MalariaPhase 1/2OZGAMNCT02431650
Effectiveness of OZ439 as a Gametocytocidal and Transmission Blocking Agent
A Phase 1/2 study testing OZ439 and Primaquine in people with Malaria, run by Medicines for Malaria Venture at 1 site in Australia.
Trial summary
This is a single-centre, controlled, open label study using P. falciparum-induced blood stage malaria (IBSM) infection to assess the effectiveness of OZ439 as a gametocytocidal agent, as well as its treatment effects on gametocyte infectivity and development in vector mosquitoes. Read more about this study
- Who is it for?
- Ages 18 to 55 yearsHealthy volunteers can take part
- Conditions the study is for
- Malaria
- What is being tested?
- OZ439 and Primaquine
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 11 participants
- Where
- 1 siteAustralia
- Study dates
- Apr 2015to Sep 2016
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 55 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- Demography:
- Adult (male and females) 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 be contactable and available for the duration of the trial (maximum of 6 weeks).
- Body weight, minimum 50.0 kg, body mass index between 18.0 and 32.0 kg/m
- Health status:
- Certified as healthy by a comprehensive clinical assessment (detailed medical history and complete physical examination).
- Normal vital signs after 10 minutes resting in supine position:
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- 90mmHg < systolic blood pressure (SBP) <140 mmHg,
- 50 mmHg < diastolic blood pressure (DBP) <90 mmHg,
- 40 bpm< heart rate (HR) <100 bpm.
- Normal standard 12-lead electrocardiogram (ECG) after 5 minutes resting in supine position, QTcF=450 ms average with absence of second or third degree atrioventricular block or abnormal T wave morphology.
- Laboratory parameters within the normal range, unless the Investigator considers an abnormality to be clinically irrelevant for healthy participants enrolled in this clinical investigation. More specifically for serum creatinine, hepatic transaminase enzymes (aspartate aminotransferase, alanine aminotransferase), and total bilirubin (unless the Participant has documented Gilbert syndrome) should not exceed the upper laboratory norm and haemoglobin must be equal or higher than the lower limit of the normal range, - - As there is the risk of adverse effects of OZ439, Riamet and primaquine in early pregnancy, it is important that any participants involved in this study do not get pregnant or get their female partners pregnant.
- Regulations:
- Having given written informed consent prior to undertaking any study-related procedure.
Who cannot join
- Medical history and clinical status:
- Any history of malaria or participation to a previous malaria challenge study
- Must not have travelled to or lived (>2 weeks) in a malaria-endemic country during the past 12 months or planned travel to a malaria-endemic country during the course of the study.
- Known severe reaction to mosquito bites other than local itching and redness
- Has evidence of increased cardiovascular disease risk (defined as >10%, 5 year risk) as determined by the method of Gaziano et al. (1). Risk factors include sex, age, systolic blood pressure (mm/Hg), smoking status, body mass index (BMI, kg/m) and reported diabetes status.
- History of splenectomy.
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- Presence or history of drug hypersensitivity, or allergic disease diagnosed and treated by a physician or history of a severe allergic reaction, anaphylaxis or convulsions following any vaccination or infusion.
- Presence of current or suspected serious chronic diseases such as cardiac or autoimmune disease (HIV or other immunodeficiencies), insulin-dependent and NIDDM diabetes (excluding glucose intolerance if E04 is met ), progressive neurological disease, severe malnutrition, acute or progressive hepatic disease, acute or progressive renal disease, psoriasis, rheumatoid arthritis, asthma, epilepsy or obsessive compulsive disorder, skin carcinoma excluding non-spreadable skin cancers such as basal cell and squamous cell carcinoma
- Participants with history of schizophrenia, bi-polar disease, or other severe (disabling) chronic psychiatric diagnosis including depression or receiving psychiatric drugs or who has been hospitalized within the past 5 years prior to enrollment for psychiatric illness, history of suicide attempt or confinement for danger to self or others.
