Safety and Efficacy Study of IV Artesunate to Treat Malaria

• Sponsor: U.S. Army Medical Research and Development Command (U.S. Fed)
• Overall Status: Completed
• CT.gov ID: NCT00298610
• Collaborator: Military Infectious Diseases Research Program (MIDRP) (Other)
• Enrollment: 30
• Location: 1
• Arm: 1
• Duration (Months): 19
• Patients Per Site Per Month: 1.6

Study Details

Study Description

Brief Summary

The purpose of this study is to determine how GMP IV Artesunate is metabolized and cleared by individuals with uncomplicated malaria infection and to determine how fast it eliminates malaria infection from the body.

Condition or Disease	Intervention/Treatment	Phase
Malaria	Drug: Artesunate; Drug: Malarone	Phase 2

Detailed Description

This is an unblinded non-randomized phase II pharmacokinetic study of a new GMP formulation of intravenous artesunate. Artesunate has been used throughout Asia and Africa for many years. Its overall efficacy associated with the ability to lower parasitemia is well established. To date, pharmacokinetic studies have not been done in Africa using GMP (Good Manufacturing Practices)-produced drug. The objective of this study is to show that GMP IV artesunate rapidly clears parasites in Adult Kenyan populations with malaria and that the pharmacokinetic profile of the drug approximates other populations of adults tested (Asians and North Americans).

Study Design

• Study Type: Interventional
• Actual Enrollment: 30 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II, Open Label, Study of the Safety, Tolerability, Efficacy and Pharmacokinetics of Intravenous Artesunate in Adults With Uncomplicated Malaria
• Study Start Date: Mar 1, 2006
• Actual Primary Completion Date: Oct 1, 2007
• Actual Study Completion Date: Oct 1, 2007

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Artesunate and Malarone Subject are given intravenous Artesunate once a day for 3 days. Following completion of Artesunate treatment, all subjects received Malarone follow-on therapy to ensure parasitologic cure.	Drug: Artesunate; Intravenous Artesunate (2.4 mg/kg) once a day for three days; Other Names: quinidine ; Drug: Malarone; (proguanil/atovaquone) follow-on therapy (4 tablets once daily for three days); Other Names: atovaquone and proguanil hydrochloride

Outcome Measures

Primary Outcome Measures

1. Change in Percentage of Parasites Detected at 48 Hours [48 hours]

   Change in Percentage of Parasites Detected at 48 Hours. With positive numbers to represent increases and negative numbers to represent decreases

Secondary Outcome Measures

1. Percentage of Parasite Clearance [24 and 48 hours post dose]

   The target variable is detection (percentage) of asexual stage parasites of Plasmodium falciparum malaria in bloodstream by Giemsa - stained microscopy of thick and thin blood smears

2. Number of Subjects With Fever Clearance [Within 48 hours post dose]

   Temperature is measured by oral digital thermometers, and fever clearance time is defined as the first time with resolution of fever (<37.5C) sustained for 24 hours

3. Safety - Severity of Adverse Events [up to 14 days]

   Determine the safety (defined as severity of AE's using the Common Toxicity Criteria)

4. Safety - Adverse Events Relationship to Study Drug [up to 14 days]

   Determine the safety (defined as relationship to study drug of AE's and SAE's)

5. Safety - Severity of Serious Adverse Events (SAE's) [up to 14 days]

   Determine the safety (defined as severity of SAE's using the Common Toxicity Criteria)

6. Safety - Serious Adverse Event (SAE) Relationship to Study Drug [Up to 14 days]

   Determine the safety (defined as relationship to study drug of SAE's)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Adult male & non-pregnant females, 18-65 years

• Fever, defined as >37.5ºC, during the current illness, or history (within the last 48 hours) of fever.

• Diagnosis of falciparum malaria, greater than or equal to 200 parasites/uL

• Able to communicate well with the investigator and to comply with the requirements of the entire study.

