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Trial registered on ANZCTR


Registration number
ACTRN12618001314213
Ethics application status
Approved
Date submitted
1/08/2018
Date registered
6/08/2018
Date last updated
6/08/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
An efficacy study in humans for chemically attenuated malaria parasites
Scientific title
An efficacy study in healthy malaria-naive adults for purified Plasmodium falciparum 7G8 parasites attenuated with Tafuramycin-A
Secondary ID [1] 295714 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malaria 309110 0
Condition category
Condition code
Infection 307986 307986 0 0
Studies of infection and infectious agents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The design of the study involves 3 groups of participants (n=12/group). Ten participants in each group will receive three doses (administered as an intravenous injection) of the following on Days 0, 28 and 56 of the study:
Group A: 3 x 10^7 purified P. falciparum 7G8 blood-stage pRBC attenuated with Tafuramycin-A (TF-A) (200nM) or
Group B: 3 x 10^6 purified P. falciparum 7G8 blood-stage pRBC attenuated with TF-A (200nM) or
Group C: 3 x 10^5 purified P. falciparum 7G8 blood-stage pRBC attenuated with TF-A (200nM). The vaccinations will be administered 28 days apart.

The Groups will be run sequentially, so that Group A will complete their entire study schedule (including challenge) before Group B commence their vaccinations. Group B will complete their entire study schedule (including challenge) before Group C are vaccinated.

The 2 unvaccinated participants in each group will serve as infectivity controls (to demonstrate the viability of the inoculum) and they will receive the challenge inoculum at the same time as the vaccinated volunteers, on Day 84 of the study.

Participants will be actively monitored (2 days/week) in the time period between each vaccination and prior to challenge to monitor the parasite levels in the blood and to collect samples for immunology studies.

If parasite levels reach 3,850 parasites/ml following vaccination but prior to challenge, then blood will be drawn daily to measure parasite densities in the blood using qPCR until either resolution of the infection/initiation of anti-malarial treatment. If there is any evidence of a developing malaria infection ie the numbers of parasites in the blood increase exponentially and levels in the blood reach 11,550 parasites/ml or clinical symptoms of malaria develop, the individual will immediately commence standard anti-malarial treatment with Riamet.

Study participants will receive the challenge inoculum (administered as an intravenous injection) containing 1,800 P. falciparum 7G8 parasitised red blood cells on Day 84. From Day 85, blood will be drawn daily (in the morning) until parasites are detected by qPCR. As soon as parasites are detected by qPCR in the morning blood sample, blood collection for qPCR will increase to three times a day. Initiation of anti-malarial treatment after receipt of the challenge inoculum will be according to the development of signs/symptoms of malaria as determined by the treating clinical investigator. If participants do not develop parasitemia, anti-malarial treatment will be initiated one month following receipt of the challenge inoculum.
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] 302037 0
Treatment: Drugs
Comparator / control treatment
Comparator groups:
Three different groups will be compared for a dose comparison
Group A: 3 x 10^7 purified P. falciparum 7G8 blood-stage pRBC attenuated with TF-A (200nM) or
Group B: 3 x 10^6 purified P. falciparum 7G8 blood-stage pRBC attenuated with TF-A (200nM) or
Group C: 3 x 10^5 purified P. falciparum 7G8 blood-stage pRBC attenuated with TF-A (200nM).

There is no true active control group in this study. The 2 "infectivity controls" included in each group are included to demonstrate viability of the inoculum.
Control group
Dose comparison

Outcomes
Primary outcome [1] 306960 0
To characterize the safety and tolerability in humans of three doses of purified P. falciparum 7G8 parasitised red blood cells attenuated with Tafuramycin-A.

To assess this, active and passive monitoring daily from enrollment (ie Day 0) until Study completion. Active monitoring involves scheduled visits. At scheduled visits, physical examinations will be undertaken, study participants will be assessed for solicited and unsolicited events. During a complete physical examination, the following systems will be reviewed: dermatological, head/ear/nose/throat/neck, cardiovascular, respiratory, gastrointestinal/digestive, neurological and muscoskeletal. On Days 0, 8, 27, 35, 55, 46, 83, and study completion (day 115), blood samples will be collected for haematology and bochemistry testing.
Passive monitoring (ie participants contacting and reporting any potential adverse events to study staff outside of scheduled visits) from Day 0 until study completion.
Timepoint [1] 306960 0
Active and passive monitoring daily from enrollment (ie Day 0) until Study completion. Active monitoring includes scheduled visits. Passive monitoring (ie participants contacting and reporting any potential adverse events to study staff outside of scheduled visits) from Day 0 until study completion (Day 115).
Primary outcome [2] 306961 0
To characterize the immunogenicity of purified P. falciparum of three doses of 7G8 parasitised red blood cells attenuated with Tafuramycin-A. This is a composite primary outcome. Immunological assays to assess antibody and T cell responses will be undertaken using blood samples collected on Days 0, 16,27, 44, 55, 76 and 83.
Timepoint [2] 306961 0
Compare antibody and T cell responses at Day 0 with responses at Days 16,27, 44, 55, 76 and 83.
Secondary outcome [1] 350265 0
To evaluate the protective efficacy of purified P. falciparum 7G8 parasitised red blood cells attenuated with Tafuramycin-A, following parasite challenge.
Timepoint [1] 350265 0
Development of blood-stage parasitemia and parasite multiplication rate in the blood of study participants in the time period (28 days) following administration of the challenge inoculum on Day 84. From Day 85, sample collection will be daily until parasites are detected by PCR. Sample collection will then increase to 3 times/day until anti-malarial drug treatment is initiated. If parasitemia doesn't develop, sample collection will cease on Day 111 and anti-malarial drug treatment will be initiated on Day 112.

Eligibility
Key inclusion criteria
1. Volunteers will be males, aged 18-50 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 or smoke less than or equal to 5 cigarettes/day and in good health, as assessed during pre-study medical examination and by review of screening results
6. Good peripheral venous access
7. Volunteers must be RhD positive (due to the Blood Group of the parasitised red blood cells in the vaccines).
Minimum age
18 Years
Maximum age
50 Years
Sex
Males
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Has evidence of increased cardiovascular disease risk (defined as greater than 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), reported diabetes status and smoking.
2. History of splenectomy
3. History of severe allergic reaction, anaphylaxis or convulsion following any vaccination, infusion or treatment with the 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 during the study or within 12 months of administration of the malaria inoculum.
7. Diagnosis of schizophrenia, severe depression, bi-polar disease or other severe (disabling) chronic psychiatric disorder. Participants who are receiving a single anti-depressant 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 micrograms per day or fluticasone 750 micrograms).
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 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 Clinical 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. History of malaria.
28. 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
Prevention
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Not applicable
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Not applicable
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
The design of the study involves 3 groups of participants (n=12/group). Ten participants in each group will receive three doses of the following on Days 0, 28 and 56 of the study:
Group A: 3 x 10^7 purified P. falciparum 7G8 blood-stage pRBC attenuated with TF-A (200nM) or
Group B: 3 x 10^6 purified P. falciparum 7G8 blood-stage pRBC attenuated with TF-A (200nM) or
Group C: 3 x 10^5 purified P. falciparum 7G8 blood-stage pRBC attenuated with TF-A (200nM). The vaccinations will be administered 28 days apart.

The Groups will be run sequentially, so that Group A will complete their entire study schedule (including challenge) before Group B commence their vaccinations. Group B will complete their entire study schedule (including challenge) before Group C are vaccinated.

The 2 unvaccinated participants in each group will serve as infectivity controls (to demonstrate the viability of the inoculum) and they will receive the challenge inoculum at the same time as the vaccinated volunteers, on Day 84 of the study.
Phase
Phase 1
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
16/08/2018
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
36
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 11558 0
Griffith University Clinical Trials Unit - Southport
Recruitment postcode(s) [1] 23589 0
4215 - Southport

Funding & Sponsors
Funding source category [1] 300302 0
Charities/Societies/Foundations
Name [1] 300302 0
National Foundation for Medical Research and Innovation
Country [1] 300302 0
Australia
Funding source category [2] 300306 0
Charities/Societies/Foundations
Name [2] 300306 0
Rotary District 9640
Country [2] 300306 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] 299739 0
None
Name [1] 299739 0
Address [1] 299739 0
Country [1] 299739 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301115 0
Gold Coast Hospital and Health District Research Ethics Committee (EC00160)
Ethics committee address [1] 301115 0
Ethics committee country [1] 301115 0
Australia
Date submitted for ethics approval [1] 301115 0
19/01/2018
Approval date [1] 301115 0
01/02/2018
Ethics approval number [1] 301115 0
HREC/18/QGC/23
Ethics committee name [2] 301118 0
Griffith University Human Research Ethics Committee
Ethics committee address [2] 301118 0
Ethics committee country [2] 301118 0
Australia
Date submitted for ethics approval [2] 301118 0
22/02/2018
Approval date [2] 301118 0
02/03/2018
Ethics approval number [2] 301118 0
2018/152

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

Contacts
Principal investigator
Name 85910 0
Prof Michael Good
Address 85910 0
c/- Griffith University, Gold Coast Campus, Institute for Glycomics, Building G26, Parklands Drive, Southport, 4215, QLD
Country 85910 0
Australia
Phone 85910 0
61 7 5552 8051
Fax 85910 0
Email 85910 0
glycomicstrials@griffith.edu.au
Contact person for public queries
Name 85911 0
Danielle Stanisic
Address 85911 0
c/- Griffith University, Gold Coast Campus, Institute for Glycomics, Building G26, Parklands Drive, Southport, 4215, QLD
Country 85911 0
Australia
Phone 85911 0
61 7 5552 8051
Fax 85911 0
Email 85911 0
glycomicstrials@griffith.edu.au
Contact person for scientific queries
Name 85912 0
Danielle Stanisic
Address 85912 0
c/- Griffith University, Gold Coast Campus, Institute for Glycomics, Building G26, Parklands Drive, Southport, 4215, QLD
Country 85912 0
Australia
Phone 85912 0
61 7 5552 8051
Fax 85912 0
Email 85912 0
glycomicstrials@griffith.edu.au

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseMalaria vaccines since 2000: progress, priorities, products.2020https://dx.doi.org/10.1038/s41541-020-0196-3
N.B. These documents automatically identified may not have been verified by the study sponsor.