QT Effects in Healthy Volunteers
Conditions
Brief summary
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
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.
Interventions
DRUGMoxidectin
Moxidectin is a broad spectrum macrocyclic lactone endectocide
OTHERPlacebo
Sponsors
Medicines Development for Global Health
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
1. Healthy male between 18 and 50 years of age (inclusive); 2. Body mass index (BMI) of 18 to 30 kg/m2 (inclusive) and a minimum weight of 50 kg (110 lbs); 3. 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; 4. Willing and able to give written informed consent.
Exclusion criteria
1. 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; 2. Less than 1 bowel movement every 24 hours in the absence of any laxative, suppository, or enema use during the month before Screening; 3. Abnormal fecal consistency within 24 hours of Check in (Day -1); 4. 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; 5. 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; 6. 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; 7. 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); 8. 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; 9. 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; 10. 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); 11. 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; 12. 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; 13. 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; 14. 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); 15. History or presence of substance abuse within the past 2 years or positive drug screen test at Screening or Check in (Day -1); 16. Current use or has used tobacco- or nicotine-containing products (eg, cigarettes, cigars, chewing tobacco, snuff, etc.) within 14 days before study drug dosing; 17. 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); 18. Presence of hepatitis B surface antigen or antibodies to human immunodeficiency virus (HIV) or hepatitis C virus at Screening; 19. Poor venous access in both arms; 20. Unable to understand verbal or written English or any other language for which a certified translation of the informed consent form is available; 21. 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in QTc Interval (Corrected by Friderica's Formula, dQTcF) Associated With Plasma Moxidectin Concentrations After a Single Dose | Baseline (pre-dose) and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 60, and 72 hours post dosing | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Concentrations of Moxidectin in Plasma | 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 | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Subjects With Categorical Changes From Baseline in 12-lead Electrocardiograms (ECGs) | At Baseline and Days 1, 2, 3, 4, 22 and Week 12 | Changes from baseline in QTcF exceeding regulatory standard categorical limits (\> 30msec change or exceeding 450msec). Report applies to changes of 30msec - \</= 60msec only |
| Change From Baseline in Heart Rate (HR) and Duration of Other Interval Parameters (PR and QRS) | Baseline (pre-dose) and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 60, and 72 hours post dosing | Changes from Baseline were assessed at each timepoint up to 72 hours post dose. Mean changes across the 72 hour assessment period for each parameter were calculated for each moxidectin group and the placebo group and for the population overall. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Moxidectin 4mg 10 subjects will receive a single oral dose of moxidectin 4mg
Moxidectin | 10 |
| Moxidectin 8mg 10 subjects will receive a single oral dose of moxidectin 8mg
Moxidectin | 10 |
| Moxidectin 16mg 10 subjects will receive a single oral dose of moxidectin 16mg
Moxidectin | 10 |
| Moxidectin 24mg 10 subjects will receive a single oral dose of moxidectin 24mg
Moxidectin | 10 |
| Moxidectin 36mg 10 subjects will receive a single oral dose of moxidectin 36mg
Moxidectin | 10 |
| Placebo 10 subjects will receive a single oral dose of placebo
Placebo | 10 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Delay to last visit would delay DBL | 0 | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Lost to Follow-up | 1 | 0 | 1 | 0 | 1 | 0 |
| Overall Study | Non-compliance with protocol | 0 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Moxidectin 4mg | Moxidectin 8mg | Moxidectin 16mg | Moxidectin 24mg | Moxidectin 36mg | Placebo | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 37.1 years STANDARD_DEVIATION 7.77 | 30.4 years STANDARD_DEVIATION 8.73 | 30.9 years STANDARD_DEVIATION 8.32 | 31.2 years STANDARD_DEVIATION 8.27 | 30.2 years STANDARD_DEVIATION 8.87 | 32.3 years STANDARD_DEVIATION 6.72 | 32.0 years STANDARD_DEVIATION 8.15 |
| Body Mass Index (BMI) | 26.2 kilogram /meter squared (kg/m2) STANDARD_DEVIATION 3.74 | 24.9 kilogram /meter squared (kg/m2) STANDARD_DEVIATION 3.35 | 25.8 kilogram /meter squared (kg/m2) STANDARD_DEVIATION 3.71 | 25.1 kilogram /meter squared (kg/m2) STANDARD_DEVIATION 3 | 26.7 kilogram /meter squared (kg/m2) STANDARD_DEVIATION 3.09 | 26.1 kilogram /meter squared (kg/m2) STANDARD_DEVIATION 3.11 | 25.8 kilogram /meter squared (kg/m2) STANDARD_DEVIATION 3.26 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 2 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 8 Participants | 9 Participants | 9 Participants | 10 Participants | 10 Participants | 54 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 7 Participants | 4 Participants | 5 Participants | 5 Participants | 5 Participants | 29 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 7 Participants | 3 Participants | 5 Participants | 4 Participants | 3 Participants | 5 Participants | 27 Participants |
| Region of Enrollment United States | 10 participants | 10 participants | 10 participants | 10 participants | 10 participants | 10 participants | 60 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 10 Participants | 10 Participants | 10 Participants | 10 Participants | 10 Participants | 10 Participants | 60 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 10 | 0 / 10 | 0 / 10 | 0 / 10 | 0 / 10 |
| other Total, other adverse events | 3 / 10 | 3 / 10 | 1 / 10 | 0 / 10 | 3 / 10 | 1 / 10 |
| serious Total, serious adverse events | 0 / 10 | 0 / 10 | 0 / 10 | 0 / 10 | 0 / 10 | 0 / 10 |
Outcome results
Primary
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.
Time frame: Baseline (pre-dose) and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 60, and 72 hours post dosing
Population: The ECG population included all subjects who received one dose of study drug and have at least 1 pair of pre-dose and post-dose QTc interval and was used in the model.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Moxidectin 4mg | Mean Change From Baseline in QTc Interval (Corrected by Friderica's Formula, dQTcF) Associated With Plasma Moxidectin Concentrations After a Single Dose | -5.1 millseconds |
| Moxidectin 8mg | Mean Change From Baseline in QTc Interval (Corrected by Friderica's Formula, dQTcF) Associated With Plasma Moxidectin Concentrations After a Single Dose | -4.5 millseconds |
| Moxidectin 16mg | Mean Change From Baseline in QTc Interval (Corrected by Friderica's Formula, dQTcF) Associated With Plasma Moxidectin Concentrations After a Single Dose | -4.5 millseconds |
| Moxidectin 24mg | Mean Change From Baseline in QTc Interval (Corrected by Friderica's Formula, dQTcF) Associated With Plasma Moxidectin Concentrations After a Single Dose | -6.3 millseconds |
| Moxidectin 36mg | Mean Change From Baseline in QTc Interval (Corrected by Friderica's Formula, dQTcF) Associated With Plasma Moxidectin Concentrations After a Single Dose | -3.9 millseconds |
| Placebo | Mean Change From Baseline in QTc Interval (Corrected by Friderica's Formula, dQTcF) Associated With Plasma Moxidectin Concentrations After a Single Dose | -2.9 millseconds |
| All Subjects | Mean Change From Baseline in QTc Interval (Corrected by Friderica's Formula, dQTcF) Associated With Plasma Moxidectin Concentrations After a Single Dose | -0.0077 millseconds |
Comparison: The primary analysis used a mixed-effects model to explore the relationship between the time-matched, baseline-adjusted QTcF (delta (d)QTcF) and moxidectin concentrations. dQTcF was a dependent variable and treatment, time point, and treatment by time point interaction as the independent variables with baseline QTcF as a covariate and time-matched concentrations of moxidectin as a covariate with random effects of intercept and slope for each subject.Concentrations of zero were used for placebo.p-value: 0.472790% CI: [-0.0255, 0.0101]Mixed Models Analysis
Secondary
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.
Time frame: 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
Population: Pharmacokinetic population - includes all subjects who received at least 1 dose of moxidectin and provide an adequate number of plasma samples for determination of PK parameters, analyzed according to drug received.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Moxidectin 4mg | Concentrations of Moxidectin in Plasma | 27.2 nanogram/milliliter | Geometric Coefficient of Variation 30.6 |
| Moxidectin 8mg | Concentrations of Moxidectin in Plasma | 56.7 nanogram/milliliter | Geometric Coefficient of Variation 20.8 |
| Moxidectin 16mg | Concentrations of Moxidectin in Plasma | 133 nanogram/milliliter | Geometric Coefficient of Variation 27.1 |
| Moxidectin 24mg | Concentrations of Moxidectin in Plasma | 176 nanogram/milliliter | Geometric Coefficient of Variation 18.7 |
| Moxidectin 36mg | Concentrations of Moxidectin in Plasma | 247 nanogram/milliliter | Geometric Coefficient of Variation 19.7 |
Other Pre-specified
Change From Baseline in Heart Rate (HR) and Duration of Other Interval Parameters (PR and QRS)
Changes from Baseline were assessed at each timepoint up to 72 hours post dose. Mean changes across the 72 hour assessment period for each parameter were calculated for each moxidectin group and the placebo group and for the population overall.
