Malaria Infection
Conditions
Keywords
Plasmodium falciparum, Chemoprevention, Malaria, Plasmodium eukaryotic translation elongation factor 2 (PeEF2), Exposure response, Adults, Adolescents, Asymptomatic Infection
Brief summary
This study evaluates the efficacy and safety of a single dose of M5717 plus pyronaridine tetraphosphate in clearing current Plasmodium falciparum infection and protecting against recurrent infections in asymptomatic adults and adolescents. The study will also assess the duration of protection provided by different doses of M5717 plus pyronaridine and the additional contribution of M5717 to the duration of protection using external study data.
Interventions
DRUGM5717 60 mg
Participants received single oral dose (Capsules) of 60 mg M5717 on Day 1 under fasting condition
DRUGPyronaridine
Participants received Pyronaridine tablets orally single dose of 720 (Participants \>= 65 kg) and 540 mg (Participants \>= 45 to \< 65 kg) on Study Day 1 under fasting condition
Participants received Atovaquone-Proguanil tablets 1000/400 mg once daily in a 3-day treatment regimen.
DRUGM5717 200 mg
Participants received single oral dose (Capsules) of 200 mg M5717 on Day 1 under fasting condition
DRUGM5717 660mg
Participants received single oral dose (Capsules) of 660 mg M5717 on Day 1 under fasting condition
Sponsors
Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Open Label
Eligibility
Sex/Gender
ALL
Age
12 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
* Participants with Asymptomatic Plasmodium falciparum Malaria with no Fever or other sign of Acute Uncomplicated Malaria and, with Microscopic confirmation using Giemsa-stained thick film, and a Parasitemia of \>= 40 to \<= 10,000 Asexual Parasites/Microliter (μL) of Blood. * Axillary Temperature \< 37.0 degree Celcius (ºC) or oral/Tympanic/rectal Temperature\< 37.5ºC; without history of fever during the previous 48 hours. * Have a body weight \>= 45 kilogram (kg) * Participants capable of giving Signed Informed consent which includes Compliance with the requirements and restriction listed in the Informed consent form * Other Protocol defined Inclusion Criteria could apply
Exclusion criteria
* Participants with any disease requiring Chronic Treatment * Participants with any Preplanned surgery during the study * Participants with any previous Treatment with pyronaridine as part of a combination therapy during the last 3 months * Participants with any adequate Hematological, Hepatic, and renal function as defined in the Protocol * Other protocol defined
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Parasitemia Since Negative Blood Smear After Treatment | From treatment Day 1 up to End of observation period Day 64 (Week 10) | The time (in days) to first recorded parasitemia (parasite count \>0) since the first negative blood smear (parasite count of 0) after treatment (followed at least by 1 subsequent visit with a negative blood film), i.e. the time without a positive blood smear. Median time and 95% CI was estimated using the Kaplan Meier method for each cohort. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Parasitemia (Positive Blood Smear) | From treatment Day 1 up to End of observation period Day 64 (Week 10) | Percentage of participants with a positive blood smear (parasitemia) was reported. Parasitemia is the presence of parasites in blood (parasite count \>0). |
| Percentage of Participants With Polymerase Chain Reaction (PCR)-Adjusted Parasitemia (Due to New Infections) | From treatment Day 1 up to End of observation period Day 64 (Week 10) | Percentage of participants with polymerase chain reaction (PCR)-adjusted Parasitemia (Thick Smear/Microscopy, after Adjustment for Parasitemia due to new Infections as determined by Genotyping using PCR Techniques) was reported. |
| Percentage of Participants With PCR-adjusted Parasitemia (Due to Recrudescence) | From treatment Day 1 up to End of observation period Day 64 (Week 10) | Percentage of participants with polymerase chain reaction (PCR)-adjusted Parasitemia (Thick Smear/Microscopy, after Adjustment for Parasitemia due to Recrudescence as determined by Genotyping using PCR Techniques) was reported. |
| Parasite Clearance Time | Time from dosing to the first negative (no parasites) blood film (microscopy) , assessed up to 12 weeks | Parasite clearance time defined as time from dosing to the first negative (no parasites) blood film (microscopy). Median parasite clearance time was estimated by Kaplan-Meier method |
| Number of Participants With Treatment-Emergent Adverse Events (TEAE), Serious TEAEs and Treatment Related TEAEs | Up to End of Study (approximately 12 Weeks) | An adverse event (AE) was defined as any untoward medical occurrence in a participant administered with study drug which does not necessarily had a causal relationship with the treatment. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a medicinal product, whether or not considered related to the medicinal product. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAE was defined as AEs starting or worsening after the first intake of the study drug. TEAEs included both serious TEAEs and non-serious TEAEs. Treatment-related TEAEs: reasonably related to study intervention. |
| Area Under the Blood Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M5717 and Pyronaridine | Predose, 1, 2, 4, 6, 8, and 12 hours on Day 1 and 24 hours on Day 2 | AUC0-inf was calculated by combining AUC0-t and AUCextra. AUC extra represents an extrapolated value obtained by Clast/ λz, where Clast is the calculated blood concentration at the last sampling time point at which the measured blood concentration is at or above the Lower Limit of quantification (LLQ) and λz is the apparent terminal rate constant determined by log-linear regression analysis of the measured blood concentrations of the terminal log-linear phase. |
| Area Under the Blood Concentration-Time Curve From Time Zero to 24 Hours Post-dose (AUC 0-24) of M5717 and Pyronaridine | Predose, 1, 2, 4, 6, 8, and 12 hours on Day 1 and 24 hours on Day 2 | AUC from time zero to 24 hours post dose, calculated using the mixed log linear trapezoidal rule (linear up, log down) using the nominal dosing interval. |
| Area Under the Blood Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC 0-tlast) of M5717 and Pyronaridine | Predose, 1, 2, 4, 6, 8, and 12 hours on Day 1 and 24 hours on Day 2 | Area under the blood concentration vs time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLQQ). AUC0-t was to be calculated according to the mixed log-linear trapezoidal rule. |
| Apparent Total Body Clearance From Blood (CL/f) of M5717 and Pyronaridine | Predose, 1, 2, 4, 6, 8, and 12 hours on Day 1 and 24 hours on Day 2 | Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Apparent body clearance of the drug from blood, CL= Dose/AUC0-inf. |
| Maximum Observed Blood Concentration (Cmax) of M5717 and Pyronaridine | Predose, 1, 2, 4, 6, 8, and 12 hours on Day 1 and 24 hours on Day 2 | Cmax was obtained directly from the concentration versus time curve. |
| Apparent Terminal Half-life (t1/2) of M5717 and Pyronaridine | Predose, 1, 2, 4, 6, 8, and 12 hours on Day 1 and 24 hours on Day 2 | Terminal half-life is the time measured for the concentration to decrease by one half. Terminal half-life calculated by natural log 2 divided by lambda z. |
| Time to Reach the Maximum Blood Concentration (Tmax) of M5717 and Pyronaridine | Predose, 1, 2, 4, 6, 8, and 12 hours on Day 1 and 24 hours on Day 2 | Time to reach the maximum blood concentration (Tmax) was obtained directly from the concentration versus time curve. |
| Apparent Volume of Distribution (Vz/F) During the Terminal Phase of M5717 and Pyronaridine | Predose, 1, 2, 4, 6, 8, and 12 hours on Day 1 and 24 hours on Day 2 | The Vz/f was defined as the theoretical volume in which the total amount of required to uniformly distribute to produce the desired plasma concentration. Apparent volume of distribution after oral dose (Vz/F) was influenced by the fraction absorbed. The Vz/f was calculated by dividing the dose with area under the concentration time curve from time zero to infinity multiplied with terminal elimination rate constant Lambda(z). Vz/f=Dose/AUC(0-inf) multiply Lambda(z). |
Countries
Burkina Faso, Kenya, The Gambia, Zambia
Contacts
STUDY_DIRECTORMedical Responsible
Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 25 Years STANDARD_DEVIATION 9.5 |
| Race/Ethnicity, Customized Ethnicity-Hispanic or Latino | 6 Participants |
| Race/Ethnicity, Customized Ethnicity-Not Hispanic or Latino | 48 Participants |
| Race/Ethnicity, Customized Ethnicity-Not Reported | 1 Participants |
| Race/Ethnicity, Customized Race-Black or African American | 47 Participants |
| Sex: Female, Male Female | 19 Participants |
| Sex: Female, Male Male | 28 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 | 0 / 49 | 0 / 47 | 0 / 48 | 0 / 48 |
| other Total, other adverse events | 31 / 49 | 27 / 47 | 31 / 48 | 28 / 48 |
| serious Total, serious adverse events | 0 / 49 | 1 / 47 | 0 / 48 | 0 / 48 |
Outcome results
None listed