- Frequent headaches and/or migraine, recurrent nausea, and/or vomiting (more than twice a month).
- Presence of acute infectious disease or fever (e.g., sub-lingual temperature = 38.5°C) within the five days prior to inoculation with malaria parasites.
- Evidence of acute illness within the four weeks before trial prior to screening that the Investigator deems may compromise subject safety.
- 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.
- Participant has a clinically significant disease or any condition or disease that might affect drug absorption, distribution or excretion, e.g. gastrectomy, diarrhoea.
- Participation in any investigational product study within the 12 weeks preceding the study.
- 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.
- Participant unwilling to defer blood donations for 6 months.
- Medical requirement for intravenous immunoglobulin or blood transfusions.
- Participant who has ever received a blood transfusion.
- Symptomatic postural hypotension at screening, irrespective of the decrease in blood pressure, or asymptomatic postural hypotension defined as a decrease in systolic blood pressure =20 mmHg within 2-3 minutes when changing from supine to standing position.
- History or presence of alcohol abuse (alcohol consumption more than 40 g per day) or drug habituation, or any prior intravenous usage of an illicit substance.
- Smoking more than 5 cigarettes or equivalent per day and unable to stop smoking for the duration of the study.
- Ingestion of any poppy seeds within the 24 hours prior to the screening blood test (participants will be advised by phone not to consume any poppy seeds in this time period).
- Interfering substance:
- Any medication (including St John's Wort) within 14 days before inclusion or within 5 times the elimination half-life (whichever is longer) of the medication,
- Any vaccination within the last 28 days.
- Any corticosteroids, anti-inflammatory drugs, immunomodulators or anticoagulants. Any participant currently receiving or having previously received immunosuppressive therapy, including systemic steroids including adrenocorticotrophic hormone (ACTH) or inhaled steroids in dosages which are associated with hypothalamic-pituitary-adrenal axis suppression such as 1 mg/kg/day of prednisone or its equivalent or chronic use of inhaled high potency corticosteroids (budesonide 800 µg per day or fluticasone 750 µg).
- Any recent or current systemic therapy with an antibiotic or drug with potential anti-malarial activity (chloroquine, piperaquine, benzodiazepine, flunarizine, fluoxetine, tetracycline, azithromycin, clindamycin, hydroxychloroquine, etc.).
- General conditions:
- Any participant who, in the judgment of the Investigator, is likely to be noncompliant during the study, or unable to cooperate because of a language problem or poor mental development.
- Any participant in the exclusion period of a previous study according to applicable regulations.
- Any participant who lives alone (from Day 0 until at least the end of the anti-malarial drug treatment).
- Any participant who cannot be contacted in case of emergency for the duration of the trial and up to 2 weeks following end of study visit.
- Any participant who is the Investigator or any sub-investigator, research assistant, pharmacist, study coordinator, or other staff thereof, directly involved in conducting the study.
- Any participant without a good peripheral venous access.
- Biological status:
- Positive result on any of the following tests: hepatitis B surface (HBs Ag) antigen, antihepatitis B core antibodies (anti-HBc Ab), anti-hepatitis C virus (anti-HCV) antibodies, anti-human immunodeficiency virus 1 and 2 antibodies (anti-HIV1 and anti HIV2 Ab),
- Participant is found to be G6PD deficient.
- Any drug listed in Table 2 in the urine drug screen unless there is an explanation acceptable to the medical investigator (e.g., the participant has stated in advance that they consumed a prescription or OTC product which contained the detected drug) and/or the Participant has a negative urine drug screen on retest by the pathology laboratory.
- Positive alcohol - breath test.
- Specific to the study:
- Cardiac/QT risk:
- Known pre-existing prolongation of the QTc interval considered clinically significant
- Family history of sudden death or of congenital prolongation of the QTc interval or known congenital prolongation of the QTc-interval or any clinical condition known to prolong the QTc interval. History of symptomatic cardiac arrhythmias or with clinically relevant bradycardia.
