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Trial registered on ANZCTR


Registration number
ACTRN12617000048381
Ethics application status
Approved
Date submitted
20/12/2016
Date registered
11/01/2017
Date last updated
14/05/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Blood stage pilot challenge study to assess the safety and the infectivity of Plasmodium malariae isolate (HMPBS-Pm) in healthy volunteers
Scientific title
An Experimental Study To Characterise The In Vivo Safety And Infectivity Of The Plasmodium Malariae Isolate Hmpbs-Pm In Humans
Secondary ID [1] 290793 0
None
Universal Trial Number (UTN)
Nil
Trial acronym
HMPBS-Pm
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malaria infection with P. malariae strain 301437 0
Condition category
Condition code
Infection 301157 301157 0 0
Studies of infection and infectious agents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Each participant will be inoculated on Day 0 with an estimated ~1000 viable parasites in 1.5 x 10^9 erythrocytes administered intravenously. On an outpatient basis, the participants will be monitored initially by phone then daily from Day 6 until the detection of parasites by qPCR. During this time, participants will also be monitored for the unexpected early onset of malaria symptoms, signs or parasitological evidence of malaria. On the day of commencement of treatment, participants will attend the outpatient unit for a visit encompassing first two doses of the anti-malarial treatment with the anti-malarial drug Riamet(Registered Trademark) (Artemether20mg / Lumefantrine 120 mg), transmission experiments and safety monitoring. The anti-malarial treatment will be administered as an oral tablet; 6 doses of 4 tablets (total course 24 tablets) given over a period of 60 hours following food. It is expected some of the doses to be taken by the participants at home. Participants will have a phone call from a study staff member to check on symptoms and ensure compliance/completion with treatment following the dose taken at home. A maximum of two mosquito transmission studies by each of direct (DFA) and membrane feeding assays (MFA) may be performed approximately two days prior to treatment and on the day of treatment (four feeding assays in total). A further MFA may be performed following treatment if there is evidence of gametocytemia or at the Investigator’s discretion. Further follow up visits for safety assessments will be performed on Day 28+/-3, Day 56+/-7 (as required) and Day 84+/-7 (End of Study). Each follow up visit beyond Day 28 should take place as scheduled+/-7 days. The overall period of participation will therefore be around 14 weeks from the time malaria infection. A further follow up period roughly 6 months post completion Riamet(Registered Trademark) treatment may also be requested at the Investigator’s discretion.
Intervention code [1] 296706 0
Treatment: Drugs
Comparator / control treatment
No Control
Control group
Uncontrolled

Outcomes
Primary outcome [1] 300567 0
Primary outcome 1: safety assessed by adverse events (AE) (unexpected toxicities, adverse events encountered during or after study drug administration), safety laboratory parameters, and vital signs. Clinical safety will be also be assessed by soliciting symptoms and signs of malaria (such as fever fatigue, vomiting and Diarrhea) and of adverse effects of the inoculum.
Although considered an extremely low risk, it is possible that participants may experience transfusion reactions after receiving the inoculum, or develop antibodies to the donor red blood cells that may make blood transfusion more difficult in the future. The risk of malaria infection is managed by closely monitoring the number of parasites in participants’ blood samples and administering registered anti-malarial agents at a threshold that is below the point at which advanced clinical symptoms of malaria infection are likely to occur. Safety of the IBSM is assessed by close monitoring of clinical status, including physical examination, vital signs assessment, electrocardiograms (ECG), adverse event reporting and by laboratory pathology testing, including testing for red cell alloantibodies, haematology and biochemistry.
Timepoint [1] 300567 0
Monitored throughout the study to 6 months post treatment.
Physical examination and vital signs: Screening, day 0, day on commencement of treatment and outpatient phases if clinically indicated, and day 84 (EOS).
ECG: Screening, day 0, and day 28 and day 84 (EOS).
Adverse Events: Screening to day 84 (EOS) and 6 months follow up.
Haematology and biochemistry: At Screening, InD-3 to InD-1 safety visit, pre-inoculation InD0, on the day of commencement of treatment, one week following completion of treatment, and for Day 28 and Day 84 or EOS. Any significant deviations from results obtained during screening will be followed until resolution or investigated fully. Red cell alloantibody testing: Screening and EOS.
Primary outcome [2] 300568 0
Primary outcome 2: infectivity assessed by parasitaemia measured by qPCR
Assessed by close monitoring of the number of parasites in the blood and clinical symptoms of malaria
Timepoint [2] 300568 0
Pre inoculation and then daily from Day 6 until PCR positive for malaria, and until Riamet(Registered Trademark) dosing. Blood sampling will occur for parasitaemia (PCR) at 0, 4 and 12 hours post commencement of treatment. Then twice daily until negative. Follow up PCR will be performed at Day 10 and Day 28/Day 84 or EOS if withdrawn before). If the participant is clinically well then frequency of blood collection to achieve two consecutive negative tests may be relaxed to provide a break from phlebotomy.
Secondary outcome [1] 330329 0
Secondary outcome 1: blood stage parasite clearance profiles by pPCR following treatment with Artemether-Lumefantrine (Riamet(Registered Trademark))
Timepoint [1] 330329 0
Pre inoculation and then daily from Day 6 until PCR positive for malaria, and until Riamet(Registered Trademark) dosing. Blood sampling will occur for parasitaemia (PCR) at 0, 4 and 12 hours post commencement of treatment. Then twice daily until parasitaemia by qPCR is undetectable or stable suggesting gametocytemia.. Follow up PCR will be performed at Day 10 and Day 28/Day 84 or EOS if withdrawn before). If the participant is clinically well then frequency of blood collection to achieve two consecutive negative tests may be relaxed to provide a break from phlebotomy.; measured twice daily
Secondary outcome [2] 330330 0
Secondary outcome 2: the infectivity of P. malariae to vector mosquitoes in the induced blood stage malaria (IBSM) model
Timepoint [2] 330330 0
Direct Feeding Assays: Up to 2 time points until participants receive the anti-malarial treatment i.e. 10-14 days following infection with blood stage parasites if gametocytes are indicated by PCR.
Indirect Feeding Assays: Up to 2 time-points prior to anti-malarial treatment i.e. 10-14 days following infection with blood stage parasites if gametocytes are indicated by PCR and one following the completion of the treatment if evidence of gametocytaemia.

Eligibility
Key inclusion criteria
01. Adult males or non-lactating and non-pregnant females, 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.
02. Body weight, minimum 50.0 kg, body mass index between 18.0 and 32.0 kg/m2, inclusive.
03. Confirmed as healthy by a comprehensive clinical assessment (detailed medical history and complete physical examination).
04. Blood group A or AB
05. Normal standard 12-lead electrocardiogram (ECG) after 5 minutes resting in supine position;
06. Laboratory parameters within the normal range, unless the Investigator considers an abnormality to be clinically irrelevant for healthy participants enrolled in this clinical investigation.
07. As there is the risk of adverse effects of the study treatment, it is important that any participants involved in this study do not get pregnant
08. All participants must be Duffy Blood group positive. Female participants of childbearing potential should be blood group Rh positive.
09. Female participants of childbearing potential must also have adequate contraception in place for the duration of the study
Minimum age
18 Years
Maximum age
55 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
01. Any history of malaria or participation in a previous malaria challenge study.
02. Must not have travelled to or lived (greater than 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
03. Has evidence of increased cardiovascular disease risk
04. History of splenectomy.
05. Presence of acute infectious disease or fever (e.g., sub-lingual temperature greater than or equal to 38.5 Degrees Celsius) within the five days prior to inoculation with malaria parasites.
06. Evidence of acute illness within the four weeks before trial prior to screening that the Investigator deems may compromise participant safety.
07. Participation and receipt of any investigational product within the 12 weeks preceding the study.
08. Blood donation, any volume, within 1 month before inclusion.
09. Participant who has ever received a blood transfusion.
10. Any vaccination within the last 28 days.
11. Any recent (less than 6 weeks) or current systemic therapy with an antibiotic or drug with potential anti-malarial activity (chloroquine, piperaquine, benzodiazepine, flunarizine, fluoxetine, tetracycline, azithromycin, clindamycin, hydroxychloroquine, etc.).
12. Cardiac/QT risk:
13. Known hypersensitivity to Riamet or any 4-aminoquinolines, artemether or other artemether derivatives, lumefantrine, or other arylaminoalcohols.
14. Known severe reaction to mosquito bites other than local itching and redness.

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)
Allocation is not concealed
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
Single group
Other design features
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis
This is an infectivity validation study and no formal statistical analysis is planned. All measured variables and derived values will be listed, including data from all patients who meet the eligibility criteria and are enrolled in the study.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
9/02/2017
Actual
9/02/2017
Date of last participant enrolment
Anticipated
2/10/2017
Actual
21/04/2017
Date of last data collection
Anticipated
Actual
4/08/2017
Sample size
Target
2
Accrual to date
Final
2
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 7170 0
Q-Pharm Pty - Clive Berghofer Research Centre (CBCRC) - Herston
Recruitment postcode(s) [1] 14931 0
4007 - Herston

Funding & Sponsors
Funding source category [1] 295217 0
Government body
Name [1] 295217 0
NHMRC
Country [1] 295217 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] 294044 0
None
Name [1] 294044 0
Address [1] 294044 0
Country [1] 294044 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296562 0
QIMR Berghofer Medical Research Institute HREC
Ethics committee address [1] 296562 0
Ethics committee country [1] 296562 0
Australia
Date submitted for ethics approval [1] 296562 0
Approval date [1] 296562 0
02/12/2016
Ethics approval number [1] 296562 0
P2268

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

Contacts
Principal investigator
Name 71302 0
Prof James McCarthy
Address 71302 0
QIMR Berghofer Medical Research Institute
300 Herston Rd
Herston QLD 4006
Country 71302 0
Australia
Phone 71302 0
+61 7 3362 0222
Fax 71302 0
+61 7 3845 3637
Email 71302 0
[email protected]
Contact person for public queries
Name 71303 0
Silvana Sekuloski
Address 71303 0
QIMR Berghofer Medical Research Institute
300 Herston Rd
Herston QLD 4006
Country 71303 0
Australia
Phone 71303 0
+61 7 3845 3856
Fax 71303 0
+61 7 3845 3507
Email 71303 0
[email protected]
Contact person for scientific queries
Name 71304 0
James McCarthy
Address 71304 0
QIMR Berghofer Medical Research Institute
300 Herston Rd
Herston QLD 4006
Country 71304 0
Australia
Phone 71304 0
+61 7 3362 0222
Fax 71304 0
+61 7 3845 3637
Email 71304 0
[email protected]

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
No additional documents have been identified.