Angina Pectoris, Coronary Heart Disease, Calcitonin Gene-related Peptide Receptor
Conditions
Keywords
angina pectoris, coronary artery disease, calcitonin gene-related peptide, exercise tolerance,
Brief summary
This study will assess the safety of telcagepant in coronary artery disease (CAD) participants with stable angina during exercise treadmill testing and evaluate whether calcitonin gene-related peptide (CGRP) receptor antagonism by telcagepant reduces exercise tolerance in these participants. Primary hypothesis is that telcagepant does not significantly decrease exercise duration compared to placebo, as measured by a treadmill exercise test; that is, the true treatment difference in exercise duration (MK-0974 - Placebo) \>= -60 seconds.
Detailed description
Amendment 3 of the protocol reduced the dose of telcagepant to be administered from a single dose of 900 mg to a single dose of 600 mg. Pooled data from both the 600-mg and the 900-mg group wiil be utilized in the analyses. Also due to supply issues regarding the 300 mg telcagepant capsules, 280 mg telcagepant tablets with demonstrated bioequivalence to the 300 mg telcagepant capsules, could be administered to participants enrolled after the implementation of Amendment 3.
Interventions
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
Inclusion: * Participant has clinically documented stable coronary artery disease as demonstrated by coronary angiography, echocardiogram, or stress test, etc., or participant is on stable doses of current medication for the treatment of coronary artery disease for a minimum of 30 days. * Participant has a history of stable angina (chronic stable angina pectoris that is triggered by physical effort and relieved by rest and/or sublingual nitroglycerin) for at least 3 months prior to study start, with no intervening symptoms of unstable angina. * Participant is able to demonstrate reproducibly positive exercise tests by completing treadmill tests on 2 separate days, within 1-8 days. * Participant agrees to refrain from drinking alcohol from 24 hours prior to study drug administration, on study procedure days, and until release from the study facility. * Participants agrees to refrain from smoking from midnight before study procedures until study procedures are complete for the day. * Participant has no clinically significant abnormality on screening laboratory safety assessment. * Participant agrees to refrain from unaccustomed strenuous physical activity from the prestudy (screening) visit, throughout the study, and until the post-study visit. Exclusion: * Participant is pregnant (positive serum beta-human chorionic gonadotropin \[β-hCG\] test at prestudy), breast-feeding, or is a female expecting to conceive within the projected duration of the study. Postmenopausal women who are currently using hormone replacement therapy are excluded from participation in the study. * Participant has electrocardiogram (ECG) findings that interfere with ECG interpretation or may cause false positive stress test (e.g., \> 1 mm horizontal or downsloping ST-segment depression at rest in any standard electrocardiographic lead, Lown-Ganong-Levine syndrome, Wolff-Parkinson-White (WPW), left bundle branch block (LBBB), left ventricular hypertrophy (LVH) with repolarization abnormality, pectus excavatum, ventricular pacemaker, etc.). Note: these ECG findings may affect stress test results; there may be other findings that have not been included which may affect test results. These ECG findings are exclusions only if these findings may jeopardize interpretation of stress test results. * Participant has heart rate-corrected QT interval (QTc) (Bazett) \> 500 ms on resting ECG. * Participant has uncontrolled high blood pressure at prestudy screening. * Participant has a baseline heart rate of \<40 or \>96 beats per minute at screening. * Participant has unstable angina, hypertrophic cardiomyopathy, valvular heart disease, congenital cardiac defect, severe aortic stenosis, class III or IV heart failure. * Participant has diabetes and is, in the opinion of the investigator, unable to comply with the pre-and post-dosing fasting requirements of the study due to risks of hypoglycemia. * Participant is unable to withhold acetohexamide, chlorpropamide, glimepride, glimepiride and pioglitazone, glimepride and rosiglitazone, glipizide, glipizide and metformin, glyburide, glyburide and metformin, tolazamide, tolbutamide, or any other medication, that in the opinion of the investigator is likely to result in hypoglycemia within 8 hours of dosing. * Participant has had myocardial infarction or coronary revascularization within the prior 2 months. * Participant has acute myocarditis or pericarditis. * Participant is obese, with adipose tissue which may interfere with ECG interpretation, or in the opinion of the investigator, whose obesity puts the participant at medical risk. * Participant has clinically significant hypokalemia or hypomagnesemia. * Participant has a history of any illness that, in the opinion of the investigator, might confound the results of the study or poses an additional risk to the participant by their participation in the study. * Participant must not have taken any of the following medications in the time frame specified: Participant is unable to refrain from or anticipates the use of any herbal remedies beginning approximately 2 weeks (or 5 half-lives) prior to administration of the initial dose of study drug, throughout the study (including washout intervals between treatments), until the post-study visit; participant is unable to refrain from taking a drug metabolized by cytochrome P450 3A4 (CYP3A4) until at least 48 hours post dose (the exact length of time a specific drug metabolized by CYP3A4 is withheld is dependent on the therapeutic index of the drug and the extent to which it is metabolized by CYP3A4); participant consumes excessive amounts of alcohol which, in the opinion of the investigator, puts the participant at medical risk by participating in the study (participant has clinical \[e.g., enlarged liver\] or laboratory evidence \[e.g., elevated alanine aminotransferase (ALT)\], of chronic alcoholism or drug abuse, in the opinion of the investigator); participants is currently a regular user (including: recreational use) of any illicit drugs or has a history of drug (including alcohol) abuse within approximately 6 months; participant has taken potent CYP3A4 inhibitors, including but not limited to cyclosporine, systemic (oral/intravenous) itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, nefazodone, human immunodeficiency virus (HIV) protease inhibitors within 1 month prior to dosing with MK-0974 or placebo and throughout the study period; participant has taken moderate CYP3A4 inhibitors, including but not limited to verapamil, diltiazem, fluconazole, fluvoxamine, fluoxetine, aprepitant within 2 weeks prior to dosing with MK-0974 or placebo and throughout the study period; participant has taken potent CYP3A4 inducers, including but not limited to rifampicin, rifabutin, carbamazepine, phenytoin, barbiturates, systemic glucocorticoids (replacements and inhaled are permitted), nevirapine, efavirenz, pioglitazone, primidone, St. John's wort within 1 month prior to dosing MK-0974 or placebo and throughout the study period; participant has taken triptans, ergot alkaloids within 48 hours prior to dosing MK-0974 or placebo and throughout the study period; participant has taken digoxin, medications that prolong QTc interval such as Class IA and Class III anti-arrhythmics (quinidine, procainamide, amiodarone, sotalol, etc), Seldane (terfenadine), Hismanal (astemizole), Propulsid (cisapride) within 1 month prior to dosing MK-0974 or placebo and throughout the study period; participant has received an investigational medication within 4 weeks prior to the prestudy (screening) visit. * Participant has a history of multiple and/or severe allergies, or has had an anaphylactic reaction or intolerability to prescription or non-prescription drugs or food. * There is any concern by the investigator regarding the safe participation of a participant in the study, or for any other reason the investigator considers the participant inappropriate to participate in the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Clinical Adverse Events (AEs) | Up to 10 days post dose in Period 1 and up to 14 days post dose in Period 2 | An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which was temporally associated with the use of the product, was also an AE. A clinical AE was an AE reported as a result of a clinical examination or reported by the participant. |
| Number of Participants With Laboratory Adverse Events | Up to 10 days post dose in Period 1 and up to 14 days post dose in Period 2 | An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which was temporally associated with the use of the product, was also an AE. A laboratory AE was an AE reported as a result of a laboratory assessment or test. |
| Total Exercise Duration on the Treadmill Test | 2.5 to approximately 2.75 hours post dose of each treatment period | Bruce (and Modified Bruce) Protocol was used to assess the exercise duration on a treadmill. This protocol consists of a standardized gradual incremental increase in external workload every 3 minutes while the participant's electrocardiogram (ECG), symptoms, and arm blood pressure were continuously monitored. Regardless of whether the participant believed he or she could continue, the test was discontinued upon evidence of chest discomfort, severe shortness of breath, dizziness, fatigue, ST-segment depression of greater than 2 mm, a fall in systolic blood pressure exceeding 10 mmHg, or the development of a ventricular tachyarrhythmia |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| ST Segment Depression at Peak Exercise | 2.5 to approximately 2.75 hours post dose of each treatment period | Bruce (and Modified Bruce) Protocol was used to assess the exercise duration on a treadmill. This protocol consists of a standardized gradual incremental increase in external workload every 3 minutes while the participant's ECG, symptoms, and arm blood pressure were continuously monitored. The time of peak exercise was considered the time at which the participant reached at least one of the criteria for stopping the treadmill test (evidence of chest discomfort, severe shortness of breath, dizziness, fatigue, ST-segment depression of greater than 2 mm, a fall in systolic blood pressure exceeding 10 mmHg, or the development of a ventricular tachyarrhythmia). The ECG for that timepoint (time of peak exercise) was evaluated and the amount of ST segment depression was determined. |
| Time to 1 mm ST Segment Depression | 2.5 to approximately 2.75 hours post dose of each treatment period | Bruce (and Modified Bruce) Protocol was used to assess the exercise duration on a treadmill. This protocol consists of a standardized gradual incremental increase in external workload every 3 minutes while the participant's ECG, symptoms, and arm blood pressure were continuously monitored. The ECG was reviewed and the time to the first ST segment depression of 1 mm was recorded. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Enrolled Participants All enrolled participants who recieved at least one dose of either telcagepant or placebo. | 64 |
| Total | 64 |
Baseline characteristics
| Characteristic | All Enrolled Participants |
|---|---|
| Age, Continuous | 63.5 years FULL_RANGE 10.38 |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 55 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 46 | 1 / 16 | 0 / 62 |
| serious Total, serious adverse events | 0 / 46 | 0 / 16 | 0 / 62 |
Outcome results
Primary
Number of Participants With Clinical Adverse Events (AEs)
An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which was temporally associated with the use of the product, was also an AE. A clinical AE was an AE reported as a result of a clinical examination or reported by the participant.
