SJ733 Induced Blood Stage Malaria Challenge Study
Condition: Plasmodium Falciparum Malaria
MeSH terms: Malaria; Malaria, Falciparum
Intervention: (+)-SJ000557733
Intervention description: (+)-SJ000557733 (SJ733), in short SJ733, will be the second PfATP4 inhibitor to enter clinical development after KAE609 (Novartis) which is currently in Phase 2 stage. KAE609 (cipargamin; previously known as NITD609) is a spirotetrahydro-β-carbolines (spiroindolone). KAE609 inhibits QP15C20_SJ733_Challenge Protocol_v2.0_26July2016 Page 28 of 110 PfATP4, which results in a disruption of parasite sodium homeostasis. Compared to KAE609, SJ733 has the potential to be a very fast acting, antimalarial drug for human therapeutic application and may have a different safety profile in human participants. Finally, SJ733 blocks parasite transmission in vivo at potencies close to those where it is efficacious in blood stages, indicating its potential for transmission blockade in humans.
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 17.0
Sex: All
Minimum age: 18 Years
Maximum age: 55 Years
Healthy volunteers: Accepts Healthy Volunteers

Summary:

      This is a single-centre, open-label, study using induced blood stage malaria (IBSM) infection
      to characterize the activity of (+)-SJ000557733 or SJ733 for short, against early Plasmodium
      falciparum blood stage infection. The study will be conducted in two cohorts (n=8 per
      cohort). The anticipated efficacious dose range is expected to be within a range of 125 to
      600 mg. The dose used in the first cohort was determined on the basis of the safety and PK
      data generated in the FIM study (NCT02661373) currently ongoing in United States (US) and
      will be 150 mg. Depending on the pharmacodynamics data (effect of SJ733 on parasitaemia)
      obtained from this first cohort, the dose in Cohort 2 may be adjusted but will not exceed 600
      mg. Based on the PK from all three cohort from the FIM study, the median estimated dose to
      obtain the target SJ733 AUC of 13,000 (ug hr/L) is 370 mg. The dose of cohort 2 (≤600mg) is
      intended to provide further concentration-response information in the human challenge model.

      For Cohort 2 only, a second dose of SJ733 may be administered at peak gametocytaemia to
      assess if SJ733 can reduce gametocytes and subsequent infectivity to mosquitoes (a washout of
      ~15 days post initial SJ733 treatment will be observed). Depending on the data obtained from
      the first two cohorts, there may be a subsequent cohort, with the investigated dose of SJ733
      to be determined by the Sponsor and Principal Investigator (PI) and endorsed by the Safety
      Review Team. Should this third dose be investigated, a substantial amendment including
      preliminary data from the first two cohorts will be submitted to the HREC for approval.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Adult, male and women of non-child bearing potential (WNCBP as defined in Section
             6.17), participants between 18 and 55 years of age inclusive, who do not live alone
             (from Day 0 until at least the end of the antimalarial drug treatment) and will 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/m2, inclusive.

          -  Certified as healthy by a comprehensive clinical assessment (detailed medical history
             and complete physical examination).

          -  Normal vital signs after 5 minutes resting in supine position:

             90 mmHg ≤ 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 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 in accordance with Sponsor-approved clinically acceptable
             laboratory ranges documented prior to study start. 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 acceptable ranges approved by the Sponsor and
             haemoglobin must be equal or higher than the lower limit of the normal range.

          -  Male participants must agree to use a double barrier method of contraception including
             condom plus diaphragm or condom plus IUD or condom plus stable
             oral/transdermal/injectable hormonal contraceptive by female partner for at least 7
             days prior to the time of the first dose of study drug through 90 days after the 5th
             half-life of the last dose of study drug (half-life of ~20 hours). Abstinent
             participants have to agree starting a double barrier method if they start sexual
             relationships during the study and up to 95 days after the last dose of study drug.

          -  Having given written informed consent prior to undertaking any study-related
             procedure.

        Exclusion Criteria:

          -  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 region during the
             past 12 months or planned travel to a malaria-endemic region during the course of the
             study (for endemic regions see http://www.map.ox.ac.uk/browse-resources/).

          -  Has evidence of increased cardiovascular disease risk (defined as >10%, 5 year risk
             for those greater than 35 years of age), as determined by the Australian Absolute
             Cardiovascular Disease Risk Calculator (http://www.cvdcheck.org.au/). Risk factors
             include sex, age, systolic blood pressure (mm/Hg), smoking status, total and HDL
             cholesterol (mmol/L) 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
             non-insulin dependent diabetes (excluding glucose intolerance if E03 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.

          -  History of photosensitivity.

          -  History of G6PD deficiency.

          -  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.

          -  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 participant safety.

          -  Significant inter-current 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, diarrhea.

          -  Participation in any investigational product study within the 12 weeks preceding the
             study.

          -  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 treatment drug dose in the study.

          -  Participant unwilling to defer blood donations to the ARCBS 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.

          -  Tobacco use of more than 5 cigarettes or equivalent per day and unable to stop smoking
             during 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).

          -  Excessive consumption of beverages containing xanthine bases, including red bull,
             chocolate etc. more than 400 mg of caffeine per day (more than 4 cups or glasses per
             day).

          -  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 micrograms per day or fluticasone
             750 micrograms).

          -  Any recent (less than 6 weeks) or current systemic therapy with an antibiotic or drug
             with potential antimalarial activity (chloroquine, piperaquine, benzodiazepine,
             flunarizine, fluoxetine, tetracycline, azithromycin, clindamycin, hydroxychloroquine,
             etc.).

          -  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 antimalarial
             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 employee of the sponsor or research site personnel directly affiliated with this
             study or their immediate family members defined as a spouse, parent, sibling, or child
             whether biological or legally adopted.

          -  Any participant without a good peripheral venous access.Male participant with a female
             partner who is pregnant or lactating from the time of administration of study
             medication.

          -  Positive result on any of the following tests: hepatitis B surface (HBs Ag) antigen,
             anti-hepatitis 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).

          -  A positive urine drug test at screening, pre-inoculation, or pre any SJ733 dose. Any
             drug listed in Table 2 (Drug Screening) 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.

          -  A positive alcohol breath test at screening, pre-inoculation or pre any SJ733 dose.

          -  Cardiac/QT risk:

          -  Known pre-existing prolongation of the QTcB/QTcF interval considered clinically
             significant.

          -  History of symptomatic cardiac arrhythmias or with clinically relevant bradycardia.
             Electrolyte disturbances, particularly hypokalaemia, hypocalcaemia or hypomagnesaemia.

          -  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.

          -  A history of clinically significant ECG abnormalities.

          -  Known hypersensitivity to SJ733 or any of its excipients or artemether or other
             artemisinin derivatives, lumefantrine, or other arylaminoalcohols.

          -  Unwillingness to abstain from consumption of citrus (grapefruit, Seville orange, etc.)
             for at least 28 days prior to initiation of the study (inoculation, Day 0) and for the
             study duration.

          -  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 antimalarial
             treatment.

          -  Use of prescription or non-prescription drugs and herbal supplements (such as St
             John's Wort) within 14 days or 5 half-lives (whichever is the longer) prior to the
             inoculation administration. (As an exception, ibuprofen (preferred) may be used at
             doses of up to 1.2 g/day, or paracetamol at doses of up to 2 g/day. Limited use of
             other non-prescription medications or dietary supplements not believed to affect
             subject safety or the overall results of the study, may be permitted on a case-by-case
             basis following approval by the Sponsor in consultation with the Investigator.) (Note:
             diazepam interferes with the analysis of blood levels of SJ733 and thus should not
             have been used for at least 8 weeks prior to administration of the study drug).

          -  Known severe reaction to mosquito bites other than local itching and redness.
             Participants are requested to refrain from taking non-approved concomitant medication
             from recruitment until the conclusion of the study.

        Participants who are excluded from participation on study days for any of the above reasons
        may be eligible to participate on a postponed schedule if the Investigator considers this
        appropriate.