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Trial registered on ANZCTR


Registration number
ACTRN12614000228684
Ethics application status
Approved
Date submitted
25/02/2014
Date registered
4/03/2014
Date last updated
26/10/2015
Type of registration
Prospectively registered

Titles & IDs
Public title
A safety and tolerability study in humans for chemically attenuated malaria parasites
Scientific title
A safety and tolerability study in humans for P. falciparum 7G8 blood stage parasites attenuated with different doses of Tafuramycin-A
Secondary ID [1] 284159 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malaria 291251 0
Condition category
Condition code
Infection 291596 291596 0 0
Studies of infection and infectious agents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Volunteers will be inoculated on Day 0 of the study with human red blood cells infected with Plasmodium falciparum 7G8 and attenuated with Tafuramycin-A. Three different groups will be compared.

Group A: 3 x 10^7 Plasmodium falciparum 7G8 infected red blood cells attenuated with 50nM of Tafuramycin-A, administered intravenously
Group B: 3 x 10^7 Plasmodium falciparum 7G8 infected red blood cells attenuated with 200nM of Tafuramycin-A, administered intravenously
Group C: 3 x 10^7 Plasmodium falciparum 7G8 infected red blood cells attenuated with 200nM of Tafuramycin-A, administered intravenously
Duration of inoculum: one dose at day 0.

Participants will be actively monitored up to Day 28 post injection and parasite levels in the blood will be monitored during this time period.

At Day 28, scheduled anti-malarial drug treatment (Riamet, also known as Artemether-Lumefantrine) will be administered. If however, there is evidence of a developing malaria infection prior to Day 28 (ie indicating attenuation of the parasites was incomplete), then participants will immediately commence anti-malarial treatment with Riamet.
Duration and dosage of anti-malarial treatment: Artemether (20mg) and Lumefantrine (120mg): 4 tablets orally as a single dose under direct supervision by clinical staff at the following times: 0, 8hrs, 24hrs, 36hrs, 47hrs and 60hrs making a total dose of 24 tablets in 6 doses.
Intervention code [1] 288857 0
Treatment: Drugs
Comparator / control treatment
Volunteers will be inoculated on Day 0 of the study with human red blood cells infected with Plasmodium falciparum 7G8 and attenuated with Tafuramycin-A. Three different groups will be compared.

Three different groups will be compared
Group A: 3 x 10^7 Plasmodium falciparum 7G8 infected red blood cells attenuated with 50nM of Tafuramycin-A
Group B: 3 x 10^7 Plasmodium falciparum 7G8 infected red blood cells attenuated with 200nM of Tafuramycin-A
Group C: 3 x 10^7 Plasmodium falciparum 7G8 infected red blood cells attenuated with 200nM of Tafuramycin-A Duration of inoculum: one dose at day 0.
Control group
Dose comparison

Outcomes
Primary outcome [1] 291541 0
Primary Outcome 1: To characterize the safety and tolerability in humans of P. falciparum 7G8 blood stage parasites attenuated with different doses of Tafuramycin-A.
Timepoint [1] 291541 0
Active monitoring daily from inoculation (ie Day 0) until Day 28. The final visit on Day 90. Passive monitoring (ie participants contacting and reporting any potential adverse events to study staff outside of scheduled visits) from Day 0-Day 90.
Secondary outcome [1] 307014 0
Secondary Outcome 1: To characterize the persistence in the peripheral blood of P. falciparum 7G8 blood stage parasites attenuated with different doses of Tafuramycin-A.

Parasite levels in the blood will be assessed by a sensitive molecular detection method (quantitative PCR) and microscopy.
Timepoint [1] 307014 0
From Day2-Day28 post administration of attenuated P. falciparum 7G8 infected red blood cells
Secondary outcome [2] 307015 0
Secondary Outcome 2: To characterize the immunogenicity of P. falciparum 7G8 blood stage parasites attenuated with different doses of Tafuramycin-A.

This will be assessed by implementing different immunological assays including flow cytometry and ELISAs.
Timepoint [2] 307015 0
Compare antibody and T cell responses at Day0 with responses at Day8, Day14, Day28, Day90.

Secondary outcome [3] 307016 0
Secondary Outcome 3: To identify the antigenic targets of the immune response against the attenuated P. falciparum 7G8 blood stage parasites.
Timepoint [3] 307016 0
Recognition of Plasmodium specific antigens (as assessed by cellular and antibody responses) will be compared at Day0 and Day14.

