Randomized,controlled trial of telcagepant over four migraine attacks

Abstract

Methods: This study evaluated the calcitonin gene-related peptide (CGRP) receptor antagonist telcagepant (tablet formulation) for treatment of a migraine attack and across four attacks. Adults with migraine were randomized, double-blind, to telcagepant 140 mg, telcagepant 280 mg, or control treatment sequences to treat four moderate-to-severe migraine attacks. Control patients received placebo for three attacks and telcagepant 140 mg for one attack. Efficacy for the first attack (Attack 1) and consistency of efficacy over multiple attacks were assessed. For an individual patient, consistent efficacy was defined as ≥3 successes, and lack of consistent efficacy was defined as ≥2 failures, in treatment response. A total of 1677 patients treated ≥1 attack and 1263 treated all four attacks.

Results: Based on Attack 1 data, telcagepant 140 mg and 280 mg were significantly (p < .001) more effective than placebo for 2-hour pain freedom, 2-hour pain relief, 2-hour absence of migraine-associated symptoms (phonophobia, photophobia, nausea), and 2–24 hours sustained pain freedom. The percentage of patients with 2-hour pain freedom consistency and 2-hour pain relief consistency was significantly (p < .001) higher for both telcagepant treatment sequences versus control. Adverse events within 48 hours for telcagepant with an incidence ≥2% and twice that of placebo were somnolence (placebo = 2.3%, 140 mg = 5.9%, 280 mg = 5.7%) and vomiting (placebo = 1.4%, 140 mg = 1.0%, 280 mg = 2.9%).

Conclusion: Telcagepant 140 mg and 280 mg were effective for treatment of a migraine attack and were more consistently effective than control for intermittent treatment of up to four migraine attacks. Telcagepant was generally well tolerated. (Clinicaltrials.gov; NCT00483704)

Keywords

Telcagepant calcitonin gene-related peptide migraine randomized controlled trial consistency

Introduction

Calcitonin gene-related peptide (CGRP) is a neuropeptide that is believed to play a key role in the pathophysiology of migraine (1–5). Evidence that antagonism of CGRP receptors might provide a new treatment option for migraine sufferers was first provided in a trial of the intravenously administered CGRP receptor antagonist olcegepant (6). These findings have subsequently been confirmed with the orally bioavailable CGRP receptor antagonist telcagepant (7–9). Due to their novel mechanism of action, CGRP receptor antagonists could potentially be useful in patients who do not benefit from or tolerate standard treatments such as triptans, or for whom standard treatments are contraindicated. Comparative data suggest that telcagepant has efficacy similar to some established triptan treatments, but possibly may be better tolerated in some patients (7,8). CGRP receptor antagonists are not direct vasoconstrictors (10) and therefore may, in theory, offer a treatment option for patients with cardiovascular disease in whom triptans are contraindicated (11).

Previous trials have evaluated the efficacy of telcagepant for treatment of a single migraine attack (7–9). Assessment of consistency of response over multiple attacks is important for acute migraine treatments to fully characterize the efficacy profile. Perception of inconsistent response may contribute to poor adherence to medications. Trials to assess consistency of response are recommended by the International Headache Society (12) and by the European Medicines Agency (13) prior to approval of a new migraine treatment. Therefore, one aim of the present trial was to evaluate the consistency of efficacy of telcagepant. In order to do this, we developed a novel study design, which allowed a formal statistical consistency comparison to a control group and was intended to overcome some of the limitations of previous study designs used to assess consistency. The trial also aimed to assess the tolerability of telcagepant for the intermittent acute treatment of up to four migraine attacks.

An additional aim of the trial was to confirm the efficacy and tolerability of a new tablet formulation of telcagepant. The previous telcagepant trials used a liquid-filled capsule formulation (7–9). The tablet formulation was developed because the shelf life and size of the capsule formulation were not adequate for commercial purposes. Two doses of telcagepant (140 mg and 280 mg) were assessed to help evaluate the dose-response relationship.

Patients and methods

Patients

Patients were eligible for the study if they were ≥18 years of age, had a history of migraine with or without aura for at least one one year according to International Headache Society criteria (14), had experienced one to eight moderate or severe migraine attacks per month in the two months prior to the screening visit, and were in good general health. Patients with stable cardiovascular disease (without stroke, unstable angina or other symptomatic ischemic event within the previous three months) were not excluded. Patients taking migraine preventive medications were eligible provided that their prescribed daily dose had not changed during the three months prior to screening. Due to potential pharmacokinetic interactions with telcagepant, patients taking potent CYP3A4 inhibitors, potent CYP3A4 inducers or specific CYP3A4 substrates with a narrow therapeutic window within one month of the screening visit were ineligible, and these medications were not permitted during the study.

