Safety, Tolerability and Chemoprotective Activity of P218 in PfSPZ Challenge Model
Condition: Malaria
MeSH terms: Malaria
Intervention: P218 (1000 mg) Oral Capsules; Placebo Oral Capsules; P218 (100 mg) Oral Capsules; PfSPZ Challenge
Intervention description: 1000 mg P218 (4 x 250 mg capsules); Placebo capsules matched to the P218 capsules with regard to appearance and taste; 100 mg P218 (2 x 50 mg capsules); 3200 P. falciparum Sporozoites by direct venous inoculation (DVI)
Phase: Phase 1
Study type: Interventional
Primary purpose: Prevention
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: In each of the three treatment cohorts, subjects will be randomly allocated to receive either P218 or placebo.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking description: Placebo capsules matched to the drug product with regard to appearance and taste
Enrollment: 32.0
Sex: All
Minimum age: 18 Years
Maximum age: 45 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: malaria; PfSPZ Challenge; chemoprotection

Summary:

      This was a single centre, randomised, double-blind, placebo-controlled Phase Ib study, to
      evaluate the safety, tolerability and chemoprotective activity of P218 in a controlled P.
      falciparum sporozoite infection model.

      Healthy men and women, aged 18 to 45 years were to be enrolled in 3 study cohorts and to be
      administered either P218 or placebo twice, 48 hours apart. Subjects in cohorts 2 and 3 were
      to be inoculated with P. falciparum sporozoites. Enrolment in cohorts was to proceed
      sequentially, to facilitate review of data by a Safety Review Team (SRT) before proceeding
      with a subsequent cohort.

      In cohort 1, safety and tolerability of P218 was assessed. In cohorts 2 and 3,
      chemoprotective activity of P218 against malaria infection was assessed, as well as the
      Influence of time of initiation of the P218 treatment on the protective effect.
    

Eligibility criteria:

        Subjects meeting all of the following criteria are eligible to participate in this study:

          1. Informed Consent Form signed voluntarily before any study-related procedure is
             performed, indicating that the subject understands the purpose of and procedures
             required for the study and is willing to participate in the study, including
             administration of rescue treatment.

          2. Male or female, between 18 and 45 years old (extremes included) at screening.

          3. Body weight of at least 50 kg and a body mass index (BMI) of 19 to 30 kg/m2 (extremes
             included).

          4. Good general health without clinically relevant medical illness, physical exam
             findings including vital signs, and laboratory abnormalities as determined by the
             investigator.

          5. Willing to adhere to the prohibitions and restrictions (see Section 4.3) specified in
             this protocol, including willingness to stay confined to the inpatient unit for
             required duration and willingness to avoid to travel outside of Benelux during the
             study period.

          6. Female subjects should fulfil one of the following criteria:

               1. At least 1 year post-menopausal (amenorrhea >12 months and follicle-stimulating
                  hormone (FSH) >30 mIU/mL) prior to screening;

               2. Surgically sterile (bilateral oophorectomy, hysterectomy or tubal ligation);

               3. Will use contraceptives as outlined in inclusion criteria 7 and 8.

          7. Female subjects of childbearing potential must agree to the use of a highly effective
             method of birth control from screening visit to until 40 days after the last dose of
             IMP (covering a full menstrual cycle of 30 days starting after 5 half-lives of last
             dose of IMP).

             Note: Highly effective birth control methods include: combined (estrogen and
             progestogen containing) oral/intravaginal/transdermal hormonal contraception
             associated with inhibition of ovulation, progestogen-only oral/injectable/implantable
             hormonal contraception associated with inhibition of ovulation, intrauterine device,
             intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomised partner
             or sexual abstinence.

          8. Male subjects who are sexually active with a female partner of childbearing potential
             must agree to the use of an effective method of birth control from the day of the
             first IMP dose until 100 days thereafter (covering a full sperm cycle of 90 days
             starting after 5 half-lives of last dose of IMP).

