Malaria, Falciparum, Malaria, Vivax
Conditions
Keywords
Acute uncomplicated Plasmodium Falciparum malaria, Blood stage Plasmodium Vivax malaria
Brief summary
A Phase IIa Exploratory, Open label, Single Dose Regimen, Multiple Dose Testing Clinical Study to Assess the Preliminary Efficacy, Tolerability and Pharmacokinetics of OZ439 in adult patients with acute, uncomplicated Plasmodium falciparum or vivax malaria mono-infection.
Detailed description
This exploratory Phase IIa study aims to investigate the preliminary efficacy in terms of parasite reduction and clearance in malaria patients, and the tolerability of OZ439 administered as single dose regimen at 3 different doses in parallel cohorts of patients with either acute uncomplicated Plasmodium falciparum or Plasmodium vivax malaria mono-infection (10 patients per plasmodium species per dose level). Treatment with OZ439 will be given as a single dose on Day 0, starting in the first cohort at a dose of 800 mg. Established antimalarial therapy will be given at the latest at 36 hours post dosing. The primary endpoint will be the derived parasite reduction rate (PRR) at 24 hours after study drug administration. A review of each individual study cohort (dose/species) will be conducted with the Principal Investigator and the Sponsor and a decision will be reached on whether the dose for the next cohort should increase or decrease (within 200mg-1600mg range). This decision will be based on parasite reduction rate over the first 24 hours following administration of OZ439, tolerability and exposure.
Interventions
DRUGOZ439
po, single dose
Sponsors
Mahidol University
Medicines for Malaria Venture
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
1. Male or female patients between the age of 18 and 60 years, inclusive 2. Body weight between 40 kg and 90 kg inclusive 3. Presence of mono-infection of P. falciparum or P. vivax confirmed by: * Fever, as defined by axillary temperature ≥ 37.5°C or oral/rectal/tympanic temperature ≥ 38°C, or history of fever in the previous 24 hours (history of fever must be documented) and, * Microscopically confirmed parasite infection, 5,000 to 50,000 asexual parasite count/µl of blood 4. Written informed consent, in accordance with local practice, provided by patient. If the patient is unable to write, witnessed consent is permitted according to local ethical considerations 5. Ability to swallow oral medication 6. Ability and willingness to participate and access the health facility 7. Agree to minimum of 4 days hospitalisation for drug administration and pharmacokinetic sampling
Exclusion criteria
1. Patients with signs and symptoms of severe/complicated malaria requiring parenteral treatment according to the World Health Organisation Criteria 2010 (Attachment 2) 2. Mixed Plasmodium infection 3. Severe vomiting, defined as more than three times in the 24 hours prior to inclusion in the study or inability to tolerate oral treatment, or severe diarrhoea defined as 3 or more watery stools per day 4. Presence of other serious or chronic clinical condition requiring hospitalisation. 5. Severe malnutrition (defined as the weight-for-height being below -3 standard deviation or less than 70% of median of the NCHS/WHO normalised reference values). 6. Known history or evidence of clinically significant disorders such as cardiovascular (including arrhythmia, QTc interval greater than or equal to 450 msec), respiratory (including active tuberculosis), history of jaundice, hepatic, renal, gastrointestinal, immunological (including active HIV-AIDS), neurological (including auditory), endocrine, infectious, malignancy, psychiatric, history of convulsions or other abnormality (including head trauma). 7. Known history of hypersensitivity, allergic or adverse reactions to artemisinin containing compounds or mefloquine or drug in the national guidelines for P. vivax. 8. Known active Hepatitis A IgM (HAV-IgM), Hepatitis B surface antigen (HBsAg) or Hepatitis C antibody (HCV Ab). 9. Have received any antimalarial treatment in the preceding 14 days, as determined by history and screening test. 10. Have received antibacterial with known antimalarial activity in the preceding 14 days. 11. Have received an investigational drug within the past 4 weeks. 12. Liver function tests (ASAT/ALAT levels) more than 2 x ULN 13. Hb level below 10 g/dL. 14. Bilirubin levels greater than 40 µmol/L. 15. Serum creatinine levels more than 2 times the upper limit of normal range in absence of dehydration. In case of important dehydration the creatinine should be lower than 2X ULN after oral/parenteral rehydration. 16. Female patients must be neither pregnant (as demonstrated by a negative serum pregnancy test) nor lactating, and must be willing to take measures not to become pregnant during the study period and safety follow-up period
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Derived Parasite Reduction Rate at 24 Hours (PPR24) | 24 hours after study drug administration | PRR24 is the log10 change in parasitemia over 24 hours estimated from a regression model fit separately for each patient. The relationship between parasite counts and time was analyzed by fitting a variable lag phase, then a linear decline to the natural log of parasite count versus time relationship. The slope of this log linear relationship is the primary end-point. The time points chosen for the regression are those that yield the highest degree of significance when assessing the regression when the number of time points are greater than or equal to 3. No extrapolation was performed. |
Participant flow
Recruitment details
Patients were recruited at two study centres in Thailand Primary study centre: Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand Sub-centre: Shoklo Malaria Research Unit, Mae Sod, Tak, Thailand The first patient was enrolled on 24 October 2010 and the last patient completed on 25 May 2012.
Pre-assignment details
There was no washout, run-in or transition following enrolment but prior to group assignment.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 - OZ439 800mg 800 mg OZ439 po single dose | 20 |
| Cohort 2 - OZ439 400mg 400 mg OZ439 p.o. single dose | 21 |
| Cohort 3 - OZ439 200mg 200mg OZ439 p.o. single dose | 20 |
| Cohort 4 - OZ439 1200mg 1200 mg OZ439 po single dose | 21 |
| Total | 82 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Protocol Violation | 1 | 0 | 3 | 1 |
Baseline characteristics
| Characteristic | Cohort 2 - OZ439 400mg | Cohort 3 - OZ439 200mg | Cohort 1 - OZ439 800mg | Cohort 4 - OZ439 1200mg | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 21 Participants | 20 Participants | 20 Participants | 21 Participants | 82 Participants |
| Age, Continuous | 29.1 years STANDARD_DEVIATION 9.82 | 26.7 years STANDARD_DEVIATION 9.75 | 27.2 years STANDARD_DEVIATION 8.37 | 29.3 years STANDARD_DEVIATION 8.19 | 28.1 years STANDARD_DEVIATION 8.97 |
| Region of Enrollment Thailand | 21 participants | 20 participants | 20 participants | 21 participants | 82 participants |
| Sex: Female, Male Female | 4 Participants | 1 Participants | 2 Participants | 4 Participants | 11 Participants |
| Sex: Female, Male Male | 17 Participants | 19 Participants | 18 Participants | 17 Participants | 71 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 20 | 6 / 20 | 10 / 20 | 8 / 21 |
| serious Total, serious adverse events | 0 / 20 | 0 / 20 | 1 / 20 | 1 / 21 |
Outcome results
Primary
Derived Parasite Reduction Rate at 24 Hours (PPR24)
PRR24 is the log10 change in parasitemia over 24 hours estimated from a regression model fit separately for each patient. The relationship between parasite counts and time was analyzed by fitting a variable lag phase, then a linear decline to the natural log of parasite count versus time relationship. The slope of this log linear relationship is the primary end-point. The time points chosen for the regression are those that yield the highest degree of significance when assessing the regression when the number of time points are greater than or equal to 3. No extrapolation was performed.
Time frame: 24 hours after study drug administration
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| 800 mg OZ439 po Single Dose | Derived Parasite Reduction Rate at 24 Hours (PPR24) | PPR24 Plasmodium Falciparum | 1.38 Log10 parasites/24h |
| 800 mg OZ439 po Single Dose | Derived Parasite Reduction Rate at 24 Hours (PPR24) | PPR24 Plasmodium Vivax | 2.05 Log10 parasites/24h |
| 400 mg OZ439 p.o. Single Dose | Derived Parasite Reduction Rate at 24 Hours (PPR24) | PPR24 Plasmodium Vivax | 2.18 Log10 parasites/24h |
| 400 mg OZ439 p.o. Single Dose | Derived Parasite Reduction Rate at 24 Hours (PPR24) | PPR24 Plasmodium Falciparum | 1.56 Log10 parasites/24h |
| 200mg OZ439 p.o. Single Dose | Derived Parasite Reduction Rate at 24 Hours (PPR24) | PPR24 Plasmodium Vivax | 2.40 Log10 parasites/24h |
| 200mg OZ439 p.o. Single Dose | Derived Parasite Reduction Rate at 24 Hours (PPR24) | PPR24 Plasmodium Falciparum | 1.71 Log10 parasites/24h |
| 1200 mg OZ439 po Single Dose | Derived Parasite Reduction Rate at 24 Hours (PPR24) | PPR24 Plasmodium Vivax | 1.96 Log10 parasites/24h |
| 1200 mg OZ439 po Single Dose | Derived Parasite Reduction Rate at 24 Hours (PPR24) | PPR24 Plasmodium Falciparum | 1.63 Log10 parasites/24h |
Comparison: PPR24 was summarised descriptively. No statistical test was performed.p-value: 0.01Regression, Linear