A Pharmacokinetic Study of TP-05 in Healthy Subjects

Study Overview
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Brief Summary
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A Phase 1, Randomized, Double-Blind, Single- and Multiple-Ascending Dose Study Evaluating the Safety, Tolerability, Food-Effect and Pharmacokinetics of TP-05 in Healthy Subjects

Detailed Description
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This Phase 1 study is a randomized, double-blind, single- and multiple-ascending dose trial to evaluate the safety, tolerability, food-effect, and pharmacokinetics of TP-05 in healthy subjects. Subjects will be enrolled in 5 sequential, ascending single dose cohorts and 3 multiple, ascending dose cohorts. Dose escalation will be approved by a safety monitoring committee before beginning the next cohort. The Safety Review Committee (SRC) will evaluate if any dose-limiting adverse events (AEs) through Day 15 (in Cohorts 1-5) or through Day 36 (in Cohorts 6-8) occurred in a cohort before proceeding to dosing in the next dose level. In addition, the SRC will review selected PK parameters after selected cohorts. Skin punch biopsies, and venous, capillary, and urine samples may be collected at various timepoints for pharmacokinetic analysis. Safety assessments include monitoring of adverse events, clinical laboratory testing, vital sign measurements, physical examinations, and ECGs. A blood sample may also be collected to evaluate tick mortality upon exposure.

Official Title
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A Phase 1, Randomized, Double-Blind, Single- and Multiple-Ascending-Dose Study Evaluating the Safety, Tolerability, Food-Effect and Pharmacokinetics of TP-05 in Healthy Subjects

Conditions
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Healthy

Intervention / Treatment
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* Drug: TP-05 (lotilaner oral capsules)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of signed and dated informed consent form (ICF) Have no clinically significant diseases captured in the medical history or evidence of clinically significant findings on the physical examination (including vital signs) and/or ECG, as determined by an investigator Exclusion Criteria: Female who is pregnant or lactating Presence or history of significant gastrointestinal, metabolic, liver or kidney disease, or surgery that may affect drug bioavailability (excluding appendectomy and cholecystectomy) History of significant cardiovascular, pulmonary, hematologic, neurological, psychiatric, endocrine, immunologic, or dermatologic disease Have a history of a malignancy (or active malignancy), with the exception of treated basal cell or squamous cell carcinoma Use of any prescription drugs (with the exception of hormonal contraceptives or hormone replacement therapy) within 14 days prior to or use of any over-the-counter drugs in the 7 days prior to the first study drug administration Positive urine alcohol test result and/or drugs of abuse at Screening or prior to the first drug administration (including cotinine, cannabinoids, amphetamines, barbiturates, cocaine, opiates, phencyclidine and benzodiazepines) Positive test results for HIV-1/HIV-2 Antibodies, Hepatitis B surface Antigen (HBsAg) or Hepatitis C Antibody (HCVAb) Treatment with an investigational drug within 30 days or 5 times the half-life (whichever is longer) prior to Screening Blood donation (excluding plasma donation) of approximately 500 mL within 56 days prior to Screening Plasma donation within 7 days prior to screening