             Note: Medically acceptable methods of contraception that may be used by the subject
             and/or partner include sterilization and vasectomy or a double barrier option
             combining oral contraceptive, contraceptive vaginal ring, contraceptive injection,
             intrauterine device or etonogestrel implant.

          9. Female subject has a negative pregnancy test at screening and upon admission in the
             clinical unit.

             Note: Pregnancy testing will consist of a serum β-human chorionic gonadotropin (β-HCG)
             test at screening and urine β-HCG tests at other visits, in all women.

             Inclusion Criteria - CHMI (controlled human malaria infection) specific:

         10. Different ways of being reachable 24/7 (e.g. by mobile phone, regular phone or
             electronic mail) during the whole study period.

        Subjects meeting any of the following criteria are excluded from participation in this
        study:

          1. Nursing (lactating) women.

          2. Participation in any other clinical drug or vaccine study within 30 days (or five
             half-lives for drugs) preceding the first dose of IMP (whichever is longer), or plans
             to participate in other investigational drug or vaccine research during the study
             period.

          3. Blood product donation to any blood bank during the 8 weeks (whole blood) or 4 weeks
             (plasma and platelets) prior to admission in the clinical unit.

          4. ECG outside normal range and deemed clinically relevant by the investigator. Examples
             of clinically significant ECG abnormalities for this study include:

               1. PR-interval >220 ms;

               2. QRS-complex >120 ms;

               3. QT interval corrected according to Bazett's formula (QTcB) or QT interval
                  corrected according to Fridericia's formula [3] (QTcF) >450 ms;

               4. Pathologic Q wave;

               5. Significant ST-T wave changes;

               6. Left or right ventricular hypertrophy;

               7. Non-sinus rhythm except isolated premature atrial contractions and ventricular
                  extrasystole <2 per 10 s ECG lead;

               8. Incomplete left bundle branch block, or complete or intermittent right or left
                  bundle branch block;

               9. Second or third degree A-V heart block.

          5. Seropositive human immunodeficiency virus (HIV) (antibody and antigen), hepatitis B
             virus (HBV) (hepatitis B surface antigen [HBsAg]) or hepatitis C virus (HCV)
             (antibody) tests.

          6. History or presence of diagnosed food or known drug allergies (including but not
             limited to allergy to any of the antimalarial rescue medications to be used in the
             study, see Section 5.2), or history of anaphylaxis or other severe allergic reactions.

             Note: Subjects with seasonal allergies/hay fever, house dust mite or allergy to
             animals that are untreated and asymptomatic at the time of dosing can be enrolled in
             the study.

          7. History of convulsion or severe head trauma.

             Note: A medical history of a single febrile convulsion during childhood is not an
             exclusion criteria.

          8. History of serious psychiatric condition that may affect participation in the study or
             preclude compliance with the protocol, including but not limited to past or present
             psychoses, disorders requiring lithium, a history of attempted or planned suicide,
             more than one previous episode of major depression, any previous single episode of
             major depression lasting for or requiring treatment for more than 6 months, or any
             episode of major depression during the 5 years preceding screening.

             Note: The Beck Depression Inventory (Attachment 2) will be used as an objective tool
             for the assessment of depression at screening. In addition to the conditions listed
             above, subjects with a score of 20 or more on the Beck Depression Inventory and/or a
             response of 1, 2 or 3 for item 9 of this inventory (related to suicidal ideation) will
             not be eligible for participation. Subjects with a Beck score of 17 to 19 may be
             enrolled at the discretion of the Investigator if they do not have a history of the
             psychiatric conditions mentioned in this criterion and their mental state is not
             considered to pose additional risk to the health of the volunteer or to the execution
             of the study and interpretation of the data gathered.

          9. A medical, occupational or family problem as a result of alcohol or illicit drug abuse
             during the past 12 months or current alcohol or illicit drug abuse or addiction
             (positive alcohol breath test or positive drug screen for amphetamines, barbiturates,
             benzodiazepines, cannabinoids, cocaine or opiates at screening or upon check-in at the
             clinical unit).

