Study of the Safety of Intravenous Artesunate

Phase 1

Completed

Conditions: Malaria, Cerebral
Malaria

Interventions: Drug: Intravenous Artesunate
Drug: Placebo

Registration Number: NCT00292942

Lead Sponsor: U.S. Army Medical Research and Development Command

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

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 26

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
4 mg/kg Intravenous Artesunate	Intravenous Artesunate	4 mg/kg of Intravenous artesunate
8 mg/kg Intravenous Artesunate	Intravenous Artesunate	8 mg/kg of Intravenous artesunate
Placebo	Placebo	Mannitol (200 mg/vial) diluted in phosphate buffer and delivered in an equivalent volume by subject's weight as artesunate.
2 mg/kg Intravenous Artesunate	Intravenous Artesunate	2 mg/kg of Intravenous artesunate

Primary Outcome Measures

Name	Time	Method
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
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.

Secondary Outcome Measures

Name	Time	Method
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)
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)
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
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)
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.
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)