Safety, Tolerability, Pharmacokinetics, and Mosquitocidal Activity of Lotilaner in Healthy Participants in Mali.

Study Design and Recruitment

There will be 3 staggered cohorts of 25 participants each ( 75 participants in total). In each cohort, participants will be randomized in a 4:1 ratio, with 20 receiving a single dose of lotilaner and 5 receiving placebo. The next cohort will commence dosing only following a favorable interim review of at least 8 days of safety and tolerability of the previous cohort(s). The IMP will be administered on the morning of Day 1, either while fasting or 30 minutes after a high-fat meal.

Participants will return to the clinical unit for follow-up visits according to the schedule of assessments for approximately 6 months.

Blood samples will be collected at regular intervals for safety assessment, PK analyses, and evaluation of mosquitocidal efficacy.

Mosquitocidal efficacy of collected blood samples from trial participants will be evaluated using mosquito membrane feeding assays.

Inclusion criteria

• Male and female volunteers aged 18-55 years of age (inclusive) at the time of signing the Informed Consent.
• Total body weight (BW) ≥50 kg, and a body mass index (BMI) of 18-32 kg/m2 (inclusive).
• Residence within the study area.
• Judged healthy based on a comprehensive clinical assessment, including a detailed medical history and full physical examination.
• Axillary temperature <37.0ºC without history of fever during the previous week.
• Willingness to adhere to the requirement regarding the use of contraception, as per the study protocol
• Willingness and ability to adhere to study requirements and to participate and communicate for the duration of the trial.
• Agreement to provide current contact details

Exclusion criteria

• Evidence of clinically significant, gastrointestinal, cardiac, lung, hepatic, neurologic, psychiatric, rheumatologic, autoimmune, dermatologic, hematological, oncologic, or renal disease by anamnesis, physical examination, and/or laboratory tests.
• Known Central Nervous System disorders or a history of seizures.
• Any surgery that may affect drug bioavailability (excluding appendectomy and cholecystectomy).
• Signs and symptoms of uncomplicated or severe malaria. An asymptomatic Plasmodium infection is not exclusionary.
• Female who is lactating or pregnant according to the serum pregnancy test at Screening.
• History of significant hypersensitivity to lotilaner (including excipients of the formulations) or any related products.
• History of a severe allergic reaction or anaphylaxis or severe hypersensitivity reactions to any drugs.
• Significant history of drug dependency or alcohol abuse (>3 units of alcohol per day, intake of excessive alcohol, acute or chronic).
• Participants who are current smokers or have used nicotine-containing products within 90 days prior to study treatment administration.
• Severe asthma (defined as asthma that is unstable or required emergent care, urgent care, hospitalization, or intubation during the past two years, or that has required the use of oral or parenteral corticosteroids at any time during the past two years).
• Known asplenia or functional asplenia.
• Known history or evidence of clinically significant cardiovascular abnormalities
• Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) or human immunodeficiency virus (HIV) 1 and 2 antibody results.
• Known diabetes or diabetes identified during screening
• Any serious medical condition or abnormality in clinical laboratory tests that, in the opinion of the investigator, precludes the Participant's safe participation in and completion of the study or affects the ability of the Participant to understand and comply with the study protocol.
• Prior antimalarial therapy or antibiotics with antimalarial activity (prophylaxis or treatment) within four weeks or five half-lives (whichever is longer) before study drug administration.
• Current or recent use of any prohibited medications according to the study protocol
• Pre-planned surgery during the study.
• Intake of lotilaner in the six months before the study drug administration.
• Receipt of any investigational product within the past 30 days or five half-lives (whichever is longer) before screening.
• Use of St. John's wort in the 28 days before study treatment administration and through the duration of the study.
• Participation or planned participation in an interventional trial with an investigational product before the last required protocol visit.
• Treatment with systemic ivermectin within four weeks or five half-lives (whichever is longer) before Screening.
• Any individual who, in the judgment of an Investigator, is likely to be non-compliant during the trial, or is unable to cooperate.
• Any individual who is an Investigator, research assistant, pharmacist, trial coordinator, or other staff thereof, directly involved in conducting the trial.