Clinical trial NCT01294709: A Study to Assess the Safety, Tolerability, and Effects of MK-0974 (Telcagepant) on Exercise Tolerance in Patients With Stable Angina (MK-0974-014)
Official title: A Double-Blind, Randomized, Placebo-Controlled, 2-Period Crossover Study to Assess the Safety, Tolerability, and Effects of MK-0974 on Exercise Tolerance in Patients With Stable Angina
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Angina Pectoris
Coronary Heart Disease
Calcitonin Gene-related Peptide Receptor
Keywords: angina pectoris
coronary artery disease
calcitonin gene-related peptide
exercise tolerance,
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2011-02-11
Enrollment: 64
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

Eligibility 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.

Primary outcomes:
measure: Number of Participants With Clinical Adverse Events (AEs)
timeFrame: Up to 10 days post dose in Period 1 and up to 14 days post dose in Period 2
measure: Number of Participants With Laboratory Adverse Events
timeFrame: Up to 10 days post dose in Period 1 and up to 14 days post dose in Period 2
measure: Total Exercise Duration on the Treadmill Test
timeFrame: 2.5 to approximately 2.75 hours post dose of each treatment period
Secondary outcomes:
measure: ST Segment Depression at Peak Exercise
timeFrame: 2.5 to approximately 2.75 hours post dose of each treatment period
measure: Time to 1 mm ST Segment Depression
timeFrame: 2.5 to approximately 2.75 hours post dose of each treatment period
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Chaitman BR, Ho AP, Behm MO, Rowe JF, Palcza JS, Laethem T, Heirman I, Panebianco DL, Kobalava Z, Martsevich SY, Free AL, Bittar N, Chrysant SG, Ho TW, Chodakewitz JA, Murphy MG, Blanchard RL. A randomized, placebo-controlled study of the effects of telcagepant on exercise time in patients with stable angina. Clin Pharmacol Ther. 2012 Mar;91(3):459-66. doi: 10.1038/clpt.2011.246. Epub 2012 Jan 25.