Standard protocol approvals, registrations, and patient consents

The study was approved by the ethical review committee for each site and each patient provided written informed consent. The trial was registered at ClinicalTrials.gov (NCT00483704). A scientific advisory committee comprised of non-Merck and Merck scientists contributed to the development of the protocol, statistical analysis plan, analysis and interpretation of the data, and authoring of the manuscript.

Study design

The study (Merck Protocol 031) was conducted at 117 sites in Europe, the United States, Canada, Australia and Colombia from August 2008 through March 2009. This was a double-blind, parallel group, multiple attacks study that included treatment with telcagepant 140 mg and 280 mg tablets and placebo. Results of a bioequivalence study (Merck unpublished data) indicated that a telcagepant 280 mg tablet is bioequivalent to the previously studied telcagepant 300 mg capsule. A modified parallel design was used. The design is summarized in Figure 1 and was comprised of one treatment sequence group that received telcagepant 140 mg for four attacks, one treatment sequence group that received telcagepant 280 mg for four attacks and a control treatment sequence group that received placebo for three attacks and telcagepant 140 mg for one attack (1 : 1 : 1). The control group consisted of two treatment sequence groups (1 : 1) where Group 1 received telcagepant 140 mg for Attack 3 and Group 2 received telcagepant 140 mg for Attack 4 (Figure 1).

Figure 1.

Study design. N = planned sample size.

For each attack, patients were instructed to administer study medication when they experienced a moderate-to-severe migraine headache. For Attack 1 only, patients could take a blinded optional second dose if they still had a moderate or severe headache two hours after dosing or if they experienced headache recurrence within 48 hours post-initial dose. For this Attack 1 optional second dose, patients initially randomized to telcagepant were allocated to receive either a repeat of their initial treatment or placebo in an equal ratio. Patients initially randomized to placebo were allocated to receive placebo as their optional second dose. The efficacy of the optional second dose is not discussed since the sample sizes were relatively small and a pre-specified pooled analysis of optional second dose efficacy across telcagepant phase 3 studies is planned.

Patients were provided with one blister card which contained study medication to treat all four attacks. Placebo tablets were visually identical to telcagepant tablets. Patients were allocated using a computer-generated randomized allocation schedule prepared by a blinded statistician at Merck, using a block size of six. Numbered containers were used to implement allocation. Personnel at each study site used a central interactive voice response system to determine which container should be given to which patient. All study personnel, including investigators, study site personnel, patients and Merck staff remained blinded to treatment allocation throughout the study. Unblinding took place after data collection was complete.

Procedure

Study eligibility was assessed at a screening visit where physical exams, vital signs, laboratory screens and electrocardiograms (ECGs) were performed. Eligible patients were randomized and provided with study medication. Patients were instructed to take study drug when they experienced a moderate or severe migraine headache. Patients were encouraged to treat their migraine headache within four hours of migraine onset and were not to treat a recurring migraine headache. After treatment, patients who did not respond, that is, whose headaches had failed to improve to mild or no pain at two hours after administration of study medication or who had headache recurrence, could then choose to use a blinded optional second dose (Attack 1 only; see above), to take a non-study rescue medication (e.g. nonsteroidal anti-inflammatory drugs [NSAIDs], triptans, anti-emetics), or to take no further medication. During the 48 hours following the initial dose of study medication, patients recorded subjective assessments of pain severity, the presence or absence of associated symptoms and the degree of functional disability at specified time intervals on a paper migraine diary (see below). Patients also recorded information about any adverse events that occurred up to the time they returned to the clinic. Patients had monthly clinic visits until they treated four migraine attacks with study medication or until the study ended. At each visit, the study site staff reviewed the diary, assessed medication compliance, and conducted safety assessments. Patients were instructed to return to the study site as close to 48 hours and up to approximately seven days after treatment of Attack 4 to allow review of the diary, assessment of medication compliance, and safety monitoring including laboratory assessments. The duration of the study comprised of up to six months from the screening visit or three months after the last patient randomized, whichever was less, followed by an additional 14 days to complete the post-treatment follow-up phone contact.

