Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12613000698774
Ethics application status
Approved
Date submitted
19/06/2013
Date registered
26/06/2013
Date last updated
16/10/2015
Type of registration
Prospectively registered

Titles & IDs
Public title
An experimental study to characterize the effectiveness of griseofulvin against early falciparum malaria blood stage infection in healthy volunteers
Scientific title
An experimental study to characterize the effectiveness of griseofulvin against early plasmodium falciparum blood stage infection in healthy volunteers
Secondary ID [1] 282703 0
Nil
Universal Trial Number (UTN)
Nil
Trial acronym
Nil
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malaria 289414 0
Condition category
Condition code
Infection 289741 289741 0 0
Studies of infection and infectious agents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a single-center, randomized controlled, study using induced blood stage malaria (IBSM) infection to characterize the effectiveness of griseofulvin as a potential treatment of early Plasmodium falciparum blood stage infection in healthy volunteers.
All participants receive a malaria inoculum injection of ~ 1,800 viable P. falciparum-infected human erythrocytes on Day 0. The study will be conducted in 2 cohorts (n= 6 in each, consisting of 2 control subjects and 4 experimental subjects) using different oral tablet doses of griseofulvin in each of the cohorts. As a stratergy to monitor adherence to the treatment tablet will be administered under direct observation followed by ingestion of food. The experimental subjects enrolled in the experimental arm of cohort 1 (n=4) will be given 1g of griseofulvin administered in two doses of 500 mg each one in the morning (AM) and one in the Evening (PM) for 4 days, beginning on Day 6. Experimental Subjects enrolled in Cohort 2 (n=4) will be administered a single dose of 2000 mg of griseofulvin on Day 6. Control arm subjects in both cohort 1 (n=2) and cohort 2 (n=2) will be treated with Mefloquine once their parasitemia reaches the target level of 1,000 parasites/ml.
Intervention code [1] 287361 0
Treatment: Drugs
Comparator / control treatment
MEFLOQUINE:
Control subjects in both cohorts 1 and 2 (n=2 each) will receive a single dose of 10 mg/kg in an oral tablet form once the threshold for commencement of treatment is reached (= 1000 parasites/ml) as determined by PCR quantification
Control group
Active

Outcomes
Primary outcome [1] 289828 0
To characterize the pharmacodynamic effect of griseofulvin on the growth of Plasmodium falciparum parasites in healthy volunteers following infection with blood stage parasites.
Assessed though PCR and PK analysis of blood samples
Timepoint [1] 289828 0
PCR blood samples Time point: Day 0, 4-13 & 28 days
PK sampling Time point: Day 7-13
Secondary outcome [1] 303335 0
To assess the tolerability of griseofulvin in the experimental human malaria challenge system.
Assessed though history and physical examination, and blood sampling for biochemistry and haematology
Timepoint [1] 303335 0
Biochemistry and haematology Time point: Day 0, 6. 7-13, 28
Physical examination. Time point: Day 0 4-5, 6, 7-13, 28

Eligibility
Key inclusion criteria
1. Volunteers will be adults (males or non pregnant females), aged between 18 and 45 years who do not live alone (from Day 1 until at least the end of the antimalarial drug treatment).
2. Volunteers must have a BMI within the range 18–30 kg/m2 and must weigh more than 50kg in adults in which the proposed dose has already been used.
3. Volunteers must understand the procedures involved and agree to participate in the study by giving fully informed, written consent.
4. Be contactable and available for the duration of the trial and be available up to 2 weeks following end of study visit. (maximum of 8 weeks).
5. Volunteers must be non-smokers for at least three months prior to screening.
6. This study will only be conducted in healthy male volunteers (that do not plan father children in the next 6 months) and female volunteers of non-childbearing potential (i.e. those who have had a hysterectomy, bilateral oophorectomy or tubal ligation or who are post-menopausal). As a precautionary measure, pregnancy testing will be conducted at screening on all eligible females, at the baseline assessment prior inoculation, prior to dosing and at the end of the study.
7. Good peripheral venous access.
Minimum age
18 Years
Maximum age
45 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. History of malaria
2. Evidence of increased cardiovascular disease risk (defined as greater than 10%, 5 year risk) as determined by the method of Gaziano et al.,
3. History of splenectomy.
4. SLE (systemic lupus erythematosus)
5. Porphyria
6. Pregnant or breast feeding
7. Men who may father children in the next six months
8. History of a severe allergic reaction, anaphylaxis or convulsions following any vaccination or infusion.
9. Presence of current or suspected serious chronic diseases or psychiatric illness
10. Volunteers unwilling to defer blood donations to the ARCBS for 6 months.
11. Known pre-existing prolongation of the QT interval or clinically significant
electrocardiogram (ECG) abnormalities
12. Recent or current therapy with an antibiotic or drug with potential antimalarial activity (tetracycline, azthromycin, clindamycin, hydroxychloroquine etc.).
13. Known hypersensitivity to griseofulvin, Mefloquine, artemether or lumefantrine.
14. Concomitant use of any drug which is metabolised by the cytochrome enzyme CYP2D621. Use of corticosteroids, anti-inflammatory drugs, any immunomodulators or anticoagulants.
15. Presence of acute infectious disease or fever (e.g., sub-lingual temperature 38.5 degrees Celsius) within the five days prior to study product administration).
16. Evidence of acute illness within the four weeks before trial prior to screening.
17. Significant intercurrent disease of any type, in particular liver, renal, cardiac, pulmonary,
neurologic, rheumatologic, or autoimmune disease by history, physical examination, and/or
laboratory studies including urinalysis.
18. Participant has a clinically significant disease or any condition or disease that might affect drug absorption, distribution or excretion, e.g. gastrectomy, diarrhoea.
19. Alcohol consumption greater than community norms (i.e. more than 21 standard drinks per week for males and 14 standard drinks per week for females).
20. Currently consuming a low fat diet.
21. A history of drug habituation, or any prior intravenous usage of an illicit substance.
22. Participation in any research study involving significant blood sampling, or blood donation to Red Cross (or other) blood bank during the 8 weeks preceding the reference drug dose in the study.
23. Have ever received a blood transfusion.
24. Positive test for HIV, Hepatitis B, hepatitis C.
25. Any clinically significant biochemical or haematologic abnormality (Hb must be greater than or equal to 11.5g/dL for females; 13.0g/dL for males)– including red cell antibodies
26. Evidence of any condition that, in the opinion of the clinical investigator, might interfere with the evaluation of the study objectives or pose excessive risks to volunteers.
27. Any circumstances or conditions, which, in the opinion of the PI, may affect full participation in the trial or compliance with the protocol.