Eligibility
Key inclusion criteria
1. Volunteers will be males, aged 18-60 years of age who do not live alone for the duration of the study.
2. Volunteers must have a BMI within the range of 18-30.
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 their study schedule (maximum of 3 months)
5. Volunteers must be non-smokers and in good health, as assessed during pre-study medical examination and by review of screening results
6. Good peripheral venous access
Minimum age
18 Years
Maximum age
60 Years
Gender
Males
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Has increased cardiovascular disease risk (defined as >10%, 5 yr risk) as determined by the method of Gaziano et al. Risk factors include: sex, age, systolic blood pressure, smoking status, body mass index (BMI, kg/mm2), and reported diabetes status and blood pressure.
2. History of splenectomy
3. History of severe allergic reaction, anaphylaxis or convulsion following any vaccination, infusion or treatment with anti-malarial drugs artemether and/or lumefantrine.
4. Presence of current or suspected chronic diseases such as cardiac or autoimmune disease (HIV or other immunodeficiencies), insulin dependent diabetes, progressive neurological disease, severe malnutrition, acute or progressive hepatic disease, acute or progressive renal disease, psoriasis, rheumatoid arthritis, asthma, epilepsy, obsessive compulsive disorder, skin carcinoma excluding non-spreadable skin cancers such as basal cell and squamous cell carcinoma.
5. Known inherited genetic anomaly (known as cytogenic disorders) eg Down’s syndrome.
6. Individuals wishing to donate blood to the Australian Red Cross Blood Service in the future.
7. The volunteer has a diagnosis of schizophrenia, bi-polar disease, severe depression or other severe (disabling) chronic psychiatric disorder. Participants who are receiving a single anti-depressant drug and are stable for at least 3 months prior to enrollment without decompensating may be allowed to enroll in the study at the investigator’s discretion.
8. Has been hospitalised in the past 5 years prior to enrolment for psychiatric illness, history of suicide attempt or confinement for danger to self or others.
9. Known pre-existing prolongation of the QTc interval. Family history of congenital prolongation of the QTc interval on electrocardiograms or of sudden death or any other clinical conditions known to prolong the QTc interval eg volunteers with a history of symptomatic cardiac arrhythmias, with clinically relevant bradycardia or with severe cardiac disease.
10. Recent or current therapy with antibiotic or drug with potential antimalarial activity (tetracycline, azithromycin, clindamycin, hydroxychloroquine etc).
11. Concomitant use of any drug which is metabolized by the cytochrome enzyme CYP2D6 (eg flecainide, metoprolol, imipramine, amitriptyline, clomipramine) OR drugs that are known to prolong the QTc interval e.g. antiarrhythmics of classes IA and III, neuroleptics, antidepressant agents, certain antibiotics (including some agents of the following classes: macrolides, fluoroquinolones, imidazole and triazole antifungal agents), certain nonsedating antihistamines (terfenadine, astemizole), cisapride.
12. Use of corticosteroids, anti-inflammatory drugs, any immunomodulators or anticoagulants. Currently receiving or have previously received immunosuppressive therapy, including systemic steroids including ACTH or inhaled steroids in dosages which are associated with hypothalamic-pituitary axis suppression such as 1mg/kg/day or prednisone or its equivalent or chronic use of inhaled high potency corticosteroids (budesonide 800 microgram per day or fluticasone 750 microgram).
13. Presence of acute infectious disease or fever (e.g. sub-lingual temperature greater than or equal to 38.5oC) within the five days prior to the study product administration.
14. Evidence of acute illness within the 4 weeks before trial prior to screening and enrollment.
15. 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.
16. Alcohol consumption greater than community norms (ie more than 21 standard drinks per week for males).
17. A history of drug habituation, or any prior intravenous usage of an illicit substance.
18. Medical requirement for intravenous administration of immunoglobulin or blood transfusions.
19. Participation in any investigational product study within 8 weeks preceding the study.
20. 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 study.
21. Have ever received a blood transfusion.
22. Positive test for HIV, Hepatitis B, Hepatitis C, Human T-cell Lymphotropic Virus I and II(HTLV I and II), TB or syphilis.
23. Any clinically significant biochemical or haematologic abnormality (Hb must be greater than or equal to 13.5g/dL).
24. Ingestion of any poppy seeds within the 48 hours prior to the screening blood test (volunteers will be advised by phone not to consume any poppy seeds in this time period).
25. Detection of any of the following drugs ( Amphetamines, Methamphetamines, Barbiturates, Benzodiazepines, Cocaine, Methadone, Opiates, Phencyclidine, Tetrahydrocannabinols, Tricyclic antidepressants) in the urine drug screen unless there is an explanation acceptable to the medical investigator (eg the subject has stated in advance that they consumed a prescription or OTC product which contained the detected drug) and/or the subject has a negative drug screen on retest by the pathology laboratory.
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 participants
27. G-6-PD deficiency
Although not exclusion criteria, volunteers will be asked to answer the following questions to enable interpretation and analysis of parasite persistence and immunogenicity data
28. History of malaria
29. Travelled to or lived ( greater than 2 weeks) in a malaria-endemic country during the past 12 months or planned to travel to a malaria-endemic country during the course of the study.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Groups of n=3 in Groups A and B and n=2 in Group C
Treatments:
Group A: Plasmodium falciparum 7G8 blood stage parasites attenuated with 50nM of Tafuramycin-A
Group B: Plasmodium falciparum 7G8 blood stage parasites attenuated with 200nM of Tafuramycin-A
Group C: Plasmodium falciparum 7G8 blood stage parasites attenuated with 200nM of Tafuramycin-A