• Willing to be admitted for the period of drug administration and/or to follow up (return to hospital)

• Provision of the written informed consent to participate as shown by a signature on the informed consent form.

Exclusion Criteria:

• Administration of any investigational drug in the period 0 to 16 weeks before entry to the study.

• The use of any medication during the period 0 to 14 days (prescribed drugs) or 0 to 5 days (OTC) before entry to the study (including herbal or dietary supplements), except those deemed by the principal investigator / clinical investigator not to interfere with the outcome of the study.

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

• History of serious adverse reaction or hypersensitivity to study drug or follow on treatment.

• Mixed malaria infection (malaria other than falciparum malaria mono-infection as detected by screening blood smear)

• Severe falciparum malaria (as defined by the WHO; Attachment 1).

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

• Transfusion of blood within past 30 days.

• Refusal to prevent pregnancy during the 14 days of the trial

• Pregnancy as defined clinically or by a positive urine BHCG at the time of screening, or nursing mothers.

• Laboratory evidence or history of significant cardiovascular, liver or renal functional abnormality, which in the opinion of the investigator would place them at increased risk. Specifically, the following will serve as exclusionary lab values:

• Creatinine >1.4 x ULN (>2.0 mg/dL)

• Glucose <LLN (65mg/dL)

• AST, ALT >3x ULN (120 U/L)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	New Nyanza Provincial Hospital	Kisumu	New Nyanza	Kenya

Sponsors and Collaborators

• U.S. Army Medical Research and Development Command
• Military Infectious Diseases Research Program (MIDRP)

Investigators

• Principal Investigator: Shon A Remich, MD, 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: NCT00298610
• Other Study ID Numbers: WRAIR 1168; KEMRI 917; HSRRB A-13331
• First Posted: Mar 2, 2006
• Last Update Posted: Oct 1, 2019
• Last Verified: Nov 1, 2016

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by U.S. Army Medical Research and Development Command: Uncomplicated Malaria; GMP artesunate
• Additional relevant MeSH terms: Malaria; Artesunate; Atovaquone; Proguanil; Quinidine; Atovaquone, proguanil drug combination

Study Results

Participant Flow

Recruitment Details	Thirty adult subjects with uncomplicated malaria were recruited from the endemic malarious region of Nyanza province in Kenya came to the New Nyanza Medical Center or sub-location recruitment sites.

Arm/Group Title	Artesunate and Malarone
Arm/Group Description	Subject are given intravenous Artesunate once a day for 3 days. Following completion of Artesunate treatment, all subjects received Malarone follow-on therapy to ensure parasitologic cure. Artesunate and Malarone: Intravenous Artesunate (2.4 mg/kg) once a day for three days and Malarone (proguanil/atovaquone) follow-on therapy (4 tablets once daily for three days)
Period Title: Overall Study
STARTED	30
COMPLETED	30
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Artesunate and Malarone
Arm/Group Description	Subject are given intravenous Artesunate once a day for 3 days. Following completion of Artesunate treatment, all subjects received Malarone follow-on therapy to ensure parasitologic cure. Artesunate and Malarone: Intravenous Artesunate (2.4 mg/kg) once a day for three days and Malarone (proguanil/atovaquone) follow-on therapy (4 tablets once daily for three days)
Overall Participants	30
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	30 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	28 (9.4)
Sex: Female, Male (Count of Participants)
Female	20 66.7%
Male	10 33.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	30 100%
White	0 0%
More than one race	0 0%
Unknown or Not Reported	0 0%
Race/Ethnicity, Customized (Count of Participants)
Tribe = Luo	27 90%
Tribe = Luyha	2 6.7%
Tribe = Other	1 3.3%
Region of Enrollment (participants) [Number]
Kenya	30 100%

Outcome Measures

1. Primary Outcome

Title	Change in Percentage of Parasites Detected at 48 Hours
Description	Change in Percentage of Parasites Detected at 48 Hours. With positive numbers to represent increases and negative numbers to represent decreases
Time Frame	48 hours