Assessments

Headache severity was assessed using a four-grade scale (no pain, mild pain, moderate pain, severe pain) at baseline (0 hour = time of taking study medication) and at 0.5, 1, 1.5, 2, 2.5, and 24 hours post-dose. The presence or absence of phonophobia, photophobia, nausea, vomiting and ratings of functional disability (four-grade scale – normal, mildly impaired, severely impaired, requires bed rest) were recorded at the same time points as the headache severity ratings. For those patients who reported pain relief (reduction of pain to mild or none) or pain freedom (no pain) at two hours post-dose, the presence or absence of headache worsening (recurrence) within 2–24 hours and 2–48 hours was recorded. The use of rescue medication (including the optional second dose) within 48 hours after the initial dose of study medication was also recorded. Patients also completed the Migraine Quality-of-Life Questionnaire (15) 24 hours after the initial dose of study medication and a Treatment Satisfaction Questionnaire for Medication assessment (16).

Tolerability and safety were assessed via spontaneous adverse event reports and routine pre- and post-study physical and laboratory examinations, ECGs and vital signs. All serious vascular events were sent to an independent assessment panel for adjudication.

Statistical analysis

There were seven primary efficacy endpoints, reflecting a requirement from regulatory authorities to demonstrate efficacy on multiple symptoms. Five of these related to two-hour endpoints from Attack 1: pain freedom, pain relief (reduction to mild or none), absence of phonophobia, absence of photophobia and absence of nausea. The other two related to the consistency of efficacy over the course of the trial: pain freedom consistency defined as the proportion of patients who were pain free at two hours for at least three attacks and pain relief consistency defined as the proportion of patients who had pain relief at two hours for at least three attacks.

There were four secondary endpoints which pertained to Attack 1 only: (i) 2–24 hours sustained pain freedom (pain free from 2–24 hours without the use of rescue medication, including the optional second dose); (ii) 2–48 hours sustained pain freedom; (iii) total migraine freedom at two hours (no pain, photophobia, phonophobia, nausea or vomiting); and (iv) 2–24 hours total migraine freedom.

The full-analysis-set (FAS) was the pre-specified primary population for assessing the efficacy of the Attack 1 endpoints. For each endpoint, the FAS population included all treated patients who had a baseline headache severity score and at least one post-dose measurement occurring at, or prior to, two hours post-dose. Non-baseline missing data were imputed using a last-observation-carried forward approach and no baseline data were carried forward. In the assessment of the consistency hypotheses, two populations were used within each endpoint. The pre-specified primary population, the modified FAS (MFAS), was defined as all patients who recorded a baseline severity for at least one of the treated attacks and experienced at least either two failures or three successes, regardless of whether or not they had data for all four attacks. A supportive analysis was conducted on those patients who completed the study, that is, treated and had data for all four attacks.

The two control treatment sequence groups were combined into a single “control” group for the analysis. Note that patients in the control group received placebo for Attack 1 and thus “placebo” is described as the comparator for all Attack 1 analyses. For the consistency analyses, the control group corresponded predominantly to treatment with placebo but also included patients who were randomized to receive one dose of telcagepant 140 mg to treat either Attack 3 or Attack 4 (depending on which of the two control groups the patient was randomized to). Within the control group, the response on the attack treated with 140 mg (either positive or negative) did count toward the total needed for inclusion in the MFAS population as well as toward the consistency endpoint itself. The MFAS population was defined separately for both the pain-free consistency and pain-relief-consistency endpoints. The percentages of patients with response and odds ratios for telcagepant 140 mg, 280 mg and control were estimated using a logistics model with categorical terms for treatment, geographic region (United States, non–United States) and baseline headache severity (moderate or severe), with age included as a continuous covariate. To control for multiplicity, a step-down closed testing procedure (17) was applied to the co-primary hypotheses and key secondary hypotheses each at a significance level of 0.05. The sequence of hypothesis testing is described in the results section. The data were analyzed using the SAS version 9.1 software package (SAS Institute, Cary, NC, USA).

Additional pre-specified exploratory analyses were performed involving the above measures at additional time points (e.g. pain relief at time points other than two hours) or different measures (e.g. functional disability, migraine quality of life) but are not included in the present report which focuses on the primary and secondary endpoints.

The seven co-primary efficacy hypotheses were that telcagepant 280 mg is superior to placebo (five Attack 1 hypotheses) or control (two consistency hypotheses) on the primary endpoints described above. Power and sample size estimates were based on the primary comparison of the telcagepant 280 mg sequence versus the control treatment sequences; the telcagepant 140 mg sequence was then allocated the same number of patients as the 280 mg sequence. Approximately 1800 patients were targeted for randomization in a 1 : 1 : 1 ratio to an initial dose of 140 mg, 280 mg or placebo. Under the assumption that approximately 20% of these patients would either drop out prior to their first attack or fail to take their study medication, this was to have yielded approximately 480 treated patients in each treatment sequence for the Attack 1 hypotheses. Furthermore, assuming that 40% of the 1800 initially randomized patients would not qualify for the MFAS population used to assess each of the two consistency endpoints, this was to have yielded approximately 360 evaluable treated patients in each treatment sequence for the consistency hypotheses. The overall power for simultaneously obtaining significance on all seven co-primary efficacy hypotheses at a significance level of 0.05 was at least 94.1%.