- Known hypersensitivity to OZ439, piperaquine or any of its excipients or 4-aminoquinolines, artemether or other artemisinin derivatives, lumefantrine, or other arylaminoalcohols.
- Unwillingness to abstain from quinine containing foods/beverages such as tonic water, lemon bitter, from inoculation (Day 0) to the end of the malaria treatment.
- Any history or presence of lactose intolerance.
- On dosing day, and during the blood collection intervals:
- Ingestion of any other drug, in the two weeks prior to dosing or during the blood sampling period that, in the opinion of the Medical Investigator, could compromise the study, e.g., through pharmacokinetic or metabolic interactions, or analytical interference. However the Medical Investigator may permit the use of paracetamol for the treatment of headache or other pain. If drug therapy other than paracetamol or drug specified in the protocol, is required during the study periods, a decision to continue or discontinue the participant's participation will be made by the Medical Investigator, based on the nature of the medication and the time the medication was taken.
- Failure to conform to the requirements of the protocol.
- Detection of any drug listed in this protocol in the urine drug screen unless there is an explanation acceptable to the medical investigator (e.g., the participant has stated in advance that they consumed a prescription or OTC product which contained the detected drug).
- Vital signs outside the reference range and considered as clinically significant by the Investigator or his representative.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: A Proof-Of-Concept Study to Assess the Effectiveness of OZ439 as a Gametocytocidal and Transmission Blocking Agent in Experimental P. Falciparum Infection
This is a single-centre, controlled, open label study using P. falciparum-induced blood stage malaria (IBSM) infection to assess the effectiveness of OZ439 as a gametocytocidal agent, as well as its treatment effects on gametocyte infectivity and development in vector mosquitoes. Previous clinical studies including one IBSM study have shown that in addition to effectively clearing replicating, asexual (pathogenic) life cycle stages of malaria, a single dose of piperaquine (480 mg) results in the production of gametocytes, as determined by gametocyte-specific transcript (pfs25) qPCR. The propensity of piperaquine to induce gametocytaemia will be employed in this study to assess the efficacy of OZ439 as a gametocytocidal and transmission blocking agent. Experimental mosquito feeding via both direct feeding on participants and artificial (indirect) membrane mosquito feeding will be performed. The study will be conducted in up to 3 cohorts where participants will be randomised into an experimental or a control group (n=2 per group) when peak gametocytemia occurs (approximately 15 days after administration of piperaquine).
Read the detailed description
This is a single-centre, controlled, open label study using P. falciparum-induced blood stage malaria (IBSM) infection to assess the effectiveness of OZ439 as a gametocytocidal agent, as well as its treatment effects on gametocyte infectivity and development in vector mosquitoes. Previous clinical studies including one IBSM study have shown that in addition to effectively clearing replicating, asexual (pathogenic) life cycle stages of malaria, a single dose of piperaquine (480 mg) results in the production of gametocytes, as determined by gametocyte-specific transcript (pfs25) qPCR. The propensity of piperaquine to induce gametocytaemia will be employed in this study to assess the efficacy of OZ439 as a gametocytocidal and transmission blocking agent. Experimental mosquito feeding via both direct feeding on participants and artificial (indirect) membrane mosquito feeding will be performed. The study will be conducted in up to 3 cohorts where participants will be randomised into an experimental or a control group (n=2 per group) when peak gametocytemia occurs (approximately 15 days after administration of piperaquine). The groups will be of equal size with participants in the experimental group receiving OZ439 and participants in the control group receiving primaquine (positive control for OZ439, to be administered 15 mg as a single dose). The dose of OZ439 that will be investigated in the experimental group of the first cohort will be 500 mg administered as a single dose. Doses used in subsequent cohort(s) will be determined following a review of observed OZ439 safety, and pharmacodynamic drug effects as defined by gametocyte clearance kinetics and transmission blocking activity. The doses used in cohort 2 and 3 may be adjusted, but will not exceed the maximum acceptable dose predefined for this study (i.e. 1200 mg OZ439) as determined in previous safety and pilot efficacy studies. The dose will be determined by the funding sponsor and the principal investigator (PI) following Safety Review team (SRT) and scientific evaluation. Subsequent cohorts will not commence until at least after day 28 of the previous cohort and review by Safety Review Team. This interval will also allow cohorting of experimental infection of mosquitoes to optimise logistics and enable iterative improvements in the system if applicable.