Outcome Measure Data

Analysis Population Description

Percentage of parasite change at 48 hours post dose

Arm/Group Title	Artesunate and Malarone
Arm/Group Description	Subject are given intravenous Artesunate once a day for 3 days. Following completion of Artesunate treatment, all subjects received Malarone follow-on therapy to ensure parasitologic cure. Artesunate and Malarone: Intravenous Artesunate (2.4 mg/kg) once a day for three days and Malarone (proguanil/atovaquone) follow-on therapy (4 tablets once daily for three days)
Measure Participants	30
Mean (Standard Deviation) [percentage of parasite change]	99.998 (0.0006)

2. Secondary Outcome

Title	Percentage of Parasite Clearance
Description	The target variable is detection (percentage) of asexual stage parasites of Plasmodium falciparum malaria in bloodstream by Giemsa - stained microscopy of thick and thin blood smears
Time Frame	24 and 48 hours post dose

Outcome Measure Data

Analysis Population Description

Percentage of parasite clearance within the first 24 and 48 hours post dose of intravenous artesunate

Arm/Group Title	Artesunate and Malarone
Arm/Group Description	Subject are given intravenous Artesunate once a day for 3 days. Following completion of Artesunate treatment, all subjects received Malarone follow-on therapy to ensure parasitologic cure. Artesunate and Malarone: Intravenous Artesunate (2.4 mg/kg) once a day for three days and Malarone (proguanil/atovaquone) follow-on therapy (4 tablets once daily for three days)
Measure Participants	30
24 hours post dose	99.421 (1.365)
48 hours post dose	99.998 (0.0006)

3. Secondary Outcome

Title	Number of Subjects With Fever Clearance
Description	Temperature is measured by oral digital thermometers, and fever clearance time is defined as the first time with resolution of fever (<37.5C) sustained for 24 hours
Time Frame	Within 48 hours post dose

Outcome Measure Data

Analysis Population Description

Summary of subject with fever clearance, defined as first sustained absence of fever (<37.5C for least 24 hours)

Arm/Group Title	Artesunate and Malarone
Arm/Group Description	Subject are given intravenous Artesunate once a day for 3 days. Following completion of Artesunate treatment, all subjects received Malarone follow-on therapy to ensure parasitologic cure. Artesunate and Malarone: Intravenous Artesunate (2.4 mg/kg) once a day for three days and Malarone (proguanil/atovaquone) follow-on therapy (4 tablets once daily for three days)
Measure Participants	30
Count of Participants [Participants]	29 96.7%

4. Secondary Outcome

Title	Safety - Severity of Adverse Events
Description	Determine the safety (defined as severity of AE's using the Common Toxicity Criteria)
Time Frame	up to 14 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Artesunate and Malarone
Arm/Group Description	Subject are given intravenous Artesunate once a day for 3 days. Following completion of Artesunate treatment, all subjects received Malarone follow-on therapy to ensure parasitologic cure. Artesunate and Malarone: Intravenous Artesunate (2.4 mg/kg) once a day for three days and Malarone (proguanil/atovaquone) follow-on therapy (4 tablets once daily for three days)
Measure Participants	30
Mild	123
Moderate	17
Severe	6

5. Secondary Outcome

Title	Safety - Adverse Events Relationship to Study Drug
Description	Determine the safety (defined as relationship to study drug of AE's and SAE's)
Time Frame	up to 14 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Artesunate and Malarone
Arm/Group Description	Subject are given intravenous Artesunate once a day for 3 days. Following completion of Artesunate treatment, all subjects received Malarone follow-on therapy to ensure parasitologic cure. Artesunate and Malarone: Intravenous Artesunate (2.4 mg/kg) once a day for three days and Malarone (proguanil/atovaquone) follow-on therapy (4 tablets once daily for three days)
Measure Participants	30
None or remote	89
Possible, probable, definate	57

