Experimental Falciparum Transmission to Anopheles

NCT02431637 | Completed Phase 1 Results

• 1 other identifier: QP14C21
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

Brief Summary

This is a single-centre, open-label study using P. falciparum-induced blood stage malaria (IBSM) infection to assess the infectivity of sexual life cycle stages of the malaria parasite (gametocytes) to mosquito vectors. Previous clinical studies have shown that treatment of participants with the antimalarial drug piperaquine, in addition to effectively clearing asexual (pathogenic) stages of the malaria life cycle, induces the production of gametocytes in the blood. The propensity of piperaquine to induce gametocytemia will be employed in this study to assess gametocyte infectivity to Anopheles mosquitoes. For this purpose, experimental mosquito feeding directly on participants and artificial membrane mosquito feeding will be performed. The study will be conducted in 3 cohorts (n=2 per cohort). 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.

Conditions

Malaria

Keywords

Induced blood stage malaria; Transmission; Standard membrane feeding assay

Outcome Measures

Primary Outcomes (1)

• Successful Infection of Vector Mosquitoes Following Both Direct and Indirect Feeding on the Blood of Infected Participants

  Seven to ten days after blood feeding, mosquitoes will be dissected to check for oocysts in midgut preparations. For permanent preparations, oocysts will be stained with 0.1% mercurochrome in PBS for 5 to 60 mins then fixed in 1%glutaraldehyde or formaldehyde. Oocysts will be counted per mosquito dissected and recorded. Relationship between parasitemia, gametocytemia and mosquito infection (both oocyst prevalence and intensity) will be determined using generalized-linear mixed models. The number of mosquitoes dying prior to dissection will be recorded.

  7-10 days after blood feeding

Secondary Outcomes (1)

• Safety: Number of AEs

  Blood stage Plasmodium falciparum Challenge Inoculum up to Day 31

Study Arms (1)

Piperaquine Phosphate after infected blood malaria challenge

EXPERIMENTAL

Volunteers will receive a dose of 480 mg piperaquine phosphate (PQP) approx. 7 days after a challenge with P. falciparum infected red blood cells. The effects of PQP on gametocyte carriage (assessed by PCR) and infectivity to mosquitos after direct and indirect feeding on blood from volunteers will be assessed.

Biological: Administration of the malaria inoculum; Drug: Piperaquine Phosphate 480 mg

Interventions

Administration of the malaria inoculum BIOLOGICAL

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. The threshold for commencement of treatment will be when PCR quantification of all participants is ≥ 5,000 parasites/mL.

Piperaquine Phosphate after infected blood malaria challenge

Piperaquine Phosphate 480 mg DRUG

When PCR quantification of all participants is ≥ 5,000 parasites/mL, participants will receive a single dose of 480 mg Piperaquine Phosphate

Piperaquine Phosphate after infected blood malaria challenge

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 the safety of Piperaquine on foetal development is unknown 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

piperaquine

Condition Hierarchy (Ancestors)

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

Limitations and Caveats

The adult mosquito mortality was high and blood feeding rates were low in these experiments, indicating an unhealthy mosquito colony. Transmission data from this group were therefore excluded from analysis.

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: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• 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)