Each participant in the cohort will be inoculated on Day 0 with ~2,800 viable parasites of Plasmodium falciparum-infected human erythrocytes (BSPC) administered intravenously. On an outpatient basis, participants will be monitored daily via phone call and then daily (AM) from day 4 (until PCR positive for presence of malaria parasites). Once PCR positive they will be monitored twice-daily morning (AM) and evening (PM) until treatment, for adverse events and the unexpected early onset of symptoms, signs or parasitological evidence of malaria. On the day designated for commencement of treatment as determined by qPCR results (approximately Study day 7), participants will be admitted to the study unit and monitored. The threshold for commencement of treatment will be when PCR quantification of all participants is = 5,000 parasites/mL. If the PCR quantification of any participant is = 5,000 parasites/mL and is accompanied by a clinical symptom score >5, before all participants have reached the treatment threshold (PCR quantification of = 1,000), then treatment of that participant will begin within a 24 h period. Participants will be followed up as inpatients for at least 48 h to ensure tolerance of the treatment and clinical response, then if clinically well on an outpatient basis for safety and clearance of malaria parasites via PCR.
Cohort1. Following initial piperaquine treatment, a repeat dose of piperaquine (960 mg) may be administered on an outpatient basis if recrudescent asexual parasitemia occurs (defined as 3 consecutively increasing parasite count over 1000 parasites/mL). Participants will also be evaluated for the presence of gametocytes in the blood, as determined by qPCR (amplification of pfs25 gametocyte-specific transcript). Assessment of OZ439 gametocytocidal properties and transmission studies will be undertaken when gametocytemia appears. Participants will be randomised into an experimental or a control group when peak gametocytemia occurs (approximately 15 days after administration of piperaquine i.e. about day 22 of the study). Participants in the experimental group (n=2 per dose cohort) will be administered OZ439 as a single 500 mg dose and participants in the control group (n=2) will receive primaquine 15 mg as a single dose. Blood will be collected (AM) from each participant in both groups for membrane feeding assays with An. stephensi vector mosquitoes. For direct feeding assays (DFA), participants will be escorted to the quarantine insectary facility at QIMR Berghofer Medical Research Institute and asked to allow vector mosquitoes to feed on the volar surface of their forearms, calves or thighs for a period of 10 ± 5 minutes. The experimental infection of mosquitoes by direct feeding on participants will be performed up to a maximum of three time points over a maximum interval of up to 10 days, approximately 15 days post-piperaquine treatment (1 direct feed prior to receiving OZ439 (active) or primaquine (control), and 2 feeds scheduled following OZ439 (active) or primaquine (control) treatment). Artificial (indirect) membrane feeding (IFA) may occur up to 10 times prior to curative anti-malarial treatment at the End of Study with Riamet® (artemether-lumefantrine)and primaquine (45 mg).
Cohort2 and 3. A similar study design and treatment procedure will be used for the two subsequent cohorts. Doses of OZ439 to be evaluated will be selected after analysis of the data from cohort1. Doses of OZ439 will not exceed 1200 mg.
Pre-emptive rescue treatment with Riamet® can commence whenever deemed necessary by the investigator. Participants can be administered the rescue Riamet® on site for initial dosing followed by monitoring, either in clinic, or by telephone for three days to ensure adherence to Riamet® therapy.