6. Secondary Outcome

Title	Safety - Severity of Serious Adverse Events (SAE's)
Description	Determine the safety (defined as severity of SAE's using the Common Toxicity Criteria)
Time Frame	up to 14 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Artesunate and Malarone
Arm/Group Description	Subject are given intravenous Artesunate once a day for 3 days. Following completion of Artesunate treatment, all subjects received Malarone follow-on therapy to ensure parasitologic cure. Artesunate and Malarone: Intravenous Artesunate (2.4 mg/kg) once a day for three days and Malarone (proguanil/atovaquone) follow-on therapy (4 tablets once daily for three days)
Measure Participants	30
Mild	0
Moderate	0
Severe	1

7. Secondary Outcome

Title	Safety - Serious Adverse Event (SAE) Relationship to Study Drug
Description	Determine the safety (defined as relationship to study drug of SAE's)
Time Frame	Up to 14 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Artesunate and Malarone
Arm/Group Description	Subject are given intravenous Artesunate once a day for 3 days. Following completion of Artesunate treatment, all subjects received Malarone follow-on therapy to ensure parasitologic cure. Artesunate and Malarone: Intravenous Artesunate (2.4 mg/kg) once a day for three days and Malarone (proguanil/atovaquone) follow-on therapy (4 tablets once daily for three days)
Measure Participants	30
None or Remote	0
Possible, Probable, Definate	1

