	25685 (8715)

7. Secondary Outcome

Title	Cmax Assessment After Single 2.0, 4.0 and 8.0 mg/kg Dose of Artesunate Daily for 3 Days (ng/mL)
Description	Cmax was calculated after single 2.0, 4.0 and 8.0 mg/kg dose of Artesunate daily for 3 days (ng/mL)
Time Frame	Pre-dose, 5, 20, 40 minutes after infution and 1, 2, 4, 8, 24 and 72 hours after infusion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	2 mg/kg Intravenous Artesunate	4 mg/kg Intravenous Artesunate	8 mg/kg Intravenous Artesunate
Arm/Group Description	2 mg/kg of Intravenous artesunate Intravenous Artesunate: Three doses of Intravenous Artesunate drug at 2, 4, or 8 mg/kg in diluent Phosphate Buffer (0.3 M, pH 8.1)	4 mg/kg of Intravenous artesunate Intravenous Artesunate: Three doses of Intravenous Artesunate drug at 2, 4, or 8 mg/kg in diluent Phosphate Buffer (0.3 M, pH 8.1)	8 mg/kg of Intravenous artesunate Intravenous Artesunate: Three doses of Intravenous Artesunate drug at 2, 4, or 8 mg/kg in diluent Phosphate Buffer (0.3 M, pH 8.1)
Measure Participants	6	6	6
Cmax 1	1735 (547)	3015 (882)	6057 (2456)
Cmax 2	1710 (715)	2923 (1050)	5943 (2110)
Cmax 3	2358 (634)	2933 (810)	5762 (3426)

8. Secondary Outcome

Title	Tmax Assessment After Single 2.0, 4.0 and 8.0 mg/kg Dose of Artesunate Daily for 3 Days (hr)
Description	Tmax was calculated after single 2.0, 4.0 and 8.0 mg/kg dose of Artesunate daily for 3 days (hr)
Time Frame	Pre-dose, 5, 20, 40 minutes after infution and 1, 2, 4, 8, 24 and 72 hours after infusion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	2 mg/kg Intravenous Artesunate	4 mg/kg Intravenous Artesunate	8 mg/kg Intravenous Artesunate
Arm/Group Description	2 mg/kg of Intravenous artesunate Intravenous Artesunate: Three doses of Intravenous Artesunate drug at 2, 4, or 8 mg/kg in diluent Phosphate Buffer (0.3 M, pH 8.1)	4 mg/kg of Intravenous artesunate Intravenous Artesunate: Three doses of Intravenous Artesunate drug at 2, 4, or 8 mg/kg in diluent Phosphate Buffer (0.3 M, pH 8.1)	8 mg/kg of Intravenous artesunate Intravenous Artesunate: Three doses of Intravenous Artesunate drug at 2, 4, or 8 mg/kg in diluent Phosphate Buffer (0.3 M, pH 8.1)
Measure Participants	6	6	6
Tmax 1 (hr)	0.244 (0.132)	0.208 (0.137)	0.208 (0.137)
Tmax 2 (hr)	0.167 (0.129)	0.208 (0.137)	0.181 (0.238)
Tmax 3 (hr)	0.122 (0.104)	0.292 (0.102)	0.250 (0.129)