Participants will be treated with a single dose of primaquine (45 mg) as described in section 4.4.2 in this protocol concurrent with their Riamet® treatment to ensure clearance of any gametocytes present.
Adverse events will be monitored via telephone monitoring, within the clinical research unit, and on outpatient review after malaria challenge inoculation and anti-malarial study drugs administration. Blood samples for safety evaluation, malaria monitoring, and red blood cell antibodies will be drawn at screening.
- Conditions
- Malaria
- Being tested
- OZ439, Primaquine
- Keywords
- Induced blood stage malaria, Transmission, Mosquito feeding, OZ439, Primaquine, Piperaquine, Artefonomel
- Medical subject headings
- Malaria
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
OZ439Drug
Also called Artefonomel
PrimaquineDrug
| Study group | Role | What they receive |
|---|---|---|
| OZ439 | Experimental | Each participant in the cohort will be inoculated on Day 0 with ~2,800 viable parasites of Plasmodium falciparum-infected human erythrocytes (BSPC) administered intravenously. when PCR quantification of all participants is ≥ 5,000 parasites/mL, they will receive a single dose of 480 mg of piperaquine phosphate to clear blood stage parasitemia. When gametocytemia is at the peak (approximately 15 days after administration of piperaquine), participants will be randomised to receive either OZ439 or a control group (primaquine treatment).
In the first cohort 500 mg OZ439 will be administered as a single dose. Doses used in subsequent cohort(s) will be determined following a review of observed safety and pharmacodynamic drug effects. Receives: Drug: OZ439 |
| Primaquine | Active comparator | Each participant in the cohort will be inoculated on Day 0 with ~2,800 viable parasites of Plasmodium falciparum-infected human erythrocytes (BSPC) administered intravenously. when PCR quantification of all participants is ≥ 5,000 parasites/mL, they will receive a single dose of 480 mg of piperaquine phosphate to clear blood stage parasitemia. When gametocytemia is at the peak (approximately 15 days after administration of piperaquine), participants will be randomised to receive either OZ439 or a control group (primaquine treatment).
Primaquine is a positive control for OZ439, to be administered 15 mg as a single dose. Receives: Drug: Primaquine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Infection Success of Vector Mosquitoes
Assessing the transmissibility by oocyst detection in mosquito midgut preparations following direct and membrane (indirect) feeding.
Measured: From day 10 to 21 post Piperaquine dosing
Secondary outcomes (1)
Safety: Number of AEs
Adverse events incidence
Measured: From Challenge inoculum on day 0 until end of study on day 31
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 May 2015 (estimated)
- Study startApr 2015
- Primary completionSep 2016
- Study completionSep 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for MalariaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 11 participants (actual)
Sponsor and investigators
- Lead sponsor
- Medicines for Malaria Venture
- Sponsor type
- University, hospital or other
- Collaborators
- Q-Pharm Pty Limited, Clinical Network Services (CNS) Pty Ltd, Sullivan Nicolaides Pathology, QIMR Berghofer Medical Research Institute, Army Malaria Institute, Australia
- Responsible party
- Sponsor
- Investigators
- James McCarthy, Prof, Principal investigator, QIMR Berghofer Medical Research Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02431650
- Sponsor's protocol ID
- QP15C05
- Acronym
- OZGAM
- Status last verified
- May 2020
- First submitted
- 17 Apr 2015
- Last updated
- 26 May 2020
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- Individual data sharing
- No
Publications
Collins KA, Wang CY, Adams M, Mitchell H, Rampton M, Elliott S, Reuling IJ, Bousema T, Sauerwein R, Chalon S, Mohrle JJ, McCarthy JS. A controlled human malaria infection model enabling evaluation of transmission-blocking interventions. J Clin Invest. 2018 Apr 2;128(4):1551-1562. doi: 10.1172/JCI98012. Epub 2018 Mar 12.