All patients who were randomized and took study treatment were included in the safety assessment. Patients were counted according to the treatment they actually received. Thus, any adverse event that occurred in the control group within 48 hours/14 days after telcagepant 140 mg was attributed to telcagepant 140 mg, and not to placebo. All adverse events reported up to 48 hours following study treatment were included in the primary safety analysis. The percentages of patients with any adverse events, any serious adverse events, adverse events resulting in discontinuation, confirmed vascular events and the most commonly occurring adverse events were calculated for each treatment group. In order to fully characterize the tolerability profile of telcagepant, a separate analysis was also performed using adverse events within 14 days after dosing. The present report focuses on adverse events over all attacks, as the tolerability of telcagepant for treatment of a single attack has been well characterized in previous studies (7–9).

Results

Patient accounting and demographics

The trial profile is shown in Figure 2. A total of 1935 patients were randomized, of which 1677 patients treated at least one attack and 1263 treated all four attacks. Three patients discontinued due to a lack of efficacy and 12 discontinued due to adverse events; these types of discontinuations were equally distributed across the treatment groups. Characteristics of the patients taking treatment and baseline characteristics of the first treated migraine attack are summarized in Table 1. The treatment groups had generally similar demographic profiles and baseline attack characteristics. Approximately 85% of the patients were women and the mean age of study participants was approximately 43 years. About 15% of patients used migraine preventive medication. The most common acute migraine treatments, used by approximately 90% of patients, were triptans and NSAIDs. Overall, 177/1677 (10.6%) patients had a secondary diagnosis of a vascular disorder, the most common of which was hypertension (120/1677 [7.2%]); secondary diagnoses of cerebral infarction, cerebrovascular accident, transient ischemic attack, or myocardial infarction were reported in 10/1677 (0.6%) patients.

Figure 2.

Trial profile. Control comprised patients assigned to placebo for three attacks and telcagepant 140 mg for one attack (Attack 3 or Attack 4). For patients not treated, “lack of qualifying event” means that the patient did not treat a moderate or severe migraine attack. For discontinued patients, “treated <4 attacks” means that the patient did not treat four moderate or severe migraine attacks (but had from one to three moderate or severe attacks for which they took study treatment). “Completed study” means that the patient treated all four attacks.

Table 1.

Characteristics of patients who took treatment of the first migraine attack, at baseline

	Telcagepant 140 mg (N = 573)	Telcagepant 280 mg (N = 549)	Control¹ (N = 555)
Patient characteristics
Mean (SD) age, years	43.4 (11.7)	42.4 (11.5)	42.5 (11.6)
Women	490 (85.5)	471 (85.8)	463 (83.4)
White	544 (94.9)	520 (94.7)	521 (93.9)
Ex-U.S.	356 (62.1)	345 (62.8)	354 (63.8)
Using preventive medication	119 (16.8)	125 (17.9)	112 (16.4)
Usual acute migraine treatment*
None	13 (2.3)	9 (1.6)	11 (2.0)
NSAID	143 (25.0)	146 (26.6)	128 (23.1)
Triptan	261 (45.5)	229 (41.7)	240 (43.2)
NSAID and triptan	99 (17.3)	104 (18.9)	110 (19.8)
Opiate	17 (3.0)	15 (2.7)	20 (3.6)
NSAID, triptan and opiate	6 (1.0)	14 (2.6)	8 (1.4)
Other	33 (5.8)	32 (5.8)	38 (6.8)
Baseline characteristics of Attack 1
Aura	82 (14.3)	82 (14.9)	89 (16.0)
Moderate headache	417 (72.8)	396 (72.1)	417 (75.1)
Severe headache	152 (26.5)	152 (27.7)	134 (24.1)
Phonophobia	381 (66.5)	364 (66.3)	381 (68.6)
Photophobia	418 (72.9)	399 (72.7)	399 (71.9)
Nausea	290 (50.6)	281 (51.2)	284 (51.2)
Vomiting	23 (4.0)	18 (3.3)	24 (4.3)
Baseline function for Attack 1
Normal	35 (6.1)	22 (4.0)	32 (5.8)
Mildly impaired	336 (58.6)	314 (57.2)	321 (57.8)
Severely impaired	148 (25.8)	171 (31.1)	137 (24.7)
Unable to do activities	48 (8.4)	40 (7.3)	61 (11.0)

Values are number (%) of patients, except for age, where the mean is given. N = number of treated patients; sample sizes differed slightly from this for some characteristics due to missing data. Likewise, some percentages do not add up to 100% (e.g. the different categories of baseline function) due to missing data. SD = standard deviation; NSAID = nonsteroidal anti-inflammatory drug.