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 59 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Part 1: a randomized, double-blind, single ascending dose (SAD) with Cohort 1-4 administered on a full stomach and Cohort 5 administered after a period of fasting Part 2: a randomized, double-blind, multiple ascending dose (MAD) escalation with Cohort 6-8 administered on a full stomach.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TP-05 SAD<br>Single dose of TP-05 (lotilaner oral capsules) at 4 dose levels in ascending order | Drug: TP-05 (lotilaner oral capsules)<br>* TP-05 (lotilaner oral capsules)<br>|
| Experimental: Placebo SAD<br>Single dose of Placebo | Drug: Placebo<br>* Placebo to match TP-05 (lotilaner oral capsules)<br>|
| Experimental: TP-05 MAD<br>Four doses of TP-05 (lotilaner oral capsules) at 3 dose levels in ascending order | Drug: TP-05 (lotilaner oral capsules)<br>* TP-05 (lotilaner oral capsules)<br>|
| Experimental: Placebo MAD<br>Four doses of Placebo | Drug: Placebo<br>* Placebo to match TP-05 (lotilaner oral capsules)<br>|
| Experimental: TP-05 Fasted<br>Single dose of TP-05 (lotilaner oral capsules) in a fasted state | Drug: TP-05 (lotilaner oral capsules)<br>* TP-05 (lotilaner oral capsules)<br>|
| Experimental: Placebo Fasted<br>Single dose of placebo in a fasted state | Drug: Placebo<br>* Placebo to match TP-05 (lotilaner oral capsules)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment emergent adverse events (TEAEs) | Evaluate the safety of TP-05 through the incidence rate of TEAEs | up to 151 days | 
| Clinically significant changes from Baseline chemistry laboratory tests | Evaluate the safety of TP-05 through clinically significant changes from Baseline chemistry laboratory tests | up to 151 days | 
| Clinically significant changes from Baseline hematology laboratory tests | Evaluate the safety of TP-05 through clinically significant changes from Baseline hematology laboratory tests | up to 151 days | 
| Clinically significant changes from Baseline general appearance | Evaluate the safety of TP-05 through clinically significant changes from Baseline general appearance | up to 151 days | 
| Clinically significant changes from Baseline physical examination of head, ears, nose, and throat | Evaluate the safety of TP-05 through clinically significant changes from Baseline physical examinations of head, ears, nose, and throat | up to 151 days | 
| Clinically significant changes from Baseline physical examination of neck (thyroid) | Evaluate the safety of TP-05 through clinically significant changes from Baseline physical examinations of neck (thyroid) | up to 151 days | 
| Clinically significant changes from Baseline physical examination of respiratory system | Evaluate the safety of TP-05 through clinically significant changes from Baseline physical examinations of respiratory system | up to 151 days | 
| Clinically significant changes from Baseline physical examination of cardiovascular system | Evaluate the safety of TP-05 through clinically significant changes from Baseline physical examinations of cardiovascular system | up to 151 days | 
| Clinically significant changes from Baseline physical examination of gastrointestinal system | Evaluate the safety of TP-05 through clinically significant changes from Baseline physical examinations of gastrointestinal system | up to 151 days | 
| Clinically significant changes from Baseline physical examination of neurological system | Evaluate the safety of TP-05 through clinically significant changes from Baseline physical examinations of neurological system | up to 151 days | 
| Clinically significant changes from Baseline physical examination of musculoskeletal system (extremities) | Evaluate the safety of TP-05 through clinically significant changes from Baseline physical examination of musculoskeletal system (extremities) | up to 151 days | 
| Clinically significant changes from Baseline physical examination of skin | Evaluate the safety of TP-05 through clinically significant changes from Baseline physical examination of skin | up to 151 days | 
| Clinically significant changes from Baseline vital signs | Evaluate the safety of TP-05 through clinically significant changes from Baseline vital signs (including temperature [degrees Celsius], pulse rate [beats per minute], respiration rate [breaths per minute], and changes in systolic and diastolic blood pressure [mmHg]) | up to 151 days | 
| Clinically significant changes from Baseline vital signs (temperature [degrees Celsius]) | Evaluate the safety of TP-05 through clinically significant changes from Baseline vital signs including temperature [degrees Celsius] | up to 151 days | 
| Clinically significant changes from Baseline vital signs (pulse rate [beats per minute]) | Evaluate the safety of TP-05 through clinically significant changes from Baseline vital signs including pulse rate [beats per minute] | up to 151 days | 
| Clinically significant changes from Baseline vital signs (respiration rate [breaths per minute]) | Evaluate the safety of TP-05 through clinically significant changes from Baseline vital signs including respiration rate [breaths per minute] | up to 151 days | 
| Clinically significant changes from Baseline vital signs (systolic and diastolic blood pressure [mmHg]) | Evaluate the safety of TP-05 through clinically significant changes from Baseline vital signs including changes in systolic and diastolic blood pressure [mmHg]) | up to 151 days | 
| Clinically significant changes from Baseline electrocardiograms (ECGs) | Evaluate the safety of TP-05 through clinically significant changes from Baseline ECGs (including changes in mean ventricular rate [beats/min], pulse rate [msec], QRS duration [msec], QT interval [msec], QTcF interval [msec]) | up to 151 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Exposure and PK of lotilaner in whole blood | PK parameters for whole blood sampling methods following dose administration will be evaluated and include Cmax at various times | up to 151 days | 
| Exposure and PK of lotilaner in whole blood | PK parameters for whole blood sampling methods following dose administration will be evaluated and include Tmax at various times | up to 151 days | 