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)
Following screening participants will be randomized into the study using a pre-designed randomization code using sealed opaque envelopes.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation will be undertaken using a randomisation table created by computer software (i.e. computerised sequence generation).
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Nil
Phase
Phase 1
Type of endpoint/s
Pharmacokinetics / pharmacodynamics
Statistical methods / analysis
Descriptive statistical analysis, combined with analysis of parasite growth rate.
This is an exploratory study designed to determine the effect on parasite growth kinetics of two predefined drug exposures. Pre-clinical data indicate an effect is likely to be observed, and if none is seen in a cohort of this size (n=4,) it is unlikely that a clinical significant effect will be observed.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/07/2013
Actual
2/07/2013
Date of last participant enrolment
Anticipated
1/12/2013
Actual
23/01/2015
Date of last data collection
Anticipated
Actual
Sample size
Target
12
Accrual to date
Final
8
Recruitment in Australia
Recruitment state(s)
QLD

Funding & Sponsors
Funding source category [1] 287472 0
Government body
Name [1] 287472 0
NHMRC
Country [1] 287472 0
Australia
Primary sponsor type
Government body
Name
Queensland Institute of Medical Research
Address
300 Herston Road, Herston, Brisbane, QLD, 4006
Country
Australia
Secondary sponsor category [1] 286217 0
None
Name [1] 286217 0
Address [1] 286217 0
Country [1] 286217 0
Other collaborator category [1] 277462 0
Individual
Name [1] 277462 0
Dr Simon Foote
Address [1] 277462 0
Australian School of Advanced Medicine
2 Technology Place, Macquarie University NSW 2109
Country [1] 277462 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 289450 0
The Queensland Institute of Medical Research HREC
Ethics committee address [1] 289450 0
Ethics committee country [1] 289450 0
Australia
Date submitted for ethics approval [1] 289450 0
Approval date [1] 289450 0
14/06/2013
Ethics approval number [1] 289450 0
P1536

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 40902 0
Dr James McCarthy
Address 40902 0
Queensland Institute of Medical Research
300 Herston Rd
Herston QLD 4006
Country 40902 0
Australia
Phone 40902 0
+61 7 33620222
Fax 40902 0
+61 7 3845 3637
Email 40902 0
[email protected]
Contact person for public queries
Name 40903 0
Silvana Sekuloski
Address 40903 0
Queensland Institute of Medical Research
300 Herston Rd
Herston QLD 4006
Country 40903 0
Australia
Phone 40903 0
+61 7 38453856
Fax 40903 0
+61 7 38453507
Email 40903 0
[email protected]
Contact person for scientific queries
Name 40904 0
James McCarthy
Address 40904 0
Queensland Institute of Medical Research
300 Herston Rd
Herston QLD 4006
Country 40904 0
Australia
Phone 40904 0
+61 7 33620222
Fax 40904 0
+61 7 3845 3637
Email 40904 0
[email protected]

No information has been provided regarding IPD availability


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No Supporting Document Provided



Results publications and other study-related documents

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