Groups will be inoculated and evaluated consecutively ie Group A will be inoculated and complete their active phase of the study (Day 0 until administration of anti-malarial treatment) before proceeding to inoculation of participants in Group B who will complete their active phase of the study (Day 0 until administration of anti-malarial treatment) before proceeding to inoculation of participants in Group C.
Phase
Phase 0
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
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 in Australia
Recruitment state(s)
QLD

Funding & Sponsors
Funding source category [1] 288784 0
Charities/Societies/Foundations
Name [1] 288784 0
The Atlantic Philanthropies
Address [1] 288784 0
The Atlantic Philanthropies
Suite 106
12 Waters Rd
Neutral Bay
NSW 2089
Country [1] 288784 0
Australia
Primary sponsor type
University
Name
Griffith University
Address
c/- Chris Davis
Griffith University, Gold Coast Campus
Institute for Glycomics, Building G26
Parklands Drive
Southport 4222
QLD
Country
Australia
Secondary sponsor category [1] 287484 0
None
Name [1] 287484 0
Address [1] 287484 0
Country [1] 287484 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 290628 0
Griffith University Human Research Ethics Committee
Ethics committee address [1] 290628 0
Griffith University, Gold Coast Campus
Rm 3.60, Science, Engineering and Architecture (G39)
Parklands Drive,
Southport, QLD, 4215
Ethics committee country [1] 290628 0
Australia
Date submitted for ethics approval [1] 290628 0
24/02/2014
Approval date [1] 290628 0
05/06/2014
Ethics approval number [1] 290628 0
GLY/01/14/HREC

Summary
Brief summary
This study is examining the safety, tolerability, persistence and immunogenicity of chemically attenuated P. falciparum 7G8 infected red blood cells. Participants will receive a single inoculum of malaria parasites attenuated with either 50nM, 100nM or 200nM of Tafuramycin-A. Following administration of the inoculum, we will measure the level of malaria parasites in the blood-stream and then administer anti-malarial treatment (Riamet) at D28. We will also be assessing the safety of the inoculum and the way the immune system responds to it. Determining the safety, persistence and immunogenicity of the Tafuramycin-A malaria parasites is important as they form the basis of a novel malaria vaccine approach.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 46518 0
Dr Danielle Stanisic
Address 46518 0
c/- Griffith University, Gold Coast Campus, Institute for Glycomics, Building G26, Parklands Drive, Southport, 4215, QLD
Country 46518 0
Australia
Phone 46518 0
61 7 555 28051
Fax 46518 0
61 7 555 28098
Email 46518 0
glycomics@griffith.edu.au
Contact person for public queries
Name 46519 0
Dr Danielle Stanisic
Address 46519 0
c/- Griffith University, Gold Coast Campus, Institute for Glycomics, Building G26, Parklands Drive, Southport, 4215, QLD
Country 46519 0
Australia
Phone 46519 0
61 7 555 28051
Fax 46519 0
61 7 555 28098
Email 46519 0
glycomics@griffith.edu.au
Contact person for scientific queries
Name 46520 0
Dr Danielle Stanisic
Address 46520 0
c/- Griffith University, Gold Coast Campus, Institute for Glycomics, Building G26, Parklands Drive, Southport, 4215, QLD
Country 46520 0
Australia
Phone 46520 0
61 7 555 28051
Fax 46520 0
61 7 555 28098
Email 46520 0
glycomics@griffith.edu.au

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary