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Trial registered on ANZCTR

Registration number

ACTRN12616000174482

Ethics application status

Approved

Date submitted

3/02/2016

Date registered

11/02/2016

Date last updated

15/05/2018

Type of registration

Prospectively registered

Titles & IDs

Public title

Chloroquine effects on Plasmodium vivax isolate HMPBS02-Pv

Scientific title

A Phase IB Experimental Study to Assess the in vivo Safety and Response to Chloroquine of Plasmodium vivax isolate HMPBS02-Pv in Healthy Participants with Induced Blood Stage Malaria Infection

Secondary ID [1]

QP15C19

Universal Trial Number (UTN)

Nil

Trial acronym

CQPv02

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Malaria infection

Condition category

Condition code

Infection

Studies of infection and infectious agents

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Description of intervention(s) / exposure: This is a single-centre, open label study using induced blood stage malaria (IBSM) infection to characterize in healthy malaria-naive participants inoculated with Plasmodium vivax (P. vivax) isolate HMPBS02-Pv the safety and the effectiveness of chloroquine in reducing parasitaemia. 8 participants in a single cohort will be inoculated on Day 0 with around 1,100 viable P. vivax-infected human erythrocytes administered intravenously. On the day designated for commencement of treatment as determined by symptom onset (approximately study Day 8), participants will be admitted to the study confinement unit and monitored. The threshold for commencement of treatment, as determined by the Investigator, will be onset of symptoms of malaria infection with parasitaemia anticipated to be at around 20,000 parasites/mL at this time. The first dose of chloroquine will be administered with food in the morning after an overnight fasting period of greater than 8 hours. Participants will be treated with chloroquine phosphate administered orally over 3 days. For adults greater than or equal to 60 kg in weight, chloroquine will be administered as 4 tablets (1 g) as an initial dose, followed by 2 tablets (500 mg) at 6, 24, and 48 hours for a total dose of 2.5 g over 3 days. For adults less than 60 kg in weight, chloroquine will be administered as 10 mg/kg as an initial dose, followed by 5 mg/kg at 6, 24, and 48 hours for a total dose of 25 mg/kg over 3 days. Each participant’s mouth will be checked following administration to ensure the medication was swallowed. Participants will be subsequently discharged from the study unit. Follow-up visits for safety assessments will be performed until day 28 after malaria infection. Paracetamol and ibuprofen are allowed as non-prescription drugs to be used by the participants in this study for relieve of any minor discomforts that might occur due to the malaria infection or the treatment with the anti-malarial drug. The dosing of these analgesics will be in accordance with the directions on the labels.
Cohort 1: All participants are allowed to take ibuprofen orally up to 1.2 g/day or paracetamol orally up to 4 g/day for as long as clinically required.
Cohort 2: All participants are allowed to use paracetamol only up to 4 g per day orally (500 mg-1 g every 4-6 hours up to a maximum of 4 g daily) for as long as clinically required.
Cohort 3: All participants are allowed to use ibuprofen only up to 1.2 g/day orally (200 to 400 mg orally every 4 to 6 hours up to a maximum of 1.2 g/day) for as long as clinically required.

Transmission studies will also be undertaken by direct skin feeding and indirect membrane feeding of mosquitoes. The experimental infection of mosquitoes by direct skin feeding on participants will be performed up to a maximum of 2 time-points and membrane feeding assays performed up to a maximum of 3 time-points prior to antimalarial treatment.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

No control group

Control group

Uncontrolled

Outcomes

Primary outcome [1]

To assess the safety of the induced P. vivax blood stage malaria (IBSM) model following inoculation of healthy participants with P. vivax isolate HMPBS02-Pv and registered anti-malarial drug treatment.
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]

Physical examination and vital signs: Complete physical examination and vital signs will be performed for all participants at screening and final visit.
Vital signs assessment will be performed daily from day 4 to admission, during confinement and then on each outpatient visit and end of study.
Abbreviated physical examination will be performed before and after the inoculation, and then on visits when malaria signs and symptoms are identified and during confinement as specified in the protocol.

ECG: Screening, day 0, on admission to unit, pre- and post- chloroquine treatment, prior to exit from clinic, day 28 (end of study).
Adverse Events: Screening to day 28 (end of study)
Haematology and biochemistry: Screening, pre-inoculum, pre- and post-chloroquine treatment, post-confinement at 120 hr (liver function tests only), 168 hr, 240 hr , 336 hr and day 28 (end of study).
Red cell alloantibody testing: Screening and day 28 (EOS).

Primary outcome [2]

To characterize the pharmacokinetic-pharmacodynamic relationship of chloroquine on clearance of P. vivax parasites from the blood in healthy participants following infection with low dose of blood stage parasites.
Assessed by pharmacokinetic (PK) sampling and qPCR analysis of blood level parasitaemia.
The population PK profile of drug treatment with chloroquine and the association between drug exposure and the observed parasite counts will be evaluated and the minimum inhibitory concentration (MIC) will be determined. The maximum concentration (Cmax) and the time it is reached (Tmax) will be reported.

Timepoint [2]

Blood sample for assessment of levels of chloroquine (and metabolites) will occur: pre-dose and then following administration of treatment drug at 1, 2, 3, 4, 6, 12, 24, 48, 72, 96, 168, 240 hours and day 28 (end of study).
Parasitaemia PCR: pre-inoculum at day 0, daily from day 4 until PCR becomes positive, twice daily until treatment day, pre-dose on treatment day, and at 2, 4, 8, 12, 16, 24, 30, 36, 48, 60, and 72 hours post-dose. PCR sampling will then be performed post-confinement at 96,120, 168, 240 hours or until two consecutive negative PCRs, and at day 28 (end of study).
Gametocyte-specific PCR: pre-inoculum on day 0, day 4, then twice daily until treatment day, pre-dose on treatment day, 72 hours post-dose, at the Investigator’s discretion until parasitaemia PCR is negative, and at day 28 (EOS).

Secondary outcome [1]

To evaluate the infectivity of P. vivax to vector mosquitoes in the induced blood stage malaria (IBSM) model.
Assessed by infection of the mosquitoes that have been fed with the infected blood. The infectivity will be assessed by midgut dissection and evaluation of production of oocysts following the feeding experiments. Thick films may be prepared from blood collected on time points coinciding with membrane feeds.

Timepoint [1]

Indirect Mosquito feed: up to 3 time-points prior to chloroquine treatment (i.e. ~6-10 days following infection with blood stage parasites) if gametocytes are determined to be present.
Direct Mosquito Feed: up to 2 time-points until participants receive standard treatment with chloroquine (approximately 6-10 days after inoculation).

Secondary outcome [2]

To characterize the pharmacokinetics of chloroquine in healthy volunteers following infection with blood stage P. vivax.
Assessed by pharmacokinetic (PK) sampling. The concentration of chloroquine (and metabolites) in plasma will be determined using a mass spectrometry assay. The results reported will include but not limited to area under the curve (determined using log-linear integration up to last time point measure (AUCt)) and extrapolated to infinity (AUC0-infinity), the gradient of the elimination phase, (lambda-z), the maximum concentration (Cmax) and the time it is reached (Tmax). Compartmental modelling will be performed using programs for PK/PD modelling such as WinNonlin and Nonmem.

Timepoint [2]

Secondary outcome [3]

To further characterise blood stage parasite growth profiles by qPCR following inoculation with P. vivax isolate HMPBS02-Pv.
Assessed by the parasite reduction ratio (PRR) of asexual and sexual parasites (where applicable) based on qPCR analysis of parasitaemia from blood samples collected pre-dose and following administration of study drug.

Timepoint [3]

Parasitaemia PCR: pre-inoculum at day 0, daily from day 4 until PCR becomes positive, twice daily until treatment day, pre-dose on treatment day, and at 2, 4, 8, 12, 16, 24, 30, 36, 48, 60, and 72 hours post-dose. PCR sampling will then be performed post-confinement at 96,120, 168, 240 hours or until two consecutive negative PCRs, and at day 28 (end of study).

Eligibility

Key inclusion criteria

1. Adults (male and non-pregnant, non-lactating female) participants 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 will be contactable and available for the duration of the trial and follow up period (maximum of 6 weeks).
2. Body mass index between 18.0 and 32.0 kg/m2, inclusive.
3. Certified as healthy by a comprehensive clinical assessment (detailed medical history and complete physical examination).
4. Normal vital signs after 5 minutes resting in supine position
5. Normal standard 12-lead electrocardiogram (ECG) after 5 minutes resting in supine position
6. Laboratory parameters within the normal range, unless the Investigator considers an abnormality to be clinically irrelevant for healthy participants enrolled in this clinical investigation.
7. As there is the risk of adverse effects of the study treatment drug (chloroquine), in pregnancy, it is important that any participants involved in this study do not get pregnant
8. All participants must be Duffy Blood group positive. Female participants of childbearing potential should be blood group Rh positive.
9. Female participants of childbearing potential and all male participants 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

1. Any history of malaria or participation to a previous malaria challenge study
2. Any history of retinal abnormalities, disease of the retina or macula of the eye, visual field defects, hearing disorders (e.g. reduced hearing, tinnitus).
3. Must not have travelled to or lived (>2 weeks) in a malaria-endemic region during the past 12 months or planned travel to a malaria-endemic region during the course of the study.
4. Has evidence of increased cardiovascular disease risk
5. History of splenectomy
6. Presence of acute infectious disease or fever (e.g., sub-lingual temperature greater than or equal to 38.5°C) within the 5 days prior to inoculation with malaria parasites.
7. Evidence of acute illness within the 4 weeks before trial prior to screening that the Investigator deems may compromise participant safety.
8. Participant has a clinically significant disease or any condition or disease that might affect drug absorption, distribution or excretion, e.g. gastrectomy, diarrhoea.
9. Participation in any investigational product study within the 12 weeks preceding the study.
10. Blood donation, any volume, within 1 month before inclusion or 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.
11. Participant who has ever received a blood transfusion
12. Any recent (less than 6 weeks) or current systemic therapy with an antibiotic or drug with potential anti-malarial activity (i.e. chloroquine, piperaquine, benzodiazepine, flunarizine, fluoxetine, tetracycline, azithromycin, clindamycin etc.)
13. Cardiac/QT risk
14. Known hypersensitivity to chloroquine, or any of its excipients or 4-aminoquinolines, artemether or other artemisinin derivatives, lumefantrine, or other arylaminoalcohols.
15. Known severe reaction to mosquito bites other than local itching and redness.
16. Unwillingness to abstain from consumption of citrus (grapefruit, Seville orange, etc.) for greater than or equal to 21 days prior to initiation of the study (inoculation, Day 0) and for the study duration

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

Single group

Other design features

Phase

Phase 1

Type of endpoint/s

Safety

Statistical methods / analysis

Recruitment

Recruitment status

Completed

Date of first participant enrolment

Anticipated

19/02/2016

Actual

19/02/2016

Date of last participant enrolment

Anticipated

30/06/2017

Actual

27/03/2017

Date of last data collection

Anticipated

Actual

12/05/2017

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

QLD

Recruitment hospital [1]

Q-Pharm Pty - Clive Berghofer Research Centre (CBCRC) - Herston

Recruitment postcode(s) [1]

4006 - Herston

Funding & Sponsors

Funding source category [1]

Charities/Societies/Foundations

Name [1]

Medicines for Malaria Venture (MMV)

Address [1]

Route de Pre-Bois 20, 1215 Geneva

Country [1]

Switzerland

Primary sponsor type

Other

Name

QIMR Berghofer Medical Research Institute

Address

300 Herston Road, Herston, Queensland 4006

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

QIMR Berghofer Human Research Ethics Committee

Ethics committee address [1]

300 Herston Road, Herston, QLD 4006

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

12/01/2016

Approval date [1]

16/02/2016

Ethics approval number [1]

Summary

Brief summary

This is a single-centre study using naturally acquired Plasmodium vivax (P. vivax) HMPBS02-Pv challenge inoculum to infect healthy participants in order to characterize the infectivity of the parasite isolate P. vivax HMPBS02-Pv in vivo. The goal is to determine the safety of the P. vivax blood stage malaria model following inoculation of healthy participants with P. vivax HMPBS02-Pv and the registered Chloroquine anti-malarial drug treatment.
This study will be conducted in consenting and eligible male or female participants. Each participant will be inoculated on Day 0 with around 1,100 viable P. vivax-infected human erythrocytes administered intravenously.
On an outpatient basis, the participants will be monitored for presence of parasites by qPCR following the challenge and then during and after the treatment, until free of parasites. 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 designated for commencement of treatment, as determined by PCR results and/or onset of clinical symptoms of malaria infection, participants will be admitted to the study unit and confined for safety monitoring and registered Chloroquine anti-malarial treatment. Based on previous studies, it is anticipated that treatment will occur on approximately Day 8 to Day 10.
Following treatment, the participants will be followed up as in-patients for 72 hours to ensure tolerance of therapy and clinical response. Once clinically well, the participants will be followed up on an out-patient basis for continued assessment of anti-malarial drug levels, and monitoring of safety, in particular liver function tests, and clearance of malaria parasites via qPCR. Follow up visits for safety assessments will be performed at specific time points until Day 28 after the malaria infection and the participants are required to be contactable and available up to 2 weeks following this end of study visit.
The overall period of participation will therefore be around 4 weeks from the time malaria infection.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Prof James McCarthy

Address

Q-Pharm Pty Limited
Level 5, Clive Berghofer Cancer Research Centre (CBCRC)
300C Herston Rd
Herston QLD 4006

Country

Australia

Phone

+61 7 3845 3636

Fax

+61 7 3845 3637

[email protected]

Contact person for public queries

Name

Dr Silvana Sekuloski

Address

QIMR Berghofer Medical Research Institute
300 Herston Rd
Herston QLD 4006

Country

Australia

Phone

+61 7 3845 3856

Fax

+61 7 3845 3507

[email protected]

Contact person for scientific queries

Name

Prof James McCarthy

Address

QIMR Berghofer Medical Research Institute
300 Herston Rd
Herston QLD 4006

Country

Australia

Phone

+61 7 3362 0222

Fax

+61 7 3845 3637

[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

Source	Title	Year of Publication	DOI
Embase	Population Pharmacokinetics and Pharmacodynamics of Chloroquine in a Plasmodium vivax Volunteer Infection Study.	2020	https://dx.doi.org/10.1002/cpt.1893
Embase	Early endothelial activation precedes glycocalyx degradation and microvascular dysfunction in experimentally induced plasmodium falciparum and plasmodium vivax infection.	2020	https://dx.doi.org/10.1128/IAI.00895-19
Dimensions AI	Positron emission tomography and magnetic resonance imaging in experimental human malaria to identify organ-specific changes in morphology and glucose metabolism: A prospective cohort study	2021	https://doi.org/10.1371/journal.pmed.1003567
Dimensions AI	A Plasmodium vivax experimental human infection model for evaluating the efficacy of interventions	2020	https://doi.org/10.1172/jci134923
Dimensions AI	Plasmodium vivax Controlled Human Malaria Infection – Progress and Prospects	2016	https://doi.org/10.1016/j.pt.2016.11.001

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

Documents added manually

Documents added automatically