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Trial registered on ANZCTR


Registration number
ACTRN12612001298808
Ethics application status
Approved
Date submitted
13/12/2012
Date registered
17/12/2012
Date last updated
17/12/2012
Type of registration
Prospectively registered

Titles & IDs
Public title
A study of the plasma concentration-time profile and antimalarial activity of plasma samples collected from healthy Vietnamese volunteers after the administration of artesunate-amodiaquine alone and with methylene blue.
Scientific title
Pharmacokinetics and ex vivo antimalarial activity of methylene blue combined with artesunate and amodiaquine in healthy Vietnamese volunteers.
Secondary ID [1] 281672 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malaria 287971 0
Antimalarial drug resistance 287972 0
Condition category
Condition code
Infection 288345 288345 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
In a randomized, open label, 2-way cross-over design, 16 healthy Vietnamese volunteers will be administered a single oral dose of either 2 tablets of artesunate-amodiaquine (ASAQ Winthrop-Registered Trademark) from Sanofi-Aventis; 100 mg AS and 270 mg AQ per tablet) or 2 tablets of ASAQ Winthrop plus 5 tablets of methylene blue (MB Urolene Blue-Registered Trademark) from Star Pharmaceuticals; 65 mg per tablet). The wash-out period between treatments will be 8 weeks.
Intervention code [1] 286208 0
Treatment: Drugs
Comparator / control treatment
The pharmacokinetics and tolerability of ASAQ in healthy volunteers will be compared following the administration of ASAQ alone and with MB. Also, the ex vivo antimalarial activity of plasma samples collected from the volunteers after the administration of ASAQ alone and with MB will be determined against the chloroquine-sensitive D6 and chloroquine-resistant W2 P. falciparum lines to assess whether MB enhances the blood stage activity of ASAQ, in vitro.
Control group
Active

Outcomes
Primary outcome [1] 288509 0
The pharmacokinetics (absorption, metabolism, distribution and excretion) of ASAQ will be drived from plasma concentrations versus time curves generated from the analysis of plasma samples collected from healthy volunteers after dosing with ASAQ alone and with MB.
Timepoint [1] 288509 0
For each treatment venous blood samples will be collected using an indwelling catheter, with blood samples collected immediately before drug administration and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 h after dosing. Subsequent blood samples will be collected by venipuncture at days 1, 2, 3, 7, 14, 21, and 28 after drug administration. Plasma concentrations of AS and its major active metabolite dihydroartemisinin, AQ and its major active metabolite desethylamodiaquine and MB will be measured by LC/MS/MS. Non-compartmental analysis will be used to determine the pharmacokinetics of the drugs and metabolites.
Primary outcome [2] 288510 0
Ex vivo antimalarial activity (pharmacodynamics) will be carried out on plasma ASAQ concentrations and plasma ASAQ plus MB concentrations collected from the volunteers against two P. falciparum lines (D6 and W2).
Timepoint [2] 288510 0
Plasma samples for ex vivo antimalarial activity will be collected at 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 h after dosing. Plasma samples will also be collected at days 1, 2, 3, 7, 14, 21, and 28 after drug administration. A comparison will be made of the maximum inhibitory dilution (MID) profiles generated from plasma samples collected from the volunteers after the two treatments. The MID will be determined using the in vitro tritiated-hypoxanthine assay.
Secondary outcome [1] 300361 0
The tolerability and safety of the two treatments will be compared. Possible adverse events can be gastrointestinal disturbances such as vomiting, nausea and abdominal discomfort.
Timepoint [1] 300361 0
Any adverse events will be recorded before drug administration and daily for 3 to 4 days after dosing. Blood samples for biochemical and haematological analysis will be collected before dosing and on day 7 after drug administration. Electrocardiograms will be performed immediately before and 6 h after dosing.

