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Study of the Safety of Intravenous Artesunate

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00292942
Recruitment Status : Completed
First Posted : February 16, 2006
Results First Posted : October 25, 2018
Last Update Posted : October 25, 2018
Sponsor:
Collaborator:
Walter Reed Army Institute of Research (WRAIR)
Information provided by (Responsible Party):
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.

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.

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Study Type : Interventional  (Clinical Trial)
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 : June 12, 2006
Actual Primary Completion Date : January 17, 2007
Actual Study Completion Date : January 2008

Resource links provided by the National Library of Medicine

Drug Information available for: Mannitol

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 Name: 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 Name: 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 Name: 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 Name: Mannitol




Primary Outcome Measures :
  1. Number of Participants With AEs [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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

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): NCT00292942


Locations
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United States, Maryland
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
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Study Director: Peter J Weina, MD, PhD Walter Reed Army Institute of Research (WRAIR)
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Responsible Party: U.S. Army Medical Research and Development Command
ClinicalTrials.gov Identifier: NCT00292942    
Other Study ID Numbers: WRAIR 1142
USUHS G183SP ( Other Identifier )
A-13419 ( Other Identifier: IRB )
First Posted: February 16, 2006    Key Record Dates
Results First Posted: October 25, 2018
Last Update Posted: October 25, 2018
Last Verified: February 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: WRAIR

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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:
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Malaria
Malaria, Cerebral
Protozoan Infections
Parasitic Diseases
Central Nervous System Protozoal Infections
Central Nervous System Parasitic Infections
Central Nervous System Infections
Central Nervous System Diseases
Nervous System Diseases
Artesunate
Mannitol
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Antineoplastic Agents
Antiviral Agents
Schistosomicides
Antiplatyhelmintic Agents
Anthelmintics
Diuretics, Osmotic
Diuretics
Natriuretic Agents
Physiological Effects of Drugs