A FIH Study to Investigate the Safety, Tolerability and PK of P218
Condition: Malaria
MeSH terms: Malaria
Intervention: Oral administration of P218 capsules; Oral administration of P218 matching placebo
Intervention description: Oral administration of P218 capsules. The number of capsules is determined by the dose level of the cohort.; Oral administration of P218 matching placebo. The number of capsules is identical to the corresponding number of P218 capsules administered to the volunteers on the investigational drug.
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Sequential Assignment
Intervention model description: Part A of the study was conducted as a dose escalation, and that Part B utilized a cross-over design.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 64.0
Sex: All
Minimum age: 18 Years
Maximum age: 45 Years
Healthy volunteers: Accepts Healthy Volunteers

Summary:

      The First in Human (FIH) study is separated into two parts:

        -  The first part is a Single Ascending Dose (SAD), double-blinded, randomized and
           placebo-controlled, including 8 cohorts of 8 subjects (2 placebo and 6 on active drug).

        -  The second part is a food effect cohort with an open-labelled, randomized fed/fasted
           cross-over design.

      The main objectives of the study are to confirm safety, tolerability and Pharmacokinetics
      (PK) of P218 in healthy volunteers.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Subject is a healthy male or female (of non-childbearing potential), aged 18 to 45
             years, inclusive.

          2. Satisfactory medical assessment with no clinically significant or relevant
             abnormalities as determined by medical history, physical examination, vital signs,
             12-lead electrocardiograms (ECG), and clinical laboratory evaluation (haematology,
             biochemistry, coagulation, and urinalysis) that is reasonably likely to interfere with
             the subject's participation in or ability to complete the study as assessed by the
             Investigator.

          3. Subject has a body weight of at least 50 kg and a Body Mass Index (BMI) of 18-25
             Kg/m2, inclusive.

          4. Female subjects must be of non-childbearing potential:

               1. Natural (spontaneous) post-menopausal defined as being amenorrheic for at least
                  12 months without an alternative medical cause with a screening follicle
                  stimulating hormone level > 25 IU/L (or at the local laboratory levels for
                  post-menopause).

               2. Premenopausal with irreversible surgical sterilization by hysterectomy and/or
                  bilateral oophorectomy or salpingectomy at least 6 months before screening (as
                  determined by subject medical history).

          5. Heterosexually active male subjects with a female spouse/partner of childbearing
             potential must agree to use barrier contraception (male condom), even with documented
             medical assessment of surgical success of a vasectomy, if your partner could become
             pregnant from the time of the first administration of P218 and for 100 days following
             this. Your partner must also use a method of highly effective contraception including:

               -  Combined (estrogen and progestogen containing) hormonal contraception associated
                  with inhibition of ovulation:

                    -  Oral

                    -  Intravaginal

                    -  Transdermal

               -  Progestogen-only hormonal contraception associated with inhibition of ovulation:

                    -  Oral

                    -  Injectable

                    -  Implantable

               -  Intrauterine device

               -  Intrauterine hormone-releasing system

               -  Bilateral tubal occlusion

          6. Subjects are non-smokers or ex-smokers for more than 90 days prior to screening or
             smoke no more than 5 cigarettes per day. If users of nicotine products (i.e. spray,
             patch, e-cigarette, etc.) no more than 5 cigarettes per day is allowed. Subjects must
             agree to abstain from smoking while in the unit.

          7. Ability to swallow multiple capsules at a time or (consecutively) 1 capsule at a time.

          8. Subjects must be capable of fully understanding and complying with the requirements of
             the study and must have signed the informed consent form prior to undergoing any
             study-related procedures.

          9. Subjects who are willing and able to comply with all scheduled visits, treatment plan,
             laboratory tests, and other study procedures.

        Exclusion Criteria:

          1. Male subjects with a female partner(s) who is (are) pregnant or lactating from the
             time of the administration of study medication.

          2. Women of childbearing potential, defined as all women physiologically capable of
             becoming pregnant, including women whose career, lifestyle, or sexual orientation
             precludes intercourse with a male partner and women whose partners have been
             sterilized by vasectomy or other means.

          3. Evidence or history of clinically significant hematological, renal, endocrine,
             pulmonary, gastrointestinal (including gallbladder), cardiovascular, hepatic,
             psychiatric, neurologic, or allergic disease (including drug or food allergies,
             anaphylaxis or other severe allergic reactions but excluding untreated, asymptomatic,
             seasonal allergies at the time of dosing).

