Malaria
Conditions
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.
Interventions
DRUGOZ439
OZ439 Powder for Oral Suspension
Sponsors
Queensland Institute of Medical Research
Medicines for Malaria Venture
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Individual Parasite Reduction Ratio (PRR) | 48 hours | 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. |
| 500mg Cohort Mean Parasite Reduction Ratio (PRR) | 48 hours | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| OZ439 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 Maximum concentration (Cmax) |
| OZ439 AUC(0-144) | 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 Area under the curve to 144 hours |
Countries
Australia
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Randomised Participants Twenty-four male and female subjects were enrolled in the study. | 24 |
| Total | 24 |
Baseline characteristics
| Characteristic | Randomised Participants |
|---|---|
| Age, Customized 18 - 30 Years | 21 participants |
| Age, Customized 31 - 40 Years | 3 participants |
| Age, Customized 41 - 45 Years | 0 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 24 Participants |
| Region of Enrollment Australia | 24 participants |
| Sex: Female, Male Female | 12 Participants |
| Sex: Female, Male Male | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 8 | 3 / 8 | 1 / 8 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 | 0 / 8 |
Outcome results
Primary
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.
Time frame: 48 hours
Population: As the doses of 100 mg and 200 mg of OZ439 in Cohorts 1 and 2 were inadequate to eliminate the parasites and regrowth occurred, PRR calculations were only undertaken for subjects receiving 500mg of OZ439 in Cohort 3. With a p value of 0.0046, Subject S036 was excluded from this calculation
| Arm | Measure | Value (MEAN) |
|---|---|---|
| OZ439 500mg - R017 | 500mg Cohort Mean Parasite Reduction Ratio (PRR) | 10176 none (ratio) |
Primary
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.
Time frame: 48 hours
Population: As the doses of 100 mg and 200 mg of OZ439 in Cohorts 1 and 2 were inadequate to eliminate the parasites and regrowth occurred, PRR calculations were only undertaken for subjects receiving 500mg of OZ439 in Cohort 3.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| OZ439 500mg - R017 | Individual Parasite Reduction Ratio (PRR) | 1132 none (ratio) |
| OZ439 500mg - R018 | Individual Parasite Reduction Ratio (PRR) | 217646 none (ratio) |
| OZ439 500mg - R019 | Individual Parasite Reduction Ratio (PRR) | 314040 none (ratio) |
| OZ439 500mg - R020 | Individual Parasite Reduction Ratio (PRR) | 8021 none (ratio) |
| OZ439 500mg - R021 | Individual Parasite Reduction Ratio (PRR) | 8227 none (ratio) |
| OZ439 500mg - R022 | Individual Parasite Reduction Ratio (PRR) | 13557 none (ratio) |
| OZ439 500mg - R023 | Individual Parasite Reduction Ratio (PRR) | 13560 none (ratio) |
| OZ439 500mg - R024 | Individual Parasite Reduction Ratio (PRR) | 21924 none (ratio) |
Secondary
OZ439 AUC(0-144)
OZ439 Area under the curve to 144 hours
Time frame: 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
Population: All 24 subjects randomized and completed the study.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| OZ439 500mg - R017 | OZ439 AUC(0-144) | 1056 ng*h/mL | Geometric Coefficient of Variation 23 |
| OZ439 500mg - R018 | OZ439 AUC(0-144) | 3182 ng*h/mL | Geometric Coefficient of Variation 21 |
| OZ439 500mg - R019 | OZ439 AUC(0-144) | 10755 ng*h/mL | Geometric Coefficient of Variation 40 |
Secondary
OZ439 Cmax
OZ439 Maximum concentration (Cmax)
Time frame: 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
Population: All 24 subjects randomized and completed the study.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| OZ439 500mg - R017 | OZ439 Cmax | 164 ng/mL | Geometric Coefficient of Variation 20 |
| OZ439 500mg - R018 | OZ439 Cmax | 448 ng/mL | Geometric Coefficient of Variation 33 |
| OZ439 500mg - R019 | OZ439 Cmax | 1263 ng/mL | Geometric Coefficient of Variation 47 |