A Phase Ib Induced Malaria Infection Study With the Combination of OZ439 and DSM265
Status:
Completed
Trial end date:
2015-06-01
Target enrollment:
Participant gender:
Summary
This is a single-centre, open-label, dose finding study using induced blood stage malaria
(IBSM) infection to characterize the pharmacodynamic interaction between OZ439 and DSM265,
administered around 120 minutes apart for treatment of early Plasmodium falciparum blood
stage infection. The study will be conducted in up to three cohorts (n=8 per cohort) using
different doses of OZ439 and DSM265. The doses of OZ439 and DSM265 that will be investigated
in the first cohort will be 200 mg of OZ439 and 100mg of DSM265, both administered as single
doses around 120 minutes apart. Subsequent doses in subsequent cohort(s) will be determined
following a review of observed OZ439 and DSM265 safety, and pharmacokinetic and
pharmacodynamic interaction outcomes, particularly the antimalarial activity of the drugs
given in combination as defined by parasite clearance kinetics. The doses used in Cohort 2
and 3 may be adjusted but will not exceed the maximum acceptable doses predefined for this
study (which are 400 mg for DSM265 and 500mg for OZ439) as determined in previous safety and
pilot efficacy studies. The dose will be determined by the funding sponsor and the principal
investigator (PI) following Safety Review team (SRT) and scientific evaluation. If no safe
alternative dose can be determined the option exists to curtail the study to less than three
cohorts.
Each participant in the cohort will be inoculated on Day 0 with ~1,800 viable parasites of
Plasmodium falciparum-infected human erythrocytes (BSPC) administered intravenously. On an
outpatient basis, participants will be monitored daily via phone call and then daily (AM)
from day 4 (until PCR positive for presence of malaria parasites). Once PCR positive they
will be monitored twice-daily morning (AM) and evening (PM) until treatment, for adverse
events and the unexpected early onset of symptoms, signs or parasitological evidence of
malaria. On the day designated for commencement of treatment, as determined by qPCR results,
participants will be admitted to the study unit and monitored. The threshold for commencement
of treatment will be when PCR quantification of all participants is = 1,000 parasites/mL. If
the PCR quantification of any participant is = 5,000 parasites/mL and is accompanied by a
clinical symptom score >5, or if clinical or parasitological evidence of malaria occurs in
any participant before all participants have reached the treatment threshold (PCR
quantification of = 1,000), then treatment of that participant will begin within a 24 h
period.
Following treatment with OZ439 and DSM265, participants will be followed up as inpatients for
at least 48 hours to ensure tolerance of the treatment and clinical response, then if
clinically well on an outpatient basis for safety and clearance of malaria parasites via PCR.
Compulsory commencement of treatment with Riamet® (artemether-lumefantrine) will occur on
study day 16 ±3 days post OZ439 and DSM265 treatment unless required earlier. Early standard
anti-malarial drug intervention can occur if either poor responses or fast responses are seen
following OZ439 and DSM265 treatment. This is to ensure participant safety and to avoid
participant inconvenience if useful data cannot be obtained. A poor response is defined as a
decrease in parasitaemia of less than 20% from baseline by 3 days post OZ439 and DSM265
treatment. A fast response occurs when, within the seven day period following the treatment,
two consecutive PCR assessments in 48 hours are negative. However, pre-emptive treatment with
Riamet® can commence whenever deemed necessary by the investigator. Participants will be
monitored, either in clinic, or by telephone for three days to ensure adherence to Riamet®
therapy.
Participants will be treated with a single dose (45 mg) of primaquine as described in section
4.3 in this protocol at the end of their Riamet® treatment if gametocytes are identified, to
ensure complete clearance of any gametocytes present.
Adverse events will be monitored via telephone monitoring, within the clinical research unit,
and on outpatient review after malaria challenge inoculation and antimalarial study drugs
administration. Blood samples for safety evaluation, malaria monitoring, and red blood cell
antibodies will be drawn at screening and/ or baseline and at nominated times after malaria
challenge.
Phase:
Phase 1/Phase 2
Details
Lead Sponsor:
Medicines for Malaria Venture
Collaborators:
Clinical Network Services (CNS) Pty Ltd Q-Pharm Pty Limited QIMR Berghofer Medical Research Institute