Time frame: Baseline (pre-dose) and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 60, and 72 hours post dosing
Population: ECG population - all subjects who receive one dose of study drug and have at least one pair of pre-dose and post-dose QTc data, analyzed as randomized
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Moxidectin 4mg | Change From Baseline in Heart Rate (HR) and Duration of Other Interval Parameters (PR and QRS) | Change in QRS interval | -1.6 milliseconds |
| Moxidectin 4mg | Change From Baseline in Heart Rate (HR) and Duration of Other Interval Parameters (PR and QRS) | Change in PR interval | 2.2 milliseconds |
| Moxidectin 4mg | Change From Baseline in Heart Rate (HR) and Duration of Other Interval Parameters (PR and QRS) | Change in Heart rate (HR) | -1.0 milliseconds |
| Moxidectin 8mg | Change From Baseline in Heart Rate (HR) and Duration of Other Interval Parameters (PR and QRS) | Change in PR interval | -0.1 milliseconds |
| Moxidectin 8mg | Change From Baseline in Heart Rate (HR) and Duration of Other Interval Parameters (PR and QRS) | Change in Heart rate (HR) | 0.5 milliseconds |
| Moxidectin 8mg | Change From Baseline in Heart Rate (HR) and Duration of Other Interval Parameters (PR and QRS) | Change in QRS interval | -0.7 milliseconds |
| Moxidectin 16mg | Change From Baseline in Heart Rate (HR) and Duration of Other Interval Parameters (PR and QRS) | Change in QRS interval | 0.4 milliseconds |
| Moxidectin 16mg | Change From Baseline in Heart Rate (HR) and Duration of Other Interval Parameters (PR and QRS) | Change in Heart rate (HR) | -1.1 milliseconds |
| Moxidectin 16mg | Change From Baseline in Heart Rate (HR) and Duration of Other Interval Parameters (PR and QRS) | Change in PR interval | -2.1 milliseconds |
| Moxidectin 24mg | Change From Baseline in Heart Rate (HR) and Duration of Other Interval Parameters (PR and QRS) | Change in PR interval | 4.6 milliseconds |
| Moxidectin 24mg | Change From Baseline in Heart Rate (HR) and Duration of Other Interval Parameters (PR and QRS) | Change in Heart rate (HR) | -3.6 milliseconds |
| Moxidectin 24mg | Change From Baseline in Heart Rate (HR) and Duration of Other Interval Parameters (PR and QRS) | Change in QRS interval | -0.8 milliseconds |
| Moxidectin 36mg | Change From Baseline in Heart Rate (HR) and Duration of Other Interval Parameters (PR and QRS) | Change in PR interval | -3.5 milliseconds |
| Moxidectin 36mg | Change From Baseline in Heart Rate (HR) and Duration of Other Interval Parameters (PR and QRS) | Change in Heart rate (HR) | -1.5 milliseconds |
| Moxidectin 36mg | Change From Baseline in Heart Rate (HR) and Duration of Other Interval Parameters (PR and QRS) | Change in QRS interval | 0.4 milliseconds |
| Placebo | Change From Baseline in Heart Rate (HR) and Duration of Other Interval Parameters (PR and QRS) | Change in Heart rate (HR) | -2.9 milliseconds |
| Placebo | Change From Baseline in Heart Rate (HR) and Duration of Other Interval Parameters (PR and QRS) | Change in QRS interval | 1.2 milliseconds |
| Placebo | Change From Baseline in Heart Rate (HR) and Duration of Other Interval Parameters (PR and QRS) | Change in PR interval | -1.8 milliseconds |
| All Subjects | Change From Baseline in Heart Rate (HR) and Duration of Other Interval Parameters (PR and QRS) | Change in QRS interval | 0.004 milliseconds |
| All Subjects | Change From Baseline in Heart Rate (HR) and Duration of Other Interval Parameters (PR and QRS) | Change in PR interval | -0.002 milliseconds |
| All Subjects | Change From Baseline in Heart Rate (HR) and Duration of Other Interval Parameters (PR and QRS) | Change in Heart rate (HR) | -0.005 milliseconds |
Other Pre-specified
Subjects With Categorical Changes From Baseline in 12-lead Electrocardiograms (ECGs)
Changes from baseline in QTcF exceeding regulatory standard categorical limits (\> 30msec change or exceeding 450msec). Report applies to changes of 30msec - \</= 60msec only
Time frame: At Baseline and Days 1, 2, 3, 4, 22 and Week 12
Population: Safety population - all who received at least one dose of study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Moxidectin 4mg | Subjects With Categorical Changes From Baseline in 12-lead Electrocardiograms (ECGs) | 1 participants |
| Moxidectin 8mg | Subjects With Categorical Changes From Baseline in 12-lead Electrocardiograms (ECGs) | 0 participants |
| Moxidectin 16mg | Subjects With Categorical Changes From Baseline in 12-lead Electrocardiograms (ECGs) | 0 participants |
| Moxidectin 24mg | Subjects With Categorical Changes From Baseline in 12-lead Electrocardiograms (ECGs) | 0 participants |
| Moxidectin 36mg | Subjects With Categorical Changes From Baseline in 12-lead Electrocardiograms (ECGs) | 1 participants |
| Placebo | Subjects With Categorical Changes From Baseline in 12-lead Electrocardiograms (ECGs) | 1 participants |