Effectiveness of OZ439 Against Early Plasmodium Falciparum Blood Stage Infection in Healthy Volunteers

Study Overview
=================
Brief Summary
-----------------
A single centre, open, controlled study using Blood Stage Plasmodium falciparum challenge inoculum (BSPC) as a model to assess the effectiveness of three dose levels of the experimental anti-malarial product, OZ439.

Detailed Description
-----------------
This was a single center study using blood stage Plasmodium falciparum challenge inoculum to characterize the effectiveness of OZ439 against early blood stage Plasmodium Falciparum infection. The study was conducted in three cohorts (n=8) using different doses of OZ439. Dose escalation took place after review of the observed OZ439 safety and pharmacodynamic outcome for the previous cohort by the Safety Review Team. Single doses of 100 mg, 200 mg and 500 mg were administered orally to participants in Cohort 1, Cohort 2 and Cohort 3 respectively.

Official Title
-----------------
An Experimental Study To Characterize the Effectiveness of OZ439 Against Early Plasmodium Falciparum Blood Stage Infection In Healthy Volunteers

Conditions
-----------------
Malaria

Intervention / Treatment
-----------------
* Drug: OZ439


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Volunteers will be adults (males or non pregnant females), aged between 18 and 45 years who do not live alone (from Day 1 until at least the end of the antimalarial drug treatment). Volunteers must have a BMI within the range 18-30. Volunteers must understand the procedures involved and agree to participate in the study by giving fully informed, written consent. Be contactable and available for the duration of the trial (maximum of 4 weeks). Volunteers must be non-smokers and in good health, as assessed during pre-study medical examination and by review of screening results. Female participants of childbearing potential, should be surgically sterile or using an insertable, injectable, transdermal, or combination oral contraceptive approved by the US FDA or Therapeutic Goods Administration (TGA) combined with a barrier contraceptive through completion of the study and have negative results on a serum or urine pregnancy test done before administration of study medication. Good peripheral venous access. Exclusion Criteria: History of malaria. Travelled to or lived (2 weeks or more) in a malaria-endemic country during the past 12 months or planned travel to a malaria-endemic country during the course of the study. Has evidence of increased cardiovascular disease risk (defined as greater than 10%, 5 year risk) History of splenectomy. History of a severe allergic reaction, anaphylaxis or convulsions following any vaccination or infusion. Presence of current or suspected serious chronic diseases such as cardiac or autoimmune disease (HIV or other immunodeficiencies), insulin dependent diabetes, progressive neurological disease, severe malnutrition, acute or progressive hepatic disease, acute or progressive renal disease, psoriasis, rheumatoid arthritis, asthma, epilepsy or obsessive compulsive disorder, skin carcinoma excluding non-spreadable skin cancers such as basal cell and squamous cell carcinoma. Known inherited genetic anomaly (known as cytogenetic disorders) e.g., Down's syndrome Volunteers unwilling to defer blood donations to the Australian Red Cross Blood Service (ARCBS) for 6 months. The volunteer has a diagnosis of schizophrenia, severe depression, bi-polar disease, or other severe (disabling) chronic psychiatric diagnosis. Participants who are receiving a single antidepressant drug and are stable for at least 3 months prior to enrollment without decompensating may be allowed to enroll in the study at the investigator's discretion. 10) Presence of acute infectious disease or fever (e.g., sub-lingual temperature 38.5 degrees C) within the five days prior to study product administration. Evidence of acute illness within the four weeks before trial prior to screening. Significant intercurrent disease of any type, in particular liver, renal, cardiac, pulmonary, neurologic, rheumatologic, or autoimmune disease by history, physical examination, and/or laboratory studies including urinalysis. Have ever received a blood transfusion. Evidence of any condition that, in the opinion of the clinical investigator, might interfere with the evaluation of the study objectives or pose excessive risks to participants.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: OZ439 100mg<br>OZ439 100mg Powder for Oral Suspension | Drug: OZ439<br>* OZ439 Powder for Oral Suspension<br>|
| Experimental: OZ439 200mg<br>OZ439 200mg Powder for Oral Suspension | Drug: OZ439<br>* OZ439 Powder for Oral Suspension<br>|
| Experimental: OZ439 500mg<br>OZ439 500mg Powder for Oral Suspension | Drug: OZ439<br>* OZ439 Powder for Oral Suspension<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Individual Parasite Reduction Ratio (PRR) | PRR estimates the efficacy of an anti-malarial treatment and is the ratio of the parasite density between admission and 48 hours post-treatment. Individual subject PRR and corresponding 95% CI were calculated using the slope and corresponding standard error of mean (SE) of the optimal regression model. | 48 hours | 
| 500mg Cohort Mean Parasite Reduction Ratio (PRR) | OZ439 500mg individual subject PRR and corresponding 95% CI were used to calculate the OZ439 500mg cohort specific PRR and the corresponding 95% CI: the weighted average slope estimate and corresponding SE were calculated by the inverse-variance method. | 48 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| OZ439 Cmax | OZ439 Maximum concentration (Cmax) | Pre-dose, and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours post-dose | 
| OZ439 AUC(0-144) | OZ439 Area under the curve to 144 hours | Pre-dose, and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours post-dose |