| Exposure and PK of lotilaner in whole blood | PK parameters for whole blood sampling methods following dose administration will be evaluated and include Tlag at various times | up to 151 days | 
| Exposure and PK of lotilaner in whole blood | PK parameters for whole blood sampling methods following dose administration will be evaluated and include AUC0-168 at various times | up to 151 days | 
| Exposure and PK of lotilaner in whole blood | PK parameters for whole blood sampling methods following dose administration will be evaluated and include AUC0-2880 at various times | up to 151 days | 
| Exposure and PK of lotilaner in whole blood | PK parameters for whole blood sampling methods following dose administration will be evaluated and include AUC0-t at various times | up to 151 days | 
| Exposure and PK of lotilaner in whole blood | PK parameters for whole blood sampling methods following dose administration will be evaluated and include AUC0-inf at various times | up to 151 days | 
| Exposure and PK of lotilaner in whole blood | PK parameters for whole blood sampling methods following dose administration will be evaluated and include CL/F at various times | up to 151 days | 
| Exposure and PK of lotilaner in whole blood | PK parameters for whole blood sampling methods following dose administration will be evaluated and include Vz/F at various times | up to 151 days | 
| Exposure and PK of lotilaner in whole blood | PK parameters for whole blood sampling methods following dose administration will be evaluated and include eff at various times | up to 151 days | 
| Exposure and PK of lotilaner in whole blood | PK parameters for whole blood sampling methods following dose administration will be evaluated and include Thalf at various times | up to 151 days | 
| Exposure and PK of lotilaner in whole blood | PK parameters for whole blood sampling methods following dose administration will be evaluated and include λz at various times | up to 151 days | 
| Exposure and PK of lotilaner in whole blood | PK parameters for whole blood sampling methods following dose administration will be evaluated and include AUC%extrap at various times | up to 151 days | 
| Exposure and PK of lotilaner in whole blood | PK parameters for whole blood sampling methods following dose administration will be evaluated and include MRT0-t at various times | up to 151 days | 
| Exposure and PK of lotilaner in whole blood | PK parameters for whole blood sampling methods following dose administration will be evaluated and include Rac at various times | up to 151 days | 
| Exposure and PK of lotilaner in whole blood | PK parameters for whole blood sampling methods following dose administration will be evaluated and include Ctrough at various times | up to 151 days | 
| Urine exposure and renal PK of lotilaner | PK parameters for urine sampling methods will be evaluated and include Ae. | 3 days | 
| Urine exposure and renal PK of lotilaner | PK parameters for urine sampling methods will be evaluated and include fe. | 3 days | 
| Urine exposure and renal PK of lotilaner | PK parameters for urine sampling methods will be evaluated and include CLr0-48. | 3 days | 
| Impact of fasting on the PK of lotilaner | PK parameters will be evaluated for lotilaner following dosing with food and under fasting conditions. Parameters include Cmax at various times | up to 151 days | 
| Impact of fasting on the PK of lotilaner | PK parameters will be evaluated for lotilaner following dosing with food and under fasting conditions. Parameters include Tmax at various times | up to 151 days | 
| Impact of fasting on the PK of lotilaner | PK parameters will be evaluated for lotilaner following dosing with food and under fasting conditions. Parameters include Tlag at various times | up to 151 days | 
| Impact of fasting on the PK of lotilaner | PK parameters will be evaluated for lotilaner following dosing with food and under fasting conditions. Parameters include AUC0-168 at various times | up to 151 days | 
| Impact of fasting on the PK of lotilaner | PK parameters will be evaluated for lotilaner following dosing with food and under fasting conditions. Parameters include AUC0-2880 at various times | up to 151 days | 
| Impact of fasting on the PK of lotilaner | PK parameters will be evaluated for lotilaner following dosing with food and under fasting conditions. Parameters include AUC0-t at various times | up to 151 days | 
| Impact of fasting on the PK of lotilaner | PK parameters will be evaluated for lotilaner following dosing with food and under fasting conditions. Parameters include AUC0-inf at various times | up to 151 days | 
| Impact of fasting on the PK of lotilaner | PK parameters will be evaluated for lotilaner following dosing with food and under fasting conditions. Parameters include CL/F at various times | up to 151 days | 
| Impact of fasting on the PK of lotilaner | PK parameters will be evaluated for lotilaner following dosing with food and under fasting conditions. Parameters include Vz/F at various times | up to 151 days | 
| Impact of fasting on the PK of lotilaner | PK parameters will be evaluated for lotilaner following dosing with food and under fasting conditions. Parameters include Thalf at various times | up to 151 days | 
| Impact of fasting on the PK of lotilaner | PK parameters will be evaluated for lotilaner following dosing with food and under fasting conditions. Parameters include λz at various times | up to 151 days | 
| Impact of fasting on the PK of lotilaner | PK parameters will be evaluated for lotilaner following dosing with food and under fasting conditions. Parameters include AUC%extrap at various times | up to 151 days | 
| Impact of fasting on the PK of lotilaner | PK parameters will be evaluated for lotilaner following dosing with food and under fasting conditions. Parameters include MRT0-t at various times | up to 151 days | 
| Impact of fasting on the PK of lotilaner | PK parameters will be evaluated for lotilaner following dosing with food and under fasting conditions. Parameters include Rac at various times | up to 151 days | 
| Impact of fasting on the PK of lotilaner | PK parameters will be evaluated for lotilaner following dosing with food and under fasting conditions. Parameters include Ctrough at various times | up to 151 days |