Eligibility
Key inclusion criteria
(i) Males: 17-40 years
(ii) Normal clinical parameters: medical history, physical examination
(iii) Normal haematological and biochemical indices, and electrocardiogram
(iv) Normal glucose-6-phosphate dehydrogenase (G6PD)
(v) Able to understand and willing to provide written informed consent
Minimum age
17 Years
Maximum age
40 Years
Gender
Males
Can healthy volunteers participate?
Yes
Key exclusion criteria
(i) A history of serious past medical diseases
(ii) A history of drug or alcohol abuse
(iii) Use of regular medications including prescribed and natural therapies
(iv) Use of serotonergic psychiatric medications

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Each treatment allocation will be concealed in sealed envelopes that will be opened only after the volunteer’s recruitment. The wash-out period between the two treatments will be 8 weeks.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computer generated randomization codes.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Phase
Phase 1
Type of endpoint(s)
Pharmacokinetics / pharmacodynamics
Statistical methods / analysis
Descriptive statistics (means, standard deviations, 95% confidence intervals) will be calculated for the demographic parameters and blood chemistries. Pharmacokinetic parameters will be determined by noncompartmental analysis. Maximum Inhibitory dilutions (bioassay) will be assessed by culturing malaria parasites in vitro in the presence of volunteers’ plasma samples collected after drug administration. Statistical comparisons will be made using the paired Student’s t-test, accepting a difference at the 5% level as significant.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 4752 0
Viet Nam
State/province [1] 4752 0
Hanoi

Funding & Sponsors
Funding source category [1] 286465 0
Government body
Name [1] 286465 0
Australian Army Malaria Institute
Address [1] 286465 0
Weary Dunlop Drive
Gallipoli Barracks
Enoggera
Brisbane QLD 4051
Country [1] 286465 0
Australia
Primary sponsor type
Government body
Name
Australian Army Malaria Institute
Address
Weary Dunlop Drive
Gallipoli Barracks
Enoggera
Brisbane QLD 4051
Country
Australia
Secondary sponsor category [1] 285253 0
Government body
Name [1] 285253 0
Vietnam People's Army
Address [1] 285253 0
Military Institute of Hygiene and Epidemiology, 21-Trung Liet, Dong Da, Hanoi, Vietnam
Country [1] 285253 0
Viet Nam

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 288541 0
Australian Defence Human Research Ethics Committee
Ethics committee address [1] 288541 0
ADHREC,
CP2-7-100,
Campbell Park Offices,
Campbell BC ACT 2610
Ethics committee country [1] 288541 0
Australia
Date submitted for ethics approval [1] 288541 0
Approval date [1] 288541 0
13/03/2012
Ethics approval number [1] 288541 0
649-11

Summary
Brief summary
Artemisinin combination therapies (ACT) such as artesunate-amodiaquine (ASAQ) are currently recommended worldwide for first-line treatment of uncomplicated Plasmodium falciparum malaria. However, recent reports of reduced susceptibility of artemisinins and ACTs in western Cambodia, western Thailand and south Vietnam is very worrisome and highlights the urgent need to identify alternative drug combination options for effective and affordable treatment. To extend the efficacy life of ACTs, a triple drug combination strategy may be worthy of consideration. We propose to determine whether methylene blue (MB), an old and affordable antimalarial drug, can be combined with ASAQ to extend the efficacy life of the ACT by studying the tolerability, pharmacokinetics and ex vivo antimalarial activity of ASAQ alone and with MB in healthy Vietnamese volunteers. If MB combined with ASAQ is well tolerated and does not adversely alter the pharmacokinetics of ASAQ in healthy volunteers, and enhanced blood stage ex vivo antimalarial activity can be demonstrated in volunteers' plasma containing ASAQ plus MB, then further studies a warranted to appraise the clinical value of the triple drug combination of AS+AQ+MB.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 36610 0
Dr Nguyen Ngoc Quang
Address 36610 0
Military Hospital 108,
Department of Infectious Diseases,
1 Tran Hung Dao Street, Hoan Kiem District,
Hanoi, Vietnam
Country 36610 0
Viet Nam
Phone 36610 0
84-4-903209095
Fax 36610 0
Email 36610 0
Quangnn2002@yahoo.com
Contact person for public queries
Name 36611 0
Dr Michael Edstein
Address 36611 0
Australian Army Malaria Institute,
Weary Dunlop Drive,
Gallipoli Barracks,
Enoggera,
Brisbane, QLD 4051
Country 36611 0
Australia
Phone 36611 0
61-7-33324930
Fax 36611 0
Email 36611 0
Mike.Edstein@defence.gov.au
Contact person for scientific queries
Name 36612 0
Dr Michael Edstein
Address 36612 0
Australian Army Malaria Institute,
Weary Dunlop Drive,
Gallipoli Barracks,
Enoggera,
Brisbane, QLD 4051
Country 36612 0
Australia
Phone 36612 0
61-7-33324930
Fax 36612 0
Email 36612 0
Mike.Edstein@defence.gov.au

No information has been provided regarding IPD availability
Summary results
No Results