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Trial registered on ANZCTR


Registration number
ACTRN12617000824369
Ethics application status
Approved
Date submitted
17/05/2017
Date registered
6/06/2017
Date last updated
15/05/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Genetically Attenuated Malaria Parasite as potential vaccine candidate against malaria infection
Scientific title
Safety and Immunogenicity Study of a Genetically Attenuated Malaria Vaccine candidate in healthy volunteers
Secondary ID [1] 291958 0
nil
Universal Trial Number (UTN)
nil
Trial acronym
GAP Vaccine study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
malaria 303306 0
Condition category
Condition code
Infection 302742 302742 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The proposed clinical study is a two stage open label, Phase I study. The purpose of Stage 1 in this study, is to determine the safety and tolerability of the Genetically Attenuated Plasmodium falciparum 3D7 (GAP) Vaccine Candidate (3D7-KAHRP-KO GAP parasite vaccine) when delivered intravenously to healthy volunteers. Up to three consecutive cohorts of two volunteers will be inoculated with a single escalating dose of GAP Vaccine aiming to test for safety and course of parasitaemia as determined by qPCR. The first cohort will receive a dose of ~1,800 GMO parasites. If parasitaemia does not eventuate (i.e. parasites are significantly attenuated) in Cohort 1, and no safety-limiting AEs occur, the second cohort will proceed using a dose of parasites 100-fold higher (180,000 parasites) and volunteers followed as cohort 1. If parasitaemia does not occur at this higher dose, a third and final cohort will proceed, using a dose of parasites equivalent to that released from the liver after a 5 mosquito bite Controlled Human Malaria Infection study (~3x10e6 parasites). Following each inoculation, volunteers will be monitored on an outpatient basis by qPCR, a method previously shown to be highly sensitive. The monitoring will initially include qPCR on day 0 prior to inoculation, day 1 and day 4 post inoculation and then daily or twice daily once qPCR is positive. The treatment will be initiated within 24 hours once the treatment threshold is reached or on Day 28 if they don’t reach the treatment threshold. The threshold for commencement of treatment will be when qPCR quantification of the participants in the cohort is great than or equal to 5,000 parasites/mL and/or clinical symptoms of malaria (a recorded temperature of
above 38 degrees Celcius) are observed. If the participant has a clinical symptom score greater than 6, or if clinical or parasitological evidence of malaria occurs in any participant before all participants have reached the treatment threshold (qPCR quantification of greater than or equal to 5,000). If the participants do not develop parasitaemia, or their qPCR results do not reach the treatment threshold of greater than or equal to 5000p/mL up until Day 14, monitoring by qPCR will continue three times/week until Day 28+/-3, when they will receive empiric treatment with Riamet 'Registered Trademark' commencing on study Day 28+/-3 on an outpatient basis.
The dosing with Riamet (20mg Artemether and 120mg Lumefantrine per tablet) will be as per manufactures instructions. A course of treatment comprises six doses of four tablets (total course of 24 tablets) given over a period of 60 hours. Each dose should be administered orally followed by food or drinks rich in fat (e.g., milk). The first dose, given at the time of initial diagnosis (or as advised by the PI), should be followed by five further doses given at 12, 24, 36, 48, 60 hours. The trial will be conducted under the Australian Therapeutic Goods Administration (TGA) Clinical Trial Notification Scheme (CTN).
Intervention code [1] 298088 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 302136 0
Primary Outcome: Safety and tolerability of the Genetically Attenuated Plasmodium falciparum 3D7 (GAP) Vaccine Candidate (3D7-KAHRP-KO GAP parasite vaccine): occurrence of parasitaemia, AE and SAEs safety assessment, ECG, clinical biochemistry and haematology Iblood/urine), vital signs


Timepoint [1] 302136 0
Time point: from challenge inoculum (Day 0) up to Day 90 (+/- 7 days). Safety assessments on: Screening, Day 0, daily from day 4 to day of treatment, daily during confinement, Exit of confinement, post discharge follow up at 36, 48 and 72 hours post initiation of treatment, day 28, day 90.
Secondary outcome [1] 334912 0
Infectivity of the GAP vaccine will be assessed using validated qPCR.
Timepoint [1] 334912 0
from challenge inoculum (Day 0) up to Day 90 (+/- 7 days).
Screening, Day 0, day 1, as required from day 4 to day 24, day of treatment, daily during confinement, Exit of confinement 36, 48 and 72 hours post initiation of treatment, day 28, day 90.
Secondary outcome [2] 334913 0
Attenuation of the GAP vaccine will be assessed by parasite growth rate, and unexpected early symptoms or signs of malaria.
Timepoint [2] 334913 0
from challenge inoculum (Day 0) up to Day 28 (+/- 3 days). Screening, Day 0, day 1, as required from day 4 to day 24, day of treatment, daily during confinement, Exit of confinement 36, 48 and 72 hours post initiation of treatment, day 28, day 90
Secondary outcome [3] 334914 0
The immunogenicity of the GAP vaccine doses tested will be assessed by the presence of malaria specific antibodies and T cell and innate cell response in all participants. The titre of vaccine specific antibodies and activation of innate and adaptive cells will be measured after each dose of the GAP vaccine to investigate the relationship between the doses administered and the titre of vaccine-specific antibodies and/or the cellular response.
Timepoint [3] 334914 0
from challenge inoculum (Day 0) up to Day 90 (+/- 7 days). Screening, Day 0, day 1, as required from day 4 to day 24, day of treatment, daily during confinement, Exit of confinement 36, 48 and 72 hours post initiation of treatment, day 28, day 90

Eligibility
Key inclusion criteria
I 01. Adult males between 18 and 55 years of age, inclusive who do not live alone (from Day 0 until at least the end of the anti-malarial drug treatment) and are contactable and available for the duration of the trial (maximum of 4 months).
I 02. Body weight, minimum 50.0 kg, body mass index (BMI) between 18.0 and 32.0 kg/m2, inclusive.
I 03. Participants must be willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures.
I 04. Confirmed as healthy by a comprehensive clinical assessment (detailed medical history and complete physical examination).
I 05. Normal vital signs after 5 minutes resting in supine position:
90 mmHg higher than or equal to systolic blood pressure (SBP) less than or equal to 140 mmHg,
50 mmHg higher than or equal to diastolic blood pressure (DBP)less than or equal to 90 mmHg,
40 bpm higher than or equal to resting heart rate (HR) less than or equal to 100 bpm.
I 06. Normal standard 12-lead electrocardiogram (ECG) after 5 minutes resting in supine position; 120ms less than PR<210 ms, QRS<120 ms, QTcB<340 or QTcF=450 ms with absence of second or third degree atrioventricular block or abnormal T wave morphology.
I 07. Laboratory parameters within the normal range, unless the Investigator considers an abnormality to be clinically irrelevant for healthy participants enrolled in this clinical investigation
I 08. Having given written informed consent prior to undertaking any study-related procedure.
Minimum age
18 Years
Maximum age
55 Years
Gender
Males
Can healthy volunteers participate?
Yes
Key exclusion criteria
E 01. Any history of malaria or participation in a previous malaria challenge study.
E 02. Must not have travelled to or lived (>2 weeks) in a malaria-endemic area/region during the past 12 months or planned travel during the study to a malaria-endemic region during the course of the study. In Australia areas to which travel is not permitted include coastal regions of Tropical North Queensland, the Northern Territory, and island regions of Northern Australia including
the Torres Strait and any international destinations, countries or region
within a country as listed by the Centres for Disease Control and Prevention
(https://www.cdc.gov/malaria/travelers/country_table/a.html) where malaria infection is endemic, while they are infected with the GMO parasites and until they have been verified as parasite free (both asexual and gametocyte forms) and have completed the course of treatment.
E 03. Has evidence of increased cardiovascular disease risk (defined as >10%, 5 year risk for those greater than 35 years of age, as determined by the Australian Absolute Cardiovascular Disease Risk Calculator
(http://www.cvdcheck.org.au/index.php?option=com_content&view=article&id=50&Itemid=60) (Risk factors include sex, age, systolic blood pressure (mm/Hg), smoking status, total and HDL cholesterol (mmol/L) and reported diabetes status.
E 04. History of splenectomy.
E 05. Presence of acute infectious disease or fever (e.g., sub-lingual temperature higher than or equal to 38.5 degrees celcius) within the five days prior to inoculation with malaria parasites.
E 06. Evidence of acute illness within the four weeks before trial prior to screening.
E 07. Significant inter-current 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.
E 08. Participant has a clinically significant disease or any condition or disease that might affect drug absorption, distribution or excretion, e.g. gastrectomy, diarrhea.
E 09. Participation and receipt of any investigational product within the 12 weeks preceding the study.
E 10. Participation in any research study involving blood sampling (more than 450 mL/ unit of blood), or blood donation to Red Cross (or other) blood bank during the 8 weeks preceding the reference drug dose in the study.
E 11. Participant unwilling to defer blood donations to the Australian Red Cross Blood Service (ARCBS), and organ donations during the study and for 6 months following the completion of the study.
E 12. Blood donation, any volume, within 1 month before inclusion.

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
Phase
Phase 0
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Stage 1 in this study is a pilot safety and dose ranging study. Therefore statistical considerations regarding sample size do not apply.

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
Recruitment hospital [1] 8029 0
Q-Pharm Pty - Clive Berghofer Research Centre (CBCRC) - Herston
Recruitment postcode(s) [1] 16016 0
4007 - Herston

Funding & Sponsors
Funding source category [1] 296473 0
Government body
Name [1] 296473 0
NHMRC
Address [1] 296473 0
Research Committee Secretariat NHMRC GPO Box 1421 Canberra ACT 2601
Country [1] 296473 0
Australia
Primary sponsor type
Charities/Societies/Foundations
Name
QIMR Berghofer Medical Research Institute
Address
300 Herston Road
Herston QLD
4006
Country
Australia
Secondary sponsor category [1] 295429 0
None
Name [1] 295429 0
Address [1] 295429 0
Country [1] 295429 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 297695 0
QIMR Berghofer Medical Research Institute – Human Research Ethics Committee
Ethics committee address [1] 297695 0
Ethics committee country [1] 297695 0
Australia
Date submitted for ethics approval [1] 297695 0
Approval date [1] 297695 0
21/04/2017
Ethics approval number [1] 297695 0
P2199/QP16C03
Ethics committee name [2] 297713 0
Australian Red Cross Blood Service – Human Research Ethics Committee
Ethics committee address [2] 297713 0
Ethics committee country [2] 297713 0
Australia
Date submitted for ethics approval [2] 297713 0
Approval date [2] 297713 0
01/05/2017
Ethics approval number [2] 297713 0
2016#08

Summary
Brief summary
This study will investigate the safety and protective effect of a new, experimental malaria vaccine called the GAP Vaccine. This vaccine consists of human red blood cells collected from healthy donors by the Australian Red Cross Blood Service (ARCBS) that are infected with live, genetically attenuated or modified (GM) malaria parasites of the species Plasmodium falciparum. A gene that has been shown to be critical for the ability of P. falciparum blood stage parasites to cause illness has been removed by genetic manipulation to produce this so-called Genetically Attenuated Parasite (GAP). The use of this experimental vaccine has been reviewed by the Australian Government Office of the Gene Technology Regulator (OGTR) and approved for use in this study. It is expected that information obtained from this study will assist researchers to develop vaccines to control malaria in areas of the world where this disease continues to cause much illness and many deaths.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 74854 0
Prof James McCarthy
Address 74854 0
Q-Pharm Pry Limited, level 5
300 Herston Road, Herston, QLD, 4006


Country 74854 0
Australia
Phone 74854 0
+61 7 3845 3796
Fax 74854 0
+61 7 3362 0104
Email 74854 0
J.McCarthy@uq.edu.au
Contact person for public queries
Name 74855 0
Dr Silvana Sekuloski
Address 74855 0
QIMR Berghofer Medical Research Institute
300 Herston Road, QLD, Herston, 4006

Country 74855 0
Australia
Phone 74855 0
+61 7 38453856
Fax 74855 0
+61 7 3845 3507
Email 74855 0
Silvana.Sekuloski@qimrberghofer.edu.au
Contact person for scientific queries
Name 74856 0
Prof James McCarthy
Address 74856 0
Q-Pharm Pry Limited, level 5
300 Herston Road, Herston, QLD, 4006

Country 74856 0
Australia
Phone 74856 0
+61 7 3845 3796
Fax 74856 0
+61 7 3362 0104
Email 74856 0
J.McCarthy@uq.edu.au

No data has been provided for results reporting
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