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
Study type: Interventional
Phase: Phase 1

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.
    

Detailed description: 
      Up to 16 healthy, malaria-naïve males and females, aged 18-55 years, will be enrolled in a
      maximum of 2 cohorts (up to 8 participants per cohort; a participant may be enrolled in one
      cohort only). Enrolment into the cohorts will proceed sequentially, with two target levels of
      parasitaemia previously achieved in healthy participants enrolled in malaria Volunteer
      Infection Studies (VIS) at other study sites, 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)).

      Each participant will be admitted to the clinical unit in the morning of Day -1 and
      inoculated with approximately 3200 P. falciparum sporozoites (NF54 strain) by DVI on Day 1.
      Participants will be discharged 2 h post inoculation on Day 1 and will be monitored daily via
      phone call from Day 2 until Day 6 to solicit any AEs. Participants will come to the clinical
      unit daily from Day 7 until Day 9 and together with the malaria clinical score (see
      Attachment 1), the presence of parasites will be assessed once daily by a specific qPCR
      targeting the varATS (the acidic terminal segment in Plasmodium falciparum var genes)
      multigenic family; this to accurately describe parasite growth even in case PCR positivity,
      i.e., a qPCR outcome ≥250 parasites per mL blood, is confirmed this early (very low
      probability and with low densities). Participants will be confined to the clinical unit from
      Day 10 in the morning. qPCR will be performed and malaria clinical score assessed twice daily
      and participants will be administered registered antimalarial therapy, i.e., Riamet®, when
      the following criteria are met:

        1. Cohort 1: ≥5000 parasites/mL blood or earlier if a participant has a malaria clinical
           score >6 or at Investigator's discretion.

        2. Cohort 2: ≥10000 parasites/mL blood or earlier if a participant has a malaria clinical
           score >6 or at Investigator's discretion.

      The registered 3-day antimalarial therapy regimen will be further administered and monitored.
      qPCR assessments of parasitaemia will be carried out at multiple time points (2, 6, 8, 12,
      16, 24, 36, 48 and 72 h) following initiation of Riamet® and malaria clinical score will be
      assessed twice daily during confinement in the clinical unit. Safety and tolerability will be
      monitored during the whole study duration, specific assessments will be done at periodic
      pre-specified time points from Day 10 and for at least 72 h after initiating antimalarial
      therapy, i.e., during confinement in the clinical unit (see below).

      Of note, all participants must consent to receiving antimalarial therapy, i.e., the
      registered 3-day Riamet® regimen approved for treatment of uncomplicated malaria. Even in the
      case of withdrawal from the study, all participants administered the PfSPZ-DVI Challenge are
      to receive antimalarial therapy as soon as possible, and to have all appropriate visits and
      assessments as required. If an intolerance or contraindication to Riamet® develops, Malarone®
      will be administered.

      Upon parasite clearance (defined as a qPCR value of 0 parasites per mL blood after initiating
      antimalarial therapy) and at least 72 h after initiating antimalarial therapy (estimated to
      occur on or before Day 19 and on or before Day 22 for Cohort 1 and Cohort 2, respectively),
      and if clinically well, participants will be discharged from the clinical unit and will be
      followed up for safety assessments, clinical evaluation and malaria qPCR in the clinical unit
      at the EOS visit on Day 28. All participants who received antimalarial therapy will be asked
      non-leading questions to determine the occurrence of any AEs throughout the study and at the
      EOS visit. All participants inoculated with PfSPZ-DVI Challenge will commence antimalarial
      therapy no later than Day 24 for both cohorts, regardless if they reach pre-defined
      cohort-specific PCR parasitaemia/malaria clinical score thresholds (i.e., 5000 parasites/mL
      blood for Cohort 1 and 10000 parasites/mL blood for Cohort 2 and/or a malaria clinical score
      ≥6 for Cohorts 1 and 2). Participants who start antimalarial therapy on Day 24 will only be
      discharged from confinement at the end of the EOS visit on Day 28. Antimalarial therapy may
      be initiated whenever deemed necessary by the Investigators, e.g., if there is a concern
      regarding the safety of a study participant. Therapy may be amended according to the treating
      physician if the participant does not respond to treatment or the condition worsens.
    

Intervention name(s): Artemether-Lumefantrine 20 Mg-120 Mg Oral Tablet; PfSPZ-DVI Challenge
Intervention type(s): Drug; Biological
Intervention description(s): 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)
Other intervention name(s): Riamet
Intervention MeSH terms: Lumefantrine; Artemether; Artemether, Lumefantrine Drug Combination
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)
Primary purpose: Treatment
Keywords: Malaria; PfSPZ Challenge