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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT02431637




Registration number
NCT02431637
Ethics application status
Date submitted
17/04/2015
Date registered
1/05/2015
Date last updated
26/05/2020

Titles & IDs
Public title
Experimental Falciparum Transmission to Anopheles
Scientific title
Blood Stage Challenge Study to Asses Mosquito Transmissibility in Participants Inoculated With Plasmodium Falciparum
Secondary ID [1] 0 0
QP14C21
Universal Trial Number (UTN)
Trial acronym
EFITA
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malaria 0 0
Condition category
Condition code
Infection 0 0 0 0
Other infectious diseases
Infection 0 0 0 0
Studies of infection and infectious agents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Other interventions - Administration of the malaria inoculum
Treatment: Drugs - Piperaquine Phosphate 480 mg

Experimental: Piperaquine Phosphate after infected blood malaria challenge - 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.


Other interventions: Administration of the malaria inoculum
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.

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

Intervention code [1] 0 0
Other interventions
Intervention code [2] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
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.
Timepoint [1] 0 0
7-10 days after blood feeding
Secondary outcome [1] 0 0
Safety: Number of AEs - Adverse events incidence
Timepoint [1] 0 0
Blood stage Plasmodium falciparum Challenge Inoculum up to Day 31

Eligibility
Key inclusion criteria
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:

- 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 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.
Minimum age
18 Years
Maximum age
55 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
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.

- Blood donation, any volume, within 1 month before inclusion or participation in any
research study involving to be desired 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, 3
standard drinks 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 1mg/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 non
compliant 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:

- A history of clinically significant ECG abnormalities

- 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 QTcinterval. History of symptomatic cardiac arrhythmias or
with clinically relevant bradycardia.

- Electrocardiogram (ECG) abnormalities in the standard 12-lead ECG (at screening)
which in the opinion of the Investigator is clinically relevant or will interfere
with the ECG analysis.

- Known hypersensitivity to piperaquine or any of its excipients or 4-aminoquinolines,
artemether or other artemisinin derivatives, lumefantrine, or other arylaminoalcohols.

- Unwillingness to abstain from consumption of 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 days:

- 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 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 clinically significant.

Study design
Purpose of the study
Treatment
Allocation to intervention
N/A
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)
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 0 0
Q-Pharm Clinics - Herston
Recruitment postcode(s) [1] 0 0
4006 - Herston

Funding & Sponsors
Primary sponsor type
Other
Name
Medicines for Malaria Venture
Address
Country
Other collaborator category [1] 0 0
Commercial sector/Industry
Name [1] 0 0
Q-Pharm Pty Limited
Address [1] 0 0
Country [1] 0 0
Other collaborator category [2] 0 0
Commercial sector/Industry
Name [2] 0 0
Clinical Network Services (CNS) Pty Ltd
Address [2] 0 0
Country [2] 0 0
Other collaborator category [3] 0 0
Other
Name [3] 0 0
Sullivan Nicolaides Pathology
Address [3] 0 0
Country [3] 0 0
Other collaborator category [4] 0 0
Other
Name [4] 0 0
QIMR Berghofer Medical Research Institute
Address [4] 0 0
Country [4] 0 0
Other collaborator category [5] 0 0
Other
Name [5] 0 0
Army Malaria Institute, Australia
Address [5] 0 0
Country [5] 0 0

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/show/NCT02431637
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
James McCarthy, Prof
Address 0 0
QIMR Berghofer Medical Research Institute
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications