Effect of a Single Oral Dose of Moxidectin on the Cardiac QT Interval of Healthy Volunteers

Study Overview
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Brief Summary
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This study will investigate the effect of a single oral dose of moxidectin on the QT interval associated with moxidectin plasma concentrations. The effect of moxidectin on other ECG intervals, and on safety, will also be assessed, as will preliminary pharmacokinetics and metabolism

Detailed Description
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Moxidectin is being developed as a treatment for Onchocerciasis (river blindness), a serious, debilitating, disease caused by a parasitic worm, Onchocerca volvulus. Five dose levels of moxidectin will be administered to healthy volunteers and ECG assessments undertaken at pre-specified pharmacokinetic time points to correlate QT interval with moxidectin concentration in plasma.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Potential Effect of a Single Oral Dose of Moxidectin on the Cardiac QT Interval of Healthy Volunteers

Conditions
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QT Effects in Healthy Volunteers

Intervention / Treatment
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* Drug: Moxidectin
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male between 18 and 50 years of age (inclusive); Body mass index (BMI) of 18 to 30 kg/m2 (inclusive) and a minimum weight of 50 kg (110 lbs); Biologically or surgically sterile or must commit to using a reliable method of birth control, in the opinion of the investigator, from Screening through the duration of the study; Willing and able to give written informed consent. Exclusion Criteria: Unwilling to abstain from alcohol, caffeine, xanthine containing products, Seville oranges, grapefruit juices, and fish liver oils within 72 hours before Check in (Day -1) and throughout the inpatient period of the study; Less than 1 bowel movement every 24 hours in the absence of any laxative, suppository, or enema use during the month before Screening; Abnormal fecal consistency within 24 hours of Check in (Day -1); Clinically relevant abnormal findings on medical history, clinical laboratory test results, vital sign measurements, safety 12 lead ECG results, or physical examination at Screening or Baseline which, in the opinion of the investigator, would interfere with dosing, jeopardize the safety of the subject, or impact the validity of the study results; History of clinically significant dermatologic, gastrointestinal, renal, hepatic, neurologic, hematologic, endocrine, oncologic, pulmonary, immunologic, psychiatric, or cardiovascular disease or any other condition which, in the opinion of the investigator, would interfere with dosing, jeopardizes the safety of the subject, or impacts the validity of the study results; History or hypersensitivity or allergic reactions to ivermectin, moxidectin, or any of the ingredients in the study drug as described in the Investigator's Brochure; Any condition that may affect oral drug absorption (eg, previous surgery on the gastrointestinal tract including removal of parts of the stomach, bowel, liver, gall bladder, or pancreas); History of risk factors for torsades de pointes, including unexplained syncope, known long QT syndrome, heart failure, myocardial infarction, angina, or clinically significant abnormal laboratory assessments including hypokalemia, hypercalcemia, or hypomagnesemia. Subjects are also excluded if there is a family history of long QT syndrome or Brugada syndrome; A sustained supine systolic blood pressure >150 mm Hg or <90 mm Hg or a supine diastolic blood pressure >95 mm Hg or <50 mm Hg at Screening or Check in (Day -1). Blood pressure may be retested twice in the supine position. The blood pressure abnormality is considered sustained if either the systolic or the diastolic blood pressure values are outside of the stated limits after 3 assessments, and the subject will not to be randomized; A resting heart rate (HR) of <40 beats per minute (bpm) or >100 bpm when vital signs are measured at Screening or Check in (Day -1); An uninterpretable or abnormal screening ECG indicating a second or third degree atrioventricular block, or 1 or more of the following: QRS interval >110 milliseconds (msec); QT interval corrected by Fridericia's formula (QTcF) >450 msec; PR interval >200 msec; or any rhythm other than sinus rhythm that is interpreted by the investigator to be clinically significant; Concomitant use of prescription medications, including medications known to prolong the corrected QT interval (QTc) or herbal preparations, within 14 days or 5 half-lives (whichever is longer) before study drug dosing, or use of an over the counter (OTC) medication or vitamins within 7 days before study drug dosing; Received an investigational drug during the 30 days, or 5 half lives of the study drug (whichever is longer), before Check in (Day -1) or is planning to receive another investigational drug at any time during the study; History or presence of alcohol abuse (defined as consumption of more than 210 mL of alcohol per week, or the equivalent of fourteen 4 ounce [oz] glasses of wine or fourteen 12 oz cans/bottles of beer or wine coolers per week) within 6 months before Screening or positive alcohol test at Screening or Check-in (Day -1); History or presence of substance abuse within the past 2 years or positive drug screen test at Screening or Check in (Day -1); Current use or has used tobacco- or nicotine-containing products (eg, cigarettes, cigars, chewing tobacco, snuff, etc.) within 14 days before study drug dosing; Blood donation or significant blood loss within 30 days before Check-in (Day -1) or donated plasma within 7 days before Check-in (Day -1); Presence of hepatitis B surface antigen or antibodies to human immunodeficiency virus (HIV) or hepatitis C virus at Screening; Poor venous access in both arms; Unable to understand verbal or written English or any other language for which a certified translation of the informed consent form is available; For any reason, is deemed by the investigator or medically qualified designee to be inappropriate for this study, including a subject who is unable to communicate or cooperate with the investigator, and/or is unwilling to comply with protocol defined procedures and complete the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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Male

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Moxidectin 4mg<br>10 subjects will receive a single oral dose of moxidectin 4mg | Drug: Moxidectin<br>* Moxidectin is a broad spectrum macrocyclic lactone endectocide<br>|
| Experimental: Moxidectin 8mg<br>10 subjects will receive a single oral dose of moxidectin 8mg | Drug: Moxidectin<br>* Moxidectin is a broad spectrum macrocyclic lactone endectocide<br>|
| Experimental: Moxidectin 16mg<br>10 subjects will receive a single oral dose of moxidectin 16mg | Drug: Moxidectin<br>* Moxidectin is a broad spectrum macrocyclic lactone endectocide<br>|
| Experimental: Moxidectin 24mg<br>10 subjects will receive a single oral dose of moxidectin 24mg | Drug: Moxidectin<br>* Moxidectin is a broad spectrum macrocyclic lactone endectocide<br>|
| Experimental: Moxidectin 36mg<br>10 subjects will receive a single oral dose of moxidectin 36mg | Drug: Moxidectin<br>* Moxidectin is a broad spectrum macrocyclic lactone endectocide<br>|
| Placebo Comparator: Placebo<br>10 subjects will receive a single oral dose of placebo | Other: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in QTc Interval (Corrected by Friderica's Formula, dQTcF) Associated With Plasma Moxidectin Concentrations After a Single Dose | Triplicate 10-second ECG recordings taken 1 minute apart using a Mortara continuous 12-lead digital ECG recorder connected to each subject during the Baseline to 72-hour post dose confinement period. Baseline only and baseline and placebo adjusted changes in QTc interval (corrected using the Friderica formula, QTcF) at each timepoint for each dose level were determined. The mean change from baseline (without and with placebo correction, dQTcF and ddQTcF respectively) at each of the 14 time points was calculated for each dose level. The primary outcome measure was the mean dQTcF for all subjects(the dQTcF gradient). The mean dQTcF for each active treatment group was determined at each post dose timepoint but the mean dQTcF by dose level was not calculated. The mean dQTcF at approximate moxidectin Tmax (hour 3 or hour 4) for each active treatment group and at hour 3 for the placebo group is reported. | Baseline (pre-dose) and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 60, and 72 hours post dosing | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Concentrations of Moxidectin in Plasma | Concentrations of moxidectin in plasma were assessed by collection of plasma samples at pre-specified intervals after oral dosing with moxidectin. The concentration of moxidectin was determined using a validated LC MS/MS method.The pharmacokinetic time points coincided with ECG collection timepoints (within 5 minutes and no later than 10 minutes after ECG recordings). Plasma PK parameters were estimated from the concentration measurements, including maximum concentration (Cmax) for each individual and mean for each dose cohort. | Pre-dose and at 0.5, 1, 2, 3, 4, 5, 6, 8, 12*, 24, 36, 48, 60, and 72 hours and days 8,15 and 22 post dosing |