Malaria, Falciparum
Conditions
Keywords
induced blood stage malaria infection
Brief summary
A single-centre, open-label, study using induced blood stage malaria infection to characterize the activity of MMV390048 against early Plasmodium falciparum blood stage infection.
Detailed description
Study using induced blood stage malaria infection to characterize the activity of MMV390048 against early Plasmodium falciparum blood stage infection. There will be two or more cohorts of 8 subjects. In the first cohort a single dose of 20 mg of MMV390048 will be investigated. Depending on the data obtained, the dose in Cohort 2 may be adjusted but will not exceed the maximum tolerated dose (or highest achieved dose based on a predefined exposure cap) as determined in an ongoing single ascending dose study. Each participant will be inoculated on Day 0 with \ 1,800 viable parasites of Plasmodium falciparum-infected human erythrocytes intravenously. On an outpatient basis, participants will be monitored daily until positive for presence of malaria parasites. Once positive they will be monitored twice-daily 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, participants will be admitted to the study unit and monitored. The threshold for commencement of treatment will be when quantification of all participants is ≥ 1,000 parasites/mL. If the 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 (quantification of ≥ 1,000), then treatment of that participant will begin within a 24 h period. Following treatment with MMV390048, participants will be followed up as inpatients for at least 72 hours to ensure tolerance of the treatment and clinical response, then on an outpatient basis if clinically well for monitoring of safety and clearance of malaria parasites. Compulsory treatment with Riamet® (artemether-lumefantrine) will start on day 16 (±3 days) post study treatment unless required earlier. Early intervention can occur if either poor responses or fast responses are seen following MMV390048 treatment. This is to ensure participant safety and to avoid participant inconvenience if useful data cannot be obtained. Pre-emptive treatment with Riamet® can commence whenever necessary. Participants will be treated with a single dose (45 mg) of primaquine (Primacin™) at the end of their Riamet® treatment if gametocytes are identified, to ensure complete clearance of any gametocytes present.
Interventions
DRUGMMV390048 20mg
Supplied as a powder to be prepared as a suspension for oral use
Sponsors
Q-Pharm Pty Limited
Medicines for Malaria Venture
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Participants who do not live alone from Day 0 until at least the end of the antimalarial drug treatment, and are contactable and available for the duration of the trial (≤4 months) * Body weight ≥50kg, body mass index between 18.0 and 32.0 kg/m2, inclusive * Healthy by clinical assessment * Normal vital signs * Normal 12-lead electrocardiogram * Lab tests in normal range * Agrees to use a double barrier method of contraception including condom plus diaphragm or condom plus intrauterine device or condom plus stable oral / transdermal / injectable hormonal contraceptive by female partner for ≥14 days prior to the first dose of study drug until 90 days after the last dose * Written informed consent before any study procedure
Exclusion criteria
* History of malaria or participation in a previous malaria challenge study * Must not have travelled to or lived \>2 weeks in a malaria-endemic area in past 12 months nor plan to travel to one during study * Evidence of increased cardiovascular disease risk * History of splenectomy * Presence / history of drug hypersensitivity, or allergic disease diagnosed and treated or history of a severe allergic reaction, anaphylaxis or convulsions following any vaccination or infusion * Presence of current / suspected serious chronic diseases such as cardiac or autoimmune disease, diabetes, progressive neurological disease, severe malnutrition, acute or progressive hepatic or 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, schizophrenia, bi-polar disease, or other severe (disabling) chronic psychiatric diagnosis * History of photosensitivity * History of schizophrenia, bi-polar disease, or other severe (disabling) chronic psychiatric diagnosis, including depression or receiving psychiatric drugs or hospitalized in past 5 yrs for psychiatric illness, history of suicide attempt or confinement for danger to self/others * Frequent headache and/or migraine, recurrent nausea, and/or vomiting (≥2 / month) * Acute infectious disease/fever in 5 days pre-inoculation with malaria parasites * Acute illness in 4 weeks pre-screening which may compromise subject safety * Any significant intercurrent disease, in particular liver, renal, cardiac, pulmonary, neurologic, rheumatologic, or autoimmune disease by history, physical exam or lab test * Clinically significant disease or any condition that might affect drug absorption distribution or excretion * Participation in any investigational study in last 12 weeks * Any blood sampling/donation in last 8 weeks * Unwilling to defer blood donation for 6 months * Any blood donation, in 1 month before inclusion. * Medical requirement for intravenous immunoglobulin or blood transfusion * Ever had a blood transfusion * Symptomatic postural hypotension, irrespective of the decrease in blood pressure, or asymptomatic postural hypotension * History or presence of alcohol abuse (≥40g per day) or drug habituation, or any prior intravenous use of an illicit substance * Smoking ≥5 cigarettes or equivalent /day and unable to stop smoking during confinement period * Poppy seeds in 24h pre-screening * Excessive consumption of xanthine bases, including red bull, chocolate * Any medication (including St John's Wort) in 14 days pre-study or within 5 times the medication half-life if longer * Vaccination in the last 28 days * Any corticosteroids, anti-inflammatory, immunomodulators or anticoagulants. Any currently or previous immunosuppressive therapy, including systemic steroids including adrenocorticotrophic hormone or inhaled steroids in dosages associated with hypothalamic-pituitary-adrenal axis suppression or chronic use of inhaled high potency corticosteroids * Recent or current systemic therapy with an antibiotic / potential antimalarial * Likely to be noncompliant, or unable to cooperate * Not contactable in case of emergency throughout and for 2 weeks after end of study * Staff directly involved in study conduct * Without good peripheral venous access * Positive for: hepatitis B surface antigen, anti-hepatitis B core antibodies, anti-hepatitis C virus antibodies, or anti-human immunodeficiency virus 1/2 antibodies * glucose-6-phosphate dehydrogenase deficiency * Positive urine drug screen or alcohol urine or breath test * Cardiac/QT risk: Known pre-existing prolongation of the QTcB/QTcF interval considered clinically significant. Family history of sudden death or of congenital prolongation of the corrected QT interval interval or known congenital prolongation of the corrected QT interval or any clinical condition known to prolong the corrected QT interval interval. History of symptomatic cardiac arrhythmias or with clinically relevant bradycardia. Electrolyte disturbances, particularly hypokalaemia, hypocalcaemia or hypomagnesaemia. Clinically relevant 12-lead electrocardiogram abnormality at screening or which will interfere with the analysis, or history of clinically significant abnormalities * Known hypersensitivity to MMV390048 or any of its excipients or 4-aminoquinolines, artemether or other artemisinin derivatives, lumefantrine, or other arylaminoalcohols * Unwillingness to abstain from citrus (grapefruit, Seville orange, etc.) or juice, as well as quinine containing foods/beverages for the study period * Lactose intolerance * Unwilling to restrict exposure to direct sunlight during the study. Must use sunglasses and sunblock for the study period
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| MMV390048 Area Under the Plasma Concentration Versus Time Curve (AUClast) up to Day 21 Post-dose | At pre-dose, and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24 (D1), 30, 36, 48 (D2), 72 (D3), and 144 hours (D6) and Days 8, 10, 14, 18 and D21. | Pharmacokinetic-pharmacodynamic relationship of MMV390048 on clearance of Plasmodium falciparum parasites from the blood in healthy participants following infection with blood stage parasites. The area under the plasma concentration time curve from time zero to the last measured time point. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Parasite Reduction Rate (PRR) Following MMV390048 Treatment | From dosing up to Day 21 Post-dose | The clearance of malaria parasitemia by Polymerase Chain Reaction (PCR) measurement. |
| MMV390048 Maximum Plasma Concentration (Cmax) | At pre-dose, and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24 (D1), 30, 36, 48 (D2), 72 (D3), and 144 hours (D6) and Days 8, 10, 14, 18 and D21. | Maximum Plasma Concentration (Cmax) of MMV390048 |
| MMV390048 Time to Maximum Plasma Concentration (Tmax) | From dosing up to Day 21 Post-dose | Time to Maximum Plasma Concentration (Tmax) of MMV390048 |
Countries
Australia
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 MMV390048 20mg Cohort 1 will receive a single, dose of 20mg MMV390048.
MMV390048 20mg: Supplied as a powder to be prepared as a suspension for oral use.
The study was conducted in one cohort (n=6) using a 20 mg dose of MMV390048 Powder In Bottle (PIB). Dose escalation was planned in a subsequent cohort, but due to the inconsistent pharmacokinetic profiles of the PIB formulation it was decided to reformulate the compound before proceeding with the study. | 6 |
| Total | 6 |
Baseline characteristics
| Characteristic | Cohort 1 MMV390048 20mg |
|---|---|
| Age, Continuous | 25.3 years STANDARD_DEVIATION 4.03 |
| Body Mass Index (BMI) | 24.50 kg/m^2 STANDARD_DEVIATION 4.767 |
| 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 | 6 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 6 |
| other Total, other adverse events | 5 / 6 |
| serious Total, serious adverse events | 0 / 6 |
Outcome results
Primary
MMV390048 Area Under the Plasma Concentration Versus Time Curve (AUClast) up to Day 21 Post-dose
Pharmacokinetic-pharmacodynamic relationship of MMV390048 on clearance of Plasmodium falciparum parasites from the blood in healthy participants following infection with blood stage parasites. The area under the plasma concentration time curve from time zero to the last measured time point.
Time frame: At pre-dose, and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24 (D1), 30, 36, 48 (D2), 72 (D3), and 144 hours (D6) and Days 8, 10, 14, 18 and D21.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 MMV390048 20mg | MMV390048 Area Under the Plasma Concentration Versus Time Curve (AUClast) up to Day 21 Post-dose | 9487 ng*hr/mL | Standard Deviation 2444 |
Secondary
MMV390048 Maximum Plasma Concentration (Cmax)
Maximum Plasma Concentration (Cmax) of MMV390048
Time frame: At pre-dose, and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24 (D1), 30, 36, 48 (D2), 72 (D3), and 144 hours (D6) and Days 8, 10, 14, 18 and D21.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 MMV390048 20mg | MMV390048 Maximum Plasma Concentration (Cmax) | 113 ng/mL | Standard Deviation 43.8 |
Secondary
MMV390048 Time to Maximum Plasma Concentration (Tmax)
Time to Maximum Plasma Concentration (Tmax) of MMV390048
Time frame: From dosing up to Day 21 Post-dose
Secondary
Parasite Reduction Rate (PRR) Following MMV390048 Treatment
The clearance of malaria parasitemia by Polymerase Chain Reaction (PCR) measurement.
Time frame: From dosing up to Day 21 Post-dose