          4. Current or relevant history of physical or psychiatric illness that may require
             treatment or make the subject unlikely to fully comply with the requirements or
             complete the study, or any condition that presents undue risk from the investigational
             product or study procedures.

          5. Any surgical or medical condition possibly affecting drug absorption (e.g.
             cholecystectomy, gastrectomy, bowel disease, etc.), distribution, metabolism or
             excretion.

          6. Any history of gallbladder disease, including cholecystitis and/or cholelithiasis.

          7. Any other significant disease or disorder which, in the opinion of the investigator,
             may either put the subject at risk because of the participation in the study may
             influence the result of the study, or the subject's ability to participate in the
             study.

          8. History of photosensitivity.

          9. History of megaloblastic anaemia or folate deficiency.

         10. History or clinical evidence of substance and/or alcohol abuse within the 12 months
             before screening. Alcohol abuse is defined as regular weekly intake of more than 21
             units for males and 14 units for females (using alcohol tracker
             http://www.nhs.uk/Tools/Pages/NHSAlcoholtracker.aspx).

         11. Treatment with an investigational drug within 90 days or 5 half-lives preceding the
             first dose of study medication (or as determined by the local requirement, whichever
             is the longer).

         12. Donation of blood or blood products (excluding plasma) within 90 days prior to study
             medication administration.

         13. Use of moderate/strong inhibitors or inducers of Cytochromes P450 (CYP450) or
             transporters within 30 days or 5 half-lives (whichever is the longer) prior to the
             first dose of study medication.

         14. Consumption of grapefruit, grapefruit juice or grapefruit-related citrus fruits (e.g.
             Seville oranges, pomelos) within 30 days prior to the first dose of study medication.

         15. Ingestion of any poppy seeds within the 24 hours prior to screening.

         16. Use of prescription or non-prescription drugs and dietary supplements within 7 days or
             5 half-lives (whichever is the longer) prior to the first dose of study medication.
             With the exception of paracetamol, which may be used incidentally or for a short-term
             treatment at a maximum dose of 1 gr. per day.

         17. Use of herbal supplements at least 30 days prior to the first dose of study
             medication.

         18. Any clinically significant abnormal laboratory, vital signs or other safety findings
             as determined by medical history, physical examination or other evaluations conducted
             at screening or on admission.

         19. The history or presence of any of the following cardiac conditions: known structural
             cardiac abnormalities; family history of long QT syndrome; cardiac syncope or
             recurrent, idiopathic syncope; exercise related clinically significant cardiac events.

               -  Any clinically important abnormalities in rhythm, conduction or morphology of
                  resting ECG that may interfere with the interpretation of corrected QT interval
                  (QTc) changes. This includes subjects with any of the following (at screening):

               -  Sinus node dysfunction.

               -  Clinically significant interval prolongation of the interval from the beginning
                  of the P wave to the beginning of the three distinct waves created by the passage
                  of the cardiac electrical impulse through the ventricles (QRS complex) on an
                  electrocardiogram (PR).

               -  Intermittent second or third degree atrioventricular (AV) block.

               -  Incomplete or complete bundle branch block.

               -  Abnormal T wave morphology.

               -  Prolonged QT intervals calculated using Bazett's formula (QTcB) >450 ms or
                  shortened QTcB < 350 ms. Any other ECG abnormalities in the standard 12-lead ECG
                  and 24-hour 12 lead Holter ECG or an equivalent assessment which in the opinion
                  of the Investigator will interfere with the ECG analysis.

             Subjects with borderline abnormalities may be included if the deviations do not pose a
             safety risk, and if agreed between the appointed Cardiologist and the PI.

         20. Confirmed positive results from urine drug screen (amphetamines, benzodiazepines,
             cocaine, cannabinoids, opiates, barbiturates, and methadone) or from the alcohol
             breath test at screening or on admission.

         21. A positive human immunodeficiency virus (HIV) I and II antibodies, hepatitis B surface
             antigen (HBsAg), anti Hepatitis core antibody (anti hepatitis B core antigen (HBc)
             immunoglobulin G (IgG) [and anti HBc Immunoglobulin M (IgM) if IgG is positive]), or
             hepatitis C virus (HCV) antibody at screening.

         22. Subjects have veins unsuitable for intravenous puncture or cannulation on either arm
             (e.g. veins that are difficult to locate access or puncture veins with a tendency to
             rupture during or after puncture).

         23. Any conditions which in the opinion of the investigator would make the subject
             unsuitable for enrollment or could interfere with the subjects' participation in or
             completion of the study.