Effectiveness of OZ439 as a Gametocytocidal and Transmission Blocking Agent

NCT02431650 | Completed Phase 1 Results

• 1 other identifier: QP15C05
• Study Type: interventional
• Target: 11
• Locations: 1 country
• Sites: 1

Brief 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. 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).

Conditions

Malaria

Keywords

Induced blood stage malaria; Transmission; Mosquito feeding; OZ439; Primaquine; Piperaquine; Artefonomel

Outcome Measures

Primary Outcomes (1)

• Infection Success of Vector Mosquitoes

  Assessing the transmissibility by oocyst detection in mosquito midgut preparations following direct and membrane (indirect) feeding.

  From day 10 to 21 post Piperaquine dosing

Secondary Outcomes (1)

• Safety: Number of AEs

  From Challenge inoculum on day 0 until end of study on day 31

Study Arms (2)

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.

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.

Drug: Primaquine

Interventions

OZ439 DRUG

Also known as: Artefonomel

OZ439

Primaquine DRUG

Primaquine

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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:
• mmHg \< systolic blood pressure (SBP) \<140 mmHg,
• mmHg \< diastolic blood pressure (DBP) \<90 mmHg,
• 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.

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• Medicines for Malaria Venture: lead
• Q-Pharm Pty Limited: collaborator
• Clinical Network Services (CNS) Pty Ltd: collaborator
• Sullivan Nicolaides Pathology: collaborator
• QIMR Berghofer Medical Research Institute: collaborator
• Army Malaria Institute, Australia: collaborator

Study Sites (1)

Q-Pharm Clinics

Herston, Queensland, 4006, Australia

Location

Related Publications (1)

• 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.

  PMID: 29389671 DERIVED

MeSH Terms

Conditions

Malaria

Interventions

Primaquine

Condition Hierarchy (Ancestors)

Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases

Intervention Hierarchy (Ancestors)

Aminoquinolines; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Dr. Jörg J. Möhrle
• Organization: Medicines for Malaria Venture

moehrlej@mmv.org

+41 22 555 0369

Study Officials

• James McCarthy, Prof

  QIMR Berghofer Medical Research Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 17, 2015
• First Posted: May 1, 2015
• Study Start: April 1, 2015
• Primary Completion: September 1, 2016
• Study Completion: September 1, 2016
• Last Updated: May 26, 2020
• Results First Posted: May 26, 2020

Record last verified: 2020-05

Data Sharing

• IPD Sharing: Will not share

Locations

AU (1)