             Note: Excessive use of alcohol is an intake of >21 units per week for males and >14
             units per week for females where one alcohol unit is defined as 10 mL or 8 g of pure
             alcohol. A single unit is equal to one 25-mL (single) measure of whisky (alcohol by
             volume [ABV] 40%), or a third of a pint of beer (190 mL; ABV 5-6%) or half a standard
             (175 mL) glass of wine (ABV 12%).

         10. 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.) they should use the equivalent of no more than 5 cigarettes
             per day. Subjects must agree to abstain from smoking while in the unit.

         11. Use of any prescription drugs, herbal supplements (e.g. St John's Wort) or
             over-the-counter medication within 7 days or five half-lives (whichever is longer)
             prior to the first IMP administration, or an anticipated requirement for the use of
             these during the course of the study (See Section 6.2).

             Note: If necessary, the incidental use of non-steroidal anti-inflammatory drugs
             (NSAIDs), paracetamol (2g/day, 10 gr/week), vitamins and topical treatments may be
             acceptable after approval by the study Sponsor and will be documented in the eSource
             system. The use of nutritional supplements during this time that are not believed to
             have the potential to affect subject safety nor 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.

         12. Any surgical or medical condition possibly affecting drug absorption (e.g.
             cholecystectomy, gastrectomy, bowel disease), distribution, metabolism or excretion.

         13. Any history of gallbladder disease, including cholecystitis and/or cholelithiasis.

         14. History of megaloblastic anaemia or folate deficiency.

         15. Personnel (e.g. investigator, sub-investigator, research assistant, pharmacist, study
             coordinator or anyone mentioned in the delegation log) directly involved in the
             conduct of the study.

         16. Any condition that in the opinion of the investigator would jeopardize the safety or
             rights of a person participating in the trial or would render the person unable to
             comply with the protocol.

             Exclusion Criteria - CHMI specific:

         17. Glucose-6-phosphate dehydrogenase (G6PD) deficiency (due to possible hemolysis induced
             by primaquine treatment at study end in G6PD deficient subjects).

         18. Personal history of malaria.

         19. Volunteer has travelled to or lived in a malaria-endemic area for more than 4 weeks
             during the 12 months prior to first IMP administration, or spent any time in an
             endemic area during the 4 weeks prior to first IMP administration.

         20. Plans to travel to malaria-endemic region during the study period up to last follow-up
             visit.

         21. Previous participation in any malaria vaccine or CHMI study.

         22. Falling in moderate or higher risk category for a fatal or non-fatal cardiovascular
             event within 10 years (≥5%) determined by a validated risk estimation system e.g.
             SCORE [13].

         23. Use of medications known to interact with atovaquone-proguanil (Malarone®),
             artemether-lumefantrine (Riamet®) or primaquine (Primaquine®) such as cimetidine,
             metoclopramide or antacids, or an anticipated requirement for the use of these at any
             point during the study period (see Section 6.2).

         24. Use of systemic antibiotics with known antimalarial activity within 30 days (or 5
             half-lives whichever is longer) of first IMP administration (e.g.
             trimethoprim-sulfamethoxazole, doxycycline, tetracycline, clindamycin, erythromycin,
             fluoroquinolones or azithromycin) or an anticipated requirement for the use of these
             during the study period (see Section 6.2).

         25. Receipt of blood or blood-derived products (including immunoglobulin) within 3 months
             prior to screening. Receipt of packed red blood cells given for an emergent indication
             in an otherwise healthy person, and not required as ongoing treatment is not
             exclusionary (for example packed red blood cells emergently given during an elective
             surgery).

        Note: In case of an out-of-range clinical laboratory test, vital sign or ECG value that
        will determine a subject's eligibility, or in case of a positive drug screen, a retest or
        expert evaluation can be requested. Results of any retest must be available prior to
        inoculation. The result of the retest will be considered for subject eligibility at the
        investigator's discretion. Subjects can be rescreened at the discretion of the
        investigator.