Adverse Events

Time Frame	14 Days
Adverse Event Reporting Description	AE's were solicited using standardized questionnaires at each clinic visit (Days 0 - 14+2)
Arm/Group Title	Artesunate and Malarone
Arm/Group Description	Subject are given intravenous Artesunate once a day for 3 days. Following completion of Artesunate treatment, all subjects received Malarone follow-on therapy to ensure parasitologic cure. Artesunate and Malarone: Intravenous Artesunate (2.4 mg/kg) once a day for three days and Malarone (proguanil/atovaquone) follow-on therapy (4 tablets once daily for three days)
All Cause Mortality
	Artesunate and Malarone
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Artesunate and Malarone
	Affected / at Risk (%)	# Events
Total	1/30 (3.3%)
Skin and subcutaneous tissue disorders
Stevens-Johnson Syndrome	1/30 (3.3%)	1
Other (Not Including Serious) Adverse Events
	Artesunate and Malarone
	Affected / at Risk (%)	# Events
Total	30/30 (100%)
Blood and lymphatic system disorders
Neutropenia	16/30 (53.3%)	16
Neutropenia	1/30 (3.3%)	1
Anaemia	8/30 (26.7%)	8
Anaemia	5/30 (16.7%)	5
Eosinophilia	1/30 (3.3%)	1
Eosinophilia	4/30 (13.3%)	4
Leukopenia	2/30 (6.7%)	2
Leukopenia	0/30 (0%)	0
Lymphopenia	1/30 (3.3%)	1
Lymphopenia	0/30 (0%)	0
Cardiac disorders
Bradycardia	5/30 (16.7%)	5
Bradycardia	1/30 (3.3%)	1
Tachycardia	1/30 (3.3%)	1
Tachycardia	5/30 (16.7%)	5
Eye disorders
Conjunctivitis	0/30 (0%)	0
Conjunctivitis	1/30 (3.3%)	1
Gastrointestinal disorders
Vomiting	2/30 (6.7%)	2
Vomiting	3/30 (10%)	3
Abdominal pain	0/30 (0%)	0
Abdominal pain	2/30 (6.7%)	2
Abdominal pain, upper	0/30 (0%)	0
Abdominal pain, upper	1/30 (3.3%)	1
Cheilitis	1/30 (3.3%)	1
Cheilitis	0/30 (0%)	0
Constipation	0/30 (0%)	0
Constipation	1/30 (3.3%)	1
Diarrhea	0/30 (0%)	0
Diarrhea	1/30 (3.3%)	1
Enteritis	1/30 (3.3%)	1
Enteritis	0/30 (0%)	0
Gingival pain	0/30 (0%)	0
Gingival pain	1/30 (3.3%)	1
General disorders
Pyrexia	4/30 (13.3%)	4
Pyrexia	7/30 (23.3%)	7
Chills	1/30 (3.3%)	1
Chills	2/30 (6.7%)	2
Infusion site pain	2/30 (6.7%)	2
Infusion site pain	1/30 (3.3%)	1
Fatigue	0/30 (0%)	0
Fatigue	2/30 (6.7%)	2
Chest pain	0/30 (0%)	0
Chest pain	1/30 (3.3%)	1
Oedema peripheral	0/30 (0%)	0
Oedema peripheral	1/30 (3.3%)	1
Infections and infestations
Upper respiratory tract infection	0/30 (0%)	0
Upper respiratory tract infection	2/30 (6.7%)	2
Viral infection	0/30 (0%)	0
Viral infection	2/30 (6.7%)	2
Abscess	0/30 (0%)	0
Abscess	1/30 (3.3%)	1
Furuncle	0/30 (0%)	0
Furuncle	1/30 (3.3%)	1
Herpes simplex	1/30 (3.3%)	1
Herpes simplex	0/30 (0%)	0
Hordeolum	0/30 (0%)	0
Hordeolum	1/30 (3.3%)	1
Oral candidiasis	0/30 (0%)	0
Oral candidiasis	1/30 (3.3%)	1
Viraemia	0/30 (0%)	0
Viraemia	1/30 (3.3%)	1
Investigations
Bilirubin decreased	0/30 (0%)	0
Bilirubin decreased	1/30 (3.3%)	1
Metabolism and nutrition disorders
Hyperglycaemia	0/30 (0%)	0
Hyperglycaemia	3/30 (10%)	3
Anorexia	1/30 (3.3%)	1
Anorexia	1/30 (3.3%)	1
Hypoglycaemia	0/30 (0%)	0
Hypoglycaemia	2/30 (6.7%)	2
Musculoskeletal and connective tissue disorders
Arthralgia	0/30 (0%)	0
Arthralgia	1/30 (3.3%)	1
Back pain	0/30 (0%)	0
Back pain	1/30 (3.3%)	1
Neck pain	0/30 (0%)	0
Neck pain	1/30 (3.3%)	1
Pain in extremity	0/30 (0%)	0
Pain in extremity	1/30 (3.3%)	1
Nervous system disorders
Headache	1/30 (3.3%)	1
Headache	8/30 (26.7%)	8
Dizziness	0/30 (0%)	0
Dizziness	1/30 (3.3%)	1
Syncope vasovagal	0/30 (0%)	0
Syncope vasovagal	1/30 (3.3%)	1
Respiratory, thoracic and mediastinal disorders
Cough	0/30 (0%)	0
Cough	2/30 (6.7%)	2
Tachypoea	0/30 (0%)	0
Tachypnoea	2/30 (6.7%)	2
Pharyngolaryngeal pain	0/30 (0%)	0
Pharyngolaryngeal pain	1/30 (3.3%)	1
Rhinorrhoea	0/30 (0%)	0
Rhinorrhoea	1/30 (3.3%)	1
Skin and subcutaneous tissue disorders
Dermatitis atopic	0/30 (0%)	0
Dermatitis atopic	1/30 (3.3%)	1
Pruritus	0/30 (0%)	0
Pruritus	1/30 (3.3%)	1
Rash	0/30 (0%)	0
Rash	1/30 (3.3%)	1
Rash macular	0/30 (0%)	0
Rash macular	1/30 (3.3%)	1
Stevens-Johnson syndrome	1/30 (3.3%)	1
Stevens-Johnson syndrome	0/30 (0%)	0
Vascular disorders
Hypotension	8/30 (26.7%)	8
Hypotension	9/30 (30%)	9
Hypertension	0/30 (0%)	0
Hypertension	1/30 (3.3%)	1

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.