Control includes patients assigned to placebo for three attacks and telcagepant 140 mg for one attack (Attack 3 or Attack 4).

Based on patient’s self-report on a migraine history questionnaire.

Efficacy

The results of the hypothesis testing, in the sequence that hypotheses were tested, are shown in Table 2. The observed percentages of responders in each treatment group are shown in Table 3 for each of the primary and secondary endpoints. For Attack 1, telcagepant 140 mg and 280 mg were superior to placebo for two-hour pain relief, pain freedom, absence of photophobia, absence of phonophobia, absence of nausea and 2–24-hour sustained pain freedom. Nominally significant differences (referred to as “nominal” because they were not part of the formal pre-specified co-primary and secondary hypothesis testing strategy) were seen for the secondary endpoints of 2–48 hour sustained pain freedom, two-hour total migraine freedom, and 2–24 hour total migraine freedom. The percentage of patients with pain freedom at two hours and pain relief at two hours for each attack by treatment sequence is shown in Figure 3. Figure 3 displays the increase in response rate for the attack treated with telcagepant 140 mg within each of the control groups. The response rates by attack for pooled treatment conditions, where data from the telcagepant 140 mg–treated attack in the control group (Attack 3 or Attack 4) were added to the four-attack telcagepant 140 mg treatment sequence group, are shown in Table 4. The advantage of telcagepant over placebo appeared to remain constant over attacks. Although the two telcagepant doses were not formally compared in the analysis, telcagepant 280 mg was numerically more effective on the more stringent Attack 1 endpoints (pain freedom, sustained pain freedom, total migraine freedom).

Figure 3.

Observed percentage of migraine patients reporting (A) pain freedom at two hours and (B) pain relief at two hours by treatment sequence over four attacks. 140 = telcagepant 140 mg. 280 = telcagepant 280 mg. Pbo = placebo.

Table 2.

Summary of hypothesis tests following closed testing procedure

	Odds Ratio
Comparison	(95% CI)^‡	p value
Co-primary
1. 280 mg vs. placebo in pain freedom at 2 hours, Attack 1	3.03 (2.15, 4.27)	<.001*
2. 280 mg vs. placebo in pain relief at 2 hours, Attack 1	2.80 (2.17, 3.61)	<.001*
3. 280 mg vs. control^† in pain freedom consistency	6.18 (3.36, 11.39)	<.001*
4. 280 mg vs. control^† in pain relief consistency	3.23 (2.41, 4.34)	<.001*
5. 280 mg vs. placebo in absence of phonophobia at 2 hours, Attack 1	1.61 (1.26, 2.06)	<.001*
6. 280 mg vs. placebo in absence of photophobia at 2 hours, Attack 1	1.67 (1.31, 2.14)	<.001*
7. 280 mg vs. placebo in absence of nausea at 2 hours, Attack 1	1.57 (1.21, 2.04)	<.001*
Secondary
8. 280 mg vs. placebo in 2–24 -hour sustained pain freedom, Attack 1	3.45 (2.30, 5.19)	<.001*
9. 140 mg vs. placebo in pain freedom at 2 hours, Attack 1	2.54 (1.80, 3.58)	<.001*
10. 140 mg vs. placebo in pain relief at 2 hours, Attack 1	3.03 (2.35, 3.90)	<.001*
11. 140 mg vs. control^† in pain freedom consistency	3.85 (2.05, 7.23)	<.001*
12. 140 mg vs. control^† in pain relief consistency	2.62 (1.96, 3.51)	<.001*
13. 140 mg vs. placebo in absence of phonophobia at 2 hours, Attack 1	1.74 (1.36, 2.22)	<.001*
14. 140 mg vs. placebo in absence of photophobia at 2 hours, Attack 1	1.65 (1.30, 2.11)	<.001*
15. 140 mg vs. placebo in absence of nausea at 2 hours, Attack 1	1.67 (1.28, 2.17)	<.001*
16. 140 mg vs. placebo in 2–24-hour sustained pain freedom, Attack 1	2.69 (1.78, 4.07)	<.001*

CI = confidence interval. An odds ratio >1 is in favor of the first treatment group of the corresponding pair-wise comparison. ^†Control includes patients assigned to treat placebo for three attacks and telcagepant 140 mg for one attack (Attack 3 or Attack 4). ^‡From logistic model adjusting for geographic region, