malaria
Conditions
Interventions
4 to 5 cohorts are planned with different doses. The number of participants
will be 4 to 12 participants per cohort with an active to placebo ratio of 3:1.
This means that of every 4 participants, 3
Sponsors
Merck
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: Age 1. Are between 18 and 45 years of age at the time of signing the informed consent. Type of Participant and Disease Characteristics 2. Are overtly healthy as determined by medical evaluation, including no clinically significant abnormality identified on physical examination or laboratory evaluation and no active clinically significant disorder, condition, infection or disease that would pose a risk to participant safety or interfere with the study evaluation, procedures or completion. Weight 3. Have a body weight within 50 to 100 kg and body mass index within the range 19.0 to 29.9 kg/m2 (inclusive). Sex 4. Are male or female Contraceptive use by males or females will be consistent with local regulations on contraception methods for those participating in clinical studies. * Male Participants: Agree to the following during the study intervention period and for at least 120 days after the day of the study intervention dose (covering a full sperm cycle of 90 days starting after 5 half-lives of last dose of study intervention: * Refrain from donating sperm PLUS, either: * Abstain from intercourse with a woman of childbearing potential OR * Use a male condom: * When having sexual intercourse with a woman of childbearing potential, who is not currently pregnant, and advise her to use a highly effective contraceptive method with a failure rate of < 1% per year, as described in Appendix 3 Contraception, since a condom may break or leak. * Female Participants: * Have a negative serum test at Screening and a highly sensitive urine pregnancy test within 24 hours before the first study intervention (DVI) and within 24 hours before the second study intervention (M5717) administration, as required by local regulations. [If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive]. * Are not pregnant or breastfeeding, and at least one of the following conditions applies: * Not a woman of childbearing potential * At least 1 year post-menopausal (amenorrhea * 12 months and follicle-stimulating hormone (FSH) * 40 mIU/mL) at Screening; * Surgically sterile (bilateral oophorectomy, hysterectomy or bilateral salpingectomy; tubal ligation alone is not sufficient). OR * If a woman of childbearing potential, use a highly effective contraceptive method (i.e., with a failure rate of < 1% per year), preferably with low user dependency, as described in Appendix 3 for the following time periods: * Before the first dose of the study intervention(s), if using hormonal contraception: * Has completed at least one 4-week cycle of an oral contraception pill and either had or has begun her menses OR * Has used a depot contraceptive or extended-cycle oral contraceptive for at least 28 days and has a documented negative pregnancy test using a highly sensitive assay. * During the intervention period * After the study intervention period (i.e., after the last dose of study intervention is administered) for at least 62 days, corresponding to the time needed to eliminate any study intervention(s) (5 times terminal half-live of 155 hours) plus 30 days (a menstrual cycle) after the last dose of study i
Exclusion criteria
Exclusion criteria: Medical Conditions 1. 12-Lead electrocardiogram (ECG) outside normal range (QTcF > 450 ms, PR interval > 215 ms, or QRS > 120 ms) and deemed clinically relevant by the Investigator. 2. Supine systolic blood pressure > 140 or 90 or 90 or 3xULN) (as specified in the Laboratory Manual) the day before DVI / study intervention administration (Day -1). 5. History or presence of diagnosed food or known drug allergies (including but not limited to allergy to any of the antimalarial rescue medications to be used in the study), or history of anaphylaxis or other severe allergic reactions. Note: Participants with seasonal allergies/hay fever, house dust mite allergy, or allergy to animals that are untreated and asymptomatic at the time of dosing can be enrolled in the study. 6. History of a serious psychiatric condition that may affect participation in the study or preclude compliance with the protocol. 7. Any surgical or medical condition possibly affecting drug absorption (e.g. cholecystectomy, gastrectomy, bowel disease), distribution, metabolism or excretion. 8. Any history of gallbladder disease, including cholecystitis and/or cholelithiasis. 9. Any condition that in the opinion of the investigator would jeopardize the safety or rights of a person participating in the study or would render the person unable to comply with the protocol. 10. Frequent headaches of clinical relevance and/or migraine, recurrent nausea, and/or vomiting (> 2 times per month). 11. Ingestion of any poppy seeds within 24 hours prior to each Drug Abuse Screening. 12. Personal history of malaria or medical history of possible exposure to malaria. 13. Presence of acute infectious disease or fever (i.e., sublingual temperature * 38.0°C) within the 5 days prior to DVI with malaria sporozoites. Prior/Concomitant Therapy 14. Use of medications known to interact with atovaquone-proguanil (Malarone) or artemether-lumefantrine (Riamet) such as cimetidine, metoclopramide or antacids, or an anticipated requirement for the use of these at any point during the study period (see also Section 5.1). 15. Use of systemic antibiotics with known antimalarial activity within 30 days (or 5 half-lives whichever is longer) of first study intervention administration (e.g. trimethoprim-sulfamethoxazole, doxycycline, tetracycline, clindamycin, erythromycin, fluoroquinolones or azithromycin) or an anticipated requirement for the use of these during the study period. 16. Use of any prescription drugs, herbal supplements (e.g., St John's Wort) or over-the-counter medication within 7 days or five half-lives (whichever is longer) prior to the first study intervention ad
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Response endpoints: - Number of participants over time with positive parasitemia defined as first positive qPCR outcome equal or greater than 100 asexual parasites per mL of blood within 28 days of PfSPZ challenge - Time to parasitemia, defined as time from PfSPZ DVI to the first qPCR outcome equal or greater than 100 asexual parasites per mL of blood (time frame: number of days from PfSPZ DVI challenge to positive parasitemia, or 28 days) - Number of participants with documented blood stage parasite growth, defined as an increase of qPCR measured asexual parasites per mL compared to the first parasitemia measurement, within 28 days of PfSPZ DVI - Clinical symptoms of malaria using the Malaria Clinical Score. Dose-exposure-response relationship: - Selected pharmacokinetic (PK) endpoints/concentrations (e.g. AUC0-24, AUC0-144, C24, C144) and pharmacodynamic (PD) endpoints (cured/not-cured) will be used for PK/PD modeling approaches. | — |
Secondary
| Measure | Time frame |
|---|---|
| - Nature, incidence, frequency, severity of adverse events (AEs)/ serious adverse events (SAEs), and relationship to the study intervention - Incidence of clinically significant changes and abnormalities in safety laboratory parameters (hematology, coagulation, biochemistry [specifically alanine aminotransferase (ALT) and aspartate aminotransferase (AST), alkaline phosphatase (ALP), bilirubin (total)], and urinalysis) - Incidence of clinically significant changes and abnormalities in vital signs and 12 lead electrocardiogram (ECG). Exposure endpoints: - Concentration-time curve for M5717 after single-dose administration - Pharmacokinetic parameters of M5717 such as AUC0-*, AUC0-t, AUC0-24, AUC0-144, Cmax, C24, C144, tmax, t1/2, *Z, CL/f and Vz/f to be specified in the Integrated Analysis Plan. | — |
Countries
Netherlands
Outcome results
None listed