Time frame: Up to 10 days post dose in Period 1 and up to 14 days post dose in Period 2
Population: Safety Population which consisted of all enrolled participants who actually received assigned study drug in a particular period . Adverse events are reported by dose taken in a given treatment period and not by randomly assigned treatment sequence.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Telcagepant (600 mg) | Number of Participants With Clinical Adverse Events (AEs) | 7 Participants |
| Telcagepant (900 mg) | Number of Participants With Clinical Adverse Events (AEs) | 1 Participants |
| Placebo | Number of Participants With Clinical Adverse Events (AEs) | 5 Participants |
Primary
Number of Participants With Laboratory Adverse Events
An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which was temporally associated with the use of the product, was also an AE. A laboratory AE was an AE reported as a result of a laboratory assessment or test.
Time frame: Up to 10 days post dose in Period 1 and up to 14 days post dose in Period 2
Population: Safety Population which consisted of all enrolled participants who actually received assigned study drug in a particular period . Adverse events are reported by dose taken in a given treatment period and not by randomly assigned treatment sequence.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Telcagepant (600 mg) | Number of Participants With Laboratory Adverse Events | 0 Participants |
| Telcagepant (900 mg) | Number of Participants With Laboratory Adverse Events | 0 Participants |
| Placebo | Number of Participants With Laboratory Adverse Events | 0 Participants |
Primary
Total Exercise Duration on the Treadmill Test
Bruce (and Modified Bruce) Protocol was used to assess the exercise duration on a treadmill. This protocol consists of a standardized gradual incremental increase in external workload every 3 minutes while the participant's electrocardiogram (ECG), symptoms, and arm blood pressure were continuously monitored. Regardless of whether the participant believed he or she could continue, the test was discontinued upon evidence of chest discomfort, severe shortness of breath, dizziness, fatigue, ST-segment depression of greater than 2 mm, a fall in systolic blood pressure exceeding 10 mmHg, or the development of a ventricular tachyarrhythmia
Time frame: 2.5 to approximately 2.75 hours post dose of each treatment period
Population: Enrolled participants with evaluable treadmill exercise duration data available. Data from the 600 and 900 mg telcagepant treatments were grouped for comparsion to placebo.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Telcagepant (600 mg) | Total Exercise Duration on the Treadmill Test | 405.38 Seconds |
| Telcagepant (900 mg) | Total Exercise Duration on the Treadmill Test | 412.28 Seconds |
Comparison: Telcagepant minus Placebo Treatment Difference90% CI: [-17.66, 3.86]mixed effects model
Secondary
ST Segment Depression at Peak Exercise
Bruce (and Modified Bruce) Protocol was used to assess the exercise duration on a treadmill. This protocol consists of a standardized gradual incremental increase in external workload every 3 minutes while the participant's ECG, symptoms, and arm blood pressure were continuously monitored. The time of peak exercise was considered the time at which the participant reached at least one of the criteria for stopping the treadmill test (evidence of chest discomfort, severe shortness of breath, dizziness, fatigue, ST-segment depression of greater than 2 mm, a fall in systolic blood pressure exceeding 10 mmHg, or the development of a ventricular tachyarrhythmia). The ECG for that timepoint (time of peak exercise) was evaluated and the amount of ST segment depression was determined.
Time frame: 2.5 to approximately 2.75 hours post dose of each treatment period
Population: Enrolled participants with evaluable data for assessment of ST segment depression at peak exercise available. Data from the 600 and 900 mg telcagepant treatments were grouped for comparsion to placebo.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Telcagepant (600 mg) | ST Segment Depression at Peak Exercise | -1.91 mm |
| Telcagepant (900 mg) | ST Segment Depression at Peak Exercise | -1.86 mm |
Comparison: Telcagepant minus Placebo Treatment Difference90% CI: [-0.19, 0.076]mixed effects model
Secondary
Time to 1 mm ST Segment Depression
Bruce (and Modified Bruce) Protocol was used to assess the exercise duration on a treadmill. This protocol consists of a standardized gradual incremental increase in external workload every 3 minutes while the participant's ECG, symptoms, and arm blood pressure were continuously monitored. The ECG was reviewed and the time to the first ST segment depression of 1 mm was recorded.
Time frame: 2.5 to approximately 2.75 hours post dose of each treatment period
Population: Enrolled participants with evaluable data for assessment of time to 1 mm ST segment depression available. Data from the 600 and 900 mg telcagepant treatments were grouped for comparsion to placebo.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Telcagepant (600 mg) | Time to 1 mm ST Segment Depression | 363.53 seconds |
| Telcagepant (900 mg) | Time to 1 mm ST Segment Depression | 370.67 seconds |
Comparison: Telcagepant minus Placebo Treatment Difference90% CI: [-22.03, 7.74]mixed effects model