PubMed 29389671
Study at a glance
From the registry record, last updated by the sponsor on 26 May 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Proof-Of-Concept Study to Assess the Effectiveness of OZ439 as a Gametocytocidal and Transmission Blocking Agent in Experimental P. Falciparum Infection
- ClinicalTrials.gov ID
- NCT02431650
- Acronym / sponsor ID
- OZGAM / QP15C05
- Conditions
- Malaria
- Keywords
- Induced blood stage malaria, Transmission, Mosquito feeding, OZ439, Primaquine, Piperaquine, Artefonomel
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 11 participants (actual)
- Lead sponsor
- Medicines for Malaria VentureUniversity, hospital or other
- Collaborators
- Q-Pharm Pty Limited, Clinical Network Services (CNS) Pty Ltd, Sullivan Nicolaides Pathology, QIMR Berghofer Medical Research Institute, Army Malaria Institute, Australia
- Study start
- Apr 2015 (actual)
- Primary completion
- Sep 2016 (actual)
- Study completion
- Sep 2016 (actual)
- First posted
- 1 May 2015 (estimated)
- Results
- Posted 26 May 2020
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This is a single-centre, controlled, open label study using P. falciparum-induced blood stage malaria (IBSM) infection to assess the effectiveness of OZ439 as a gametocytocidal agent, as well as its treatment effects on gametocyte infectivity and development in vector mosquitoes. Previous clinical studies including one IBSM study have shown that in addition to effectively clearing replicating, asexual (pathogenic) life cycle stages of malaria, a single dose of piperaquine (480 mg) results in the production of gametocytes, as determined by gametocyte-specific transcript (pfs25) qPCR. The propensity of piperaquine to induce gametocytaemia will be employed in this study to assess the efficacy of OZ439 as a gametocytocidal and transmission blocking agent. Experimental mosquito feeding via both direct feeding on participants and artificial (indirect) membrane mosquito feeding will be performed. The study will be conducted in up to 3 cohorts where participants will be randomised into an experimental or a control group (n=2 per group) when peak gametocytemia occurs (approximately 15 days after administration of piperaquine).
Detailed description
This is a single-centre, controlled, open label study using P. falciparum-induced blood stage malaria (IBSM) infection to assess the effectiveness of OZ439 as a gametocytocidal agent, as well as its treatment effects on gametocyte infectivity and development in vector mosquitoes. Previous clinical studies including one IBSM study have shown that in addition to effectively clearing replicating, asexual (pathogenic) life cycle stages of malaria, a single dose of piperaquine (480 mg) results in the production of gametocytes, as determined by gametocyte-specific transcript (pfs25) qPCR. The propensity of piperaquine to induce gametocytaemia will be employed in this study to assess the efficacy of OZ439 as a gametocytocidal and transmission blocking agent. Experimental mosquito feeding via both direct feeding on participants and artificial (indirect) membrane mosquito feeding will be performed. The study will be conducted in up to 3 cohorts where participants will be randomised into an experimental or a control group (n=2 per group) when peak gametocytemia occurs (approximately 15 days after administration of piperaquine). The groups will be of equal size with participants in the experimental group receiving OZ439 and participants in the control group receiving primaquine (positive control for OZ439, to be administered 15 mg as a single dose). The dose of OZ439 that will be investigated in the experimental group of the first cohort will be 500 mg administered as a single dose. Doses used in subsequent cohort(s) will be determined following a review of observed OZ439 safety, and pharmacodynamic drug effects as defined by gametocyte clearance kinetics and transmission blocking activity. The doses used in cohort 2 and 3 may be adjusted, but will not exceed the maximum acceptable dose predefined for this study (i.e. 1200 mg OZ439) as determined in previous safety and pilot efficacy studies. The dose will be determined by the funding sponsor and the principal investigator (PI) following Safety Review team (SRT) and scientific evaluation. Subsequent cohorts will not commence until at least after day 28 of the previous cohort and review by Safety Review Team. This interval will also allow cohorting of experimental infection of mosquitoes to optimise logistics and enable iterative improvements in the system if applicable.
