Experimental Falciparum Transmission to Anopheles
Condition: Malaria
MeSH terms: Malaria
Intervention: Administration of the malaria inoculum; Piperaquine Phosphate 480 mg
Intervention description: 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.; When PCR quantification of all participants is ≥ 5,000 parasites/mL, participants will receive a single dose of 480 mg Piperaquine Phosphate
Intervention MeSH terms: Piperaquine
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 6.0
Sex: All
Minimum age: 18 Years
Maximum age: 55 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Induced blood stage malaria; Transmission; Standard membrane feeding assay

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.
    

Eligibility criteria:

        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.

        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.