Study in Blood Stage Malaria Infection After DVI of Cryopreserved P. Falciparum (NF54 Strain) Sporozoites

Malaria,Falciparum Clinical Trial

Official title: A Single Centre, Open Label, Pilot Phase Ib Study to Investigate Blood Stage Malaria Infection After Direct Venous Inoculation of Cryopreserved P. Falciparum (NF54 Strain) Sporozoites (PfSPZ-DVI) in Malaria naïve Healthy Adult Volunteers

Status Completed

Clinical Trial 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.

Clinical Trial 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. ;

Related Conditions & MeSH terms

• Communicable Diseases
• Infection
• Malaria
• Malaria, Falciparum
• Malaria,Falciparum
• Parasitemia
• Parasitic Disease
• Parasitic Diseases
• Protozoan Infections

• NCT number: NCT04310085
• Study type: Interventional
• Source: Medicines for Malaria Venture
• Status: Completed
• Phase: Phase 1
• Start date: February 19, 2020
• Completion date: December 17, 2020