Each participant in the cohort will be inoculated on Day 0 with ~2,800 viable parasites of Plasmodium falciparum-infected human erythrocytes (BSPC) administered intravenously. On an outpatient basis, participants will be monitored daily via phone call and then daily (AM) from day 4 (until PCR positive for presence of malaria parasites). Once PCR positive they will be monitored twice-daily morning (AM) and evening (PM) until treatment, for adverse events and the unexpected early onset of symptoms, signs or parasitological evidence of malaria. On the day designated for commencement of treatment as determined by qPCR results (approximately Study day 7), participants will be admitted to the study unit and monitored. The threshold for commencement of treatment will be when PCR quantification of all participants is = 5,000 parasites/mL. If the PCR quantification of any participant is = 5,000 parasites/mL and is accompanied by a clinical symptom score >5, before all participants have reached the treatment threshold (PCR quantification of = 1,000), then treatment of that participant will begin within a 24 h period. Participants will be followed up as inpatients for at least 48 h to ensure tolerance of the treatment and clinical response, then if clinically well on an outpatient basis for safety and clearance of malaria parasites via PCR.
Cohort1. Following initial piperaquine treatment, a repeat dose of piperaquine (960 mg) may be administered on an outpatient basis if recrudescent asexual parasitemia occurs (defined as 3 consecutively increasing parasite count over 1000 parasites/mL). Participants will also be evaluated for the presence of gametocytes in the blood, as determined by qPCR (amplification of pfs25 gametocyte-specific transcript). Assessment of OZ439 gametocytocidal properties and transmission studies will be undertaken when gametocytemia appears. Participants will be randomised into an experimental or a control group when peak gametocytemia occurs (approximately 15 days after administration of piperaquine i.e. about day 22 of the study). Participants in the experimental group (n=2 per dose cohort) will be administered OZ439 as a single 500 mg dose and participants in the control group (n=2) will receive primaquine 15 mg as a single dose. Blood will be collected (AM) from each participant in both groups for membrane feeding assays with An. stephensi vector mosquitoes. For direct feeding assays (DFA), participants will be escorted to the quarantine insectary facility at QIMR Berghofer Medical Research Institute and asked to allow vector mosquitoes to feed on the volar surface of their forearms, calves or thighs for a period of 10 ± 5 minutes. The experimental infection of mosquitoes by direct feeding on participants will be performed up to a maximum of three time points over a maximum interval of up to 10 days, approximately 15 days post-piperaquine treatment (1 direct feed prior to receiving OZ439 (active) or primaquine (control), and 2 feeds scheduled following OZ439 (active) or primaquine (control) treatment). Artificial (indirect) membrane feeding (IFA) may occur up to 10 times prior to curative anti-malarial treatment at the End of Study with Riamet® (artemether-lumefantrine)and primaquine (45 mg).
Cohort2 and 3. A similar study design and treatment procedure will be used for the two subsequent cohorts. Doses of OZ439 to be evaluated will be selected after analysis of the data from cohort1. Doses of OZ439 will not exceed 1200 mg.
Pre-emptive rescue treatment with Riamet® can commence whenever deemed necessary by the investigator. Participants can be administered the rescue Riamet® on site for initial dosing followed by monitoring, either in clinic, or by telephone for three days to ensure adherence to Riamet® therapy.
Participants will be treated with a single dose of primaquine (45 mg) as described in section 4.4.2 in this protocol concurrent with their Riamet® treatment to ensure clearance of any gametocytes present.
