Study in Blood Stage Malaria Infection After DVI of Cryopreserved P. Falciparum (NF54 Strain) Sporozoites
Condition: Malaria,Falciparum; Parasitemia; Protozoan Infections; Parasitic Disease
MeSH terms: Infections; Communicable Diseases; Malaria; Malaria, Falciparum; Parasitemia; Parasitic Diseases; Protozoan Infections
Intervention: Artemether-Lumefantrine 20 Mg-120 Mg Oral Tablet; PfSPZ-DVI Challenge
Intervention description: artemether-lumefantrine 6 x of 4 tablets at approximately 0, 8, 24, 36, 48 and 60 h; 3200 P. falciparum Sporozoites by direct venous inoculation (DVI)
Intervention MeSH terms: Lumefantrine; Artemether; Artemether, Lumefantrine Drug Combination
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Intervention model description: All subjects will receive the PfSPZ Challenge product. In cohort 1 parasitaemia will be allowed to develop until a threshold of 5000 parasites/mL blood or a malaria clinical score ≥6 is reached. In cohort 2 the threshold is 10 000/mL or a malaria clinical score of ≥6.
Masking: None (Open Label)
Enrollment: 16.0
Sex: All
Minimum age: 18 Years
Maximum age: 55 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Malaria; PfSPZ Challenge

Summary:

      This is a single-centre, open-label, Phase Ib study designed to assess if intravenous
      injection of approximately 3200 P. falciparum (NF54 strain) sporozoites can be safely
      administered to achieve blood-stage parasitaemia with a kinetics/PCR profile that will allow
      for the future characterisation of antimalarial blood-stage activity of new chemical entities
      in a relatively small number of participants during early drug development.

      Healthy, malaria-naïve adults, aged 18-55 years, will be enrolled in a maximum of 2 cohorts.
      Enrolment into the cohorts will proceed sequentially, with two target levels of parasitaemia,
      i.e., 5000 parasites/mL blood in Cohort 1 and 10000 parasites/mL blood in Cohort 2.

      (Based on observed levels of parasitaemia in Cohort 1, the target threshold for treatment in
      Cohort 2 was maintained at 5,000 p/mL (vs 10,000 p/mL in the protocol)).

      The 3-day antimalarial therapy regimen will be further administered and monitored until
      parasite clearance. Safety and tolerability will be monitored during the whole study
      duration.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Informed Consent Form signed voluntarily before any study-related procedure is
             performed, indicating that the participant understands the purpose of and procedures
             required for the study and is willing to participate in the study, including
             administration of registered antimalarial therapy;

          2. Male or female, between 18 and 55 years old (extremes included) at screening;

          3. Body weight of at least 50 kg and a body mass index (BMI) of 19.0 to 30.0 kg/m2
             (extremes included);

          4. Good general health without clinically relevant medical illness, physical exam
             findings including vital signs, and laboratory abnormalities (e.g., without liver
             transaminases >1x ULN and according to the clinically acceptable ranges for study
             inclusion laboratory tests in Attachment 4) as determined by the Investigator;

          5. Willing to adhere to the prohibitions and restrictions specified in this protocol (see
             Section 4.3), including willingness to stay confined to the inpatient unit for the
             required duration and willingness to avoid travelling outside of Benelux during the
             study period;

          6. Female participants should fulfil one of the following criteria:

               1. At least 1 year postmenopausal (amenorrhea >12 months and follicle-stimulating
                  hormone [FSH] >30 mIU/mL) prior to screening;

               2. Surgically sterile (bilateral oophorectomy, hysterectomy or bilateral
                  salpingectomy);

               3. Will use contraceptives as outlined in inclusion criterion 7;

          7. Female participants of childbearing potential (excluding females with female partners)
             must agree to the use of a highly effective method of birth control from the screening
             visit until 40 days after the EOS visit at Day 28 (covering a full menstrual cycle of
             30 days starting after 5 half-lives of last dose of Riamet®); Note: Highly effective
             birth control methods include: combined (oestrogen- 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 from heterosexual intercourse.

          8. Female participant has a negative pregnancy test at screening and upon admission in
             the clinical unit; Note: Pregnancy testing will consist of serum β-human chorionic
             gonadotropin (β-HCG) tests at screening and at the EOS visit and a urine β-HCG tests
             on Day -1, in all women.

          9. Different ways of being reachable 24/7 (e.g., by mobile phone, regular phone or
             electronic mail) during the whole study period.

        Exclusion Criteria:

          -  1. Nursing (lactating) women; 2. Participation in any other clinical drug or vaccine
             study within 30 days (or 5 half-lives for drugs) preceding the day of PfSPZ-DVI
             Challenge (whichever is longer), or plans to participate in other investigational drug
             or vaccine research during the study period; 3. Participants who took standard
             vaccinations within 3 months before the start of the study or are planning to take
             standard vaccinations during the study period up to 8 weeks after PfSPZ-DVI Challenge;
             4. 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 on Day -1; 5.
             Mean ECG outside normal range and deemed clinically relevant by the Investigator.
             Examples of clinically significant ECG abnormalities for this study include:

          -  PR-interval >220 ms;

          -  QRS-complex >120 ms;

          -  Absolute QT greater than >500 ms;

          -  QT interval corrected according to Bazett's formula (QTcB) or QTcF >450 ms for male
             participants, >470 ms for female participants;

          -  Pathologic Q wave;

          -  Significant ST-T wave changes;

          -  Left or right ventricular hypertrophy;

          -  Non-sinus rhythm except isolated premature atrial contractions and ventricular
             extrasystole <2 per 10 s ECG lead;

          -  Incomplete left bundle branch block, or complete or intermittent right or left bundle
             branch block;

          -  Second or third degree A-V heart block. 6. Seropositive human immunodeficiency virus
             (HIV), hepatitis A immunoglobulinM (IgM) antibody, hepatitis B virus (HBV) (hepatitis
             B surface antigen [HBsAg]), hepatitis C virus (HCV) (antibody), hepatitis D antibody,
             hepatitis E IgM antibody, cytomegalovirus (CMV) IgM antibody or Epstein Barr Virus
             (EBV) IgM antibody; 7. Previous or current diagnosis of hepatitis including but not
             limited to viral hepatitis, auto-immune hepatitis, non-alcoholic steatohepatitis
             (NASH), alpha-1-antitrypsin deficiency, alcoholic liver disease, primary biliary
             cholangitis (PBC), primary sclerosing cholangitis (PSC), hemochromatosis, Wilson
             disease or suspected hepatocellular carcinoma (HCC).

             8. History or presence of diagnosed food or known drug allergies (including but not
             limited to allergy to any of the antimalarial medications to be used in the study, see
             Section 5.1), or history of anaphylaxis or other severe allergic reactions; Note:
             Participants 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.

             9. History of convulsion or severe head trauma, excluding fever convulsion under 5
             years of age; Note: A medical history of a single febrile convulsion during childhood
             is not an exclusion criterion.

             10. 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,
             participants 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. Participants 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.

             11. 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 defined as 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%).

             12. Participants 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. Participants must agree to abstain from smoking while in
             the unit; 13. Use of any prescription drugs, herbal supplements (e.g., St John's Wort)
             or over-the-counter medication within 7 days or 5 half-lives (whichever is longer)
             prior to the PfSPZ-DVI Challenge, 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) and paracetamol (2 g/day, 10
             g/week) may be acceptable at the Investigator's discretion 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 participant safety nor the overall results of
             the study, may be permitted on a case-by-case basis by the Investigator.

             14. Any surgical or medical condition possibly affecting drug absorption (e.g.,
             cholecystectomy, gastrectomy, bowel disease), distribution, metabolism or excretion;
             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
             jeopardise the safety or rights of a person participating in the study or would render
             the person unable to comply with the protocol; 17. Personal history of malaria; 18.
             Volunteer has travelled to or lived in a malaria-endemic area within 6 months prior to
             planned study enrolment; 19. Plans to travel to malaria-endemic region during the
             study period up to last follow-up visit; 20. Previous participation in any malaria
             vaccine or Controlled Human Malaria Infection (CHMI) study/VIS; 21. Falling in
             moderate or higher risk category for a fatal or non-fatal cardiovascular event within
             5 years (> 5%) determined by a validated risk estimation system, e.g., SCORE [21]; 22.
             Use of systemic antibiotics with known antimalarial activity within 5 half-lives of
             PfSPZ-DVI Challenge (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); 23.
             Receipt of blood or blood-derived products (including immunoglobulin) within 3 months
             prior to screening. Receipt of packed RBCs given for an emergent indication in an
             otherwise healthy person, and not required as ongoing treatment is not exclusionary
             (for example packed RBCs emergently given during an elective surgery).

        Note: In case of an out-of-range clinical laboratory test (according to the clinically
        acceptable ranges for study inclusion laboratory tests in Attachment 4), vital sign or ECG
        value that will determine a participant'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 participant
        eligibility at the Investigator's discretion. Participants can be rescreened at the
        discretion of the Investigator.