Adverse Events

Time Frame	up to 21 days
Arm/Group Title	Placebo		2 mg/kg Intravenous Artesunate		4 mg/kg Intravenous Artesunate		8 mg/kg Intravenous Artesunate
Arm/Group Description	Mannitol (200 mg/vial) diluted in phosphate buffer and delivered in an equivalent volume by subject's weight as artesunate. Placebo: Mannitol (200 mg/vial) diluted in Phosphate Buffer and given IV in equivalent volume by subject's weight.		2 mg/kg of Intravenous artesunate Intravenous Artesunate: Three doses of Intravenous Artesunate drug at 2, 4, or 8 mg/kg in diluent Phosphate Buffer (0.3 M, pH 8.1)		4 mg/kg of Intravenous artesunate Intravenous Artesunate: Three doses of Intravenous Artesunate drug at 2, 4, or 8 mg/kg in diluent Phosphate Buffer (0.3 M, pH 8.1)		8 mg/kg of Intravenous artesunate Intravenous Artesunate: Three doses of Intravenous Artesunate drug at 2, 4, or 8 mg/kg in diluent Phosphate Buffer (0.3 M, pH 8.1)
All Cause Mortality
	Placebo		2 mg/kg Intravenous Artesunate		4 mg/kg Intravenous Artesunate		8 mg/kg Intravenous Artesunate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/6 (0%)		0/6 (0%)		0/7 (0%)		0/7 (0%)
Serious Adverse Events
	Placebo		2 mg/kg Intravenous Artesunate		4 mg/kg Intravenous Artesunate		8 mg/kg Intravenous Artesunate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/6 (0%)		0/6 (0%)		0/7 (0%)		0/7 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		2 mg/kg Intravenous Artesunate		4 mg/kg Intravenous Artesunate		8 mg/kg Intravenous Artesunate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/6 (100%)		6/6 (100%)		6/7 (85.7%)		7/7 (100%)
Blood and lymphatic system disorders
Anemia	3/6 (50%)	3	1/6 (16.7%)	1	4/7 (57.1%)	4	0/7 (0%)	0
Leukopenia	0/6 (0%)	0	0/6 (0%)	0	0/7 (0%)	0	1/7 (14.3%)	1
Neutropenia	0/6 (0%)	0	0/6 (0%)	0	0/7 (0%)	0	1/7 (14.3%)	1
Eye disorders
Asthenopia	0/6 (0%)	0	0/6 (0%)	0	1/7 (14.3%)	1	0/7 (0%)	0
Eye pain	0/6 (0%)	0	1/6 (16.7%)	1	0/7 (0%)	0	0/7 (0%)	0
Photophobia	0/6 (0%)	0	0/6 (0%)	0	1/7 (14.3%)	1	0/7 (0%)	0
Gastrointestinal disorders
Lip pain	1/6 (16.7%)	1	0/6 (0%)	0	0/7 (0%)	0	0/7 (0%)	0
General disorders
Fatigue	0/6 (0%)	0	0/6 (0%)	0	1/7 (14.3%)	1	0/7 (0%)	0
Venipuncture site	0/6 (0%)	0	1/6 (16.7%)	1	0/7 (0%)	0	0/7 (0%)	0
Inflammation	0/6 (0%)	0	1/6 (16.7%)	1	0/7 (0%)	0	0/7 (0%)	0
Infections and infestations
Upper respiratory tract infection	0/6 (0%)	0	0/6 (0%)	0	1/7 (14.3%)	1	1/7 (14.3%)	1
Bacteriuria	1/6 (16.7%)	1	0/6 (0%)	0	0/7 (0%)	0	0/7 (0%)	0
Injury, poisoning and procedural complications
Muscle strain	0/6 (0%)	0	1/6 (16.7%)	1	0/7 (0%)	0	0/7 (0%)	0
Investigations
Alanine aminotransferase increased	0/6 (0%)	0	0/6 (0%)	0	1/7 (14.3%)	1	0/7 (0%)	0
Aspartate aminotransferase increased	0/6 (0%)	0	0/6 (0%)	0	1/7 (14.3%)	1	0/7 (0%)	0
Body temperature increased	0/6 (0%)	0	0/6 (0%)	0	0/7 (0%)	0	1/7 (14.3%)	1
Metabolism and nutrition disorders
Anorexia	0/6 (0%)	0	0/6 (0%)	0	1/7 (14.3%)	1	0/7 (0%)	0
Decreased appetite	0/6 (0%)	0	0/6 (0%)	0	0/7 (0%)	0	1/7 (14.3%)	1
Dehydration	1/6 (16.7%)	1	0/6 (0%)	0	0/7 (0%)	0	0/7 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	0/6 (0%)	0	0/6 (0%)	0	0/7 (0%)	0	1/7 (14.3%)	1
Back pain	0/6 (0%)	0	1/6 (16.7%)	1	0/7 (0%)	0	0/7 (0%)	0
Joint stiffness	0/6 (0%)	0	0/6 (0%)	0	0/7 (0%)	0	1/7 (14.3%)	1
Nervous system disorders
Dysgeusia	1/6 (16.7%)	1	4/6 (66.7%)	4	6/7 (85.7%)	6	6/7 (85.7%)	6
Headache	1/6 (16.7%)	1	3/6 (50%)	3	2/7 (28.6%)	2	1/7 (14.3%)	1
Dizziness	0/6 (0%)	0	1/6 (16.7%)	1	1/7 (14.3%)	1	1/7 (14.3%)	1
Paraesthesia	0/6 (0%)	0	1/6 (16.7%)	1	1/7 (14.3%)	1	0/7 (0%)	0
Somnolence	0/6 (0%)	0	0/6 (0%)	0	1/7 (14.3%)	1	1/7 (14.3%)	1
Parosmia	0/6 (0%)	0	1/6 (16.7%)	1	0/7 (0%)	0	0/7 (0%)	0
Syncope vasovagal	0/6 (0%)	0	0/6 (0%)	0	1/7 (14.3%)	1	0/7 (0%)	0
Respiratory, thoracic and mediastinal disorders
Nasal congestion	0/6 (0%)	0	0/6 (0%)	0	0/7 (0%)	0	1/7 (14.3%)	1
Skin and subcutaneous tissue disorders
Dermatitis	0/6 (0%)	0	0/6 (0%)	0	0/7 (0%)	0	1/7 (14.3%)	1
Erythema	0/6 (0%)	0	1/6 (16.7%)	1	0/7 (0%)	0	0/7 (0%)	0
Pruritus generalised	0/6 (0%)	0	1/6 (16.7%)	1	0/7 (0%)	0	0/7 (0%)	0
Rash pruritic	0/6 (0%)	0	0/6 (0%)	0	0/7 (0%)	0	1/7 (14.3%)	1
Vascular disorders
Flushing	0/6 (0%)	0	0/6 (0%)	0	0/7 (0%)	0	1/7 (14.3%)	1
Hot flush	0/6 (0%)	0	0/6 (0%)	0	1/7 (14.3%)	1	0/7 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.