Adverse events will be monitored via telephone monitoring, within the clinical research unit, and on outpatient review after malaria challenge inoculation and anti-malarial study drugs administration. Blood samples for safety evaluation, malaria monitoring, and red blood cell antibodies will be drawn at screening.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| OZ439 | Experimental | Drug: OZ439Each participant in the cohort will be inoculated on Day 0 with ~2,800 viable parasites of Plasmodium falciparum-infected human erythrocytes (BSPC) administered intravenously. when PCR quantification of all participants is ≥ 5,000 parasites/mL, they will receive a single dose of 480 mg of piperaquine phosphate to clear blood stage parasitemia. When gametocytemia is at the peak (approximately 15 days after administration of piperaquine), participants will be randomised to receive either OZ439 or a control group (primaquine treatment). In the first cohort 500 mg OZ439 will be administered as a single dose. Doses used in subsequent cohort(s) will be determined following a review of observed safety and pharmacodynamic drug effects. |
| Primaquine | Active comparator | Drug: PrimaquineEach participant in the cohort will be inoculated on Day 0 with ~2,800 viable parasites of Plasmodium falciparum-infected human erythrocytes (BSPC) administered intravenously. when PCR quantification of all participants is ≥ 5,000 parasites/mL, they will receive a single dose of 480 mg of piperaquine phosphate to clear blood stage parasitemia. When gametocytemia is at the peak (approximately 15 days after administration of piperaquine), participants will be randomised to receive either OZ439 or a control group (primaquine treatment). Primaquine is a positive control for OZ439, to be administered 15 mg as a single dose. |
Who may qualify
- Ages
- 18 to 55 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (13 listed)
- Adult (male and females) 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 be contactable and available for the duration of the trial (maximum of 6 weeks).
- Body weight, minimum 50.0 kg, body mass index between 18.0 and 32.0 kg/m
- Certified as healthy by a comprehensive clinical assessment (detailed medical history and complete physical examination).
- Normal vital signs after 10 minutes resting in supine position:
- 90mmHg < systolic blood pressure (SBP) <140 mmHg,
Key exclusion criteria (52 listed)
- Any history of malaria or participation to a previous malaria challenge study
- Must not have travelled to or lived (>2 weeks) in a malaria-endemic country during the past 12 months or planned travel to a malaria-endemic country during the course of the study.
- Known severe reaction to mosquito bites other than local itching and redness
- Has evidence of increased cardiovascular disease risk (defined as >10%, 5 year risk) as determined by the method of Gaziano et al. (1). Risk factors include sex, age, systolic blood pressure (mm/Hg), smoking status, body mass index (BMI, kg/m) and reported diabetes status.
- History of splenectomy.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| OZ439Also: Artefonomel | Drug | OZ439 |
| Primaquine | Drug | Primaquine |
Primary outcome
Infection Success of Vector Mosquitoes
Time frame: From day 10 to 21 post Piperaquine dosing
Assessing the transmissibility by oocyst detection in mosquito midgut preparations following direct and membrane (indirect) feeding.
1 secondary outcome
Safety: Number of AEs
Time frame: From Challenge inoculum on day 0 until end of study on day 31
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 26 May 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 29389671Collins KA, Wang CY, Adams M, Mitchell H, Rampton M, Elliott S, Reuling IJ, Bousema T, Sauerwein R, Chalon S, Mohrle JJ, McCarthy JS. A controlled human malaria infection model enabling evaluation of transmission-blocking interventions. J Clin Invest. 2018 Apr 2;128(4):1551-1562. doi: 10.1172/JCI98012. Epub 2018 Mar 12.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
James McCarthy, Prof principal investigator
QIMR Berghofer Medical Research Institute
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing OZ439 and Primaquine in people with Malaria, run by Medicines for Malaria Venture at 1 site in Australia.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 13 inclusion and 52 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 26 May 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Australia. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 26 May 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Infection Success of Vector Mosquitoes (time frame: From day 10 to 21 post Piperaquine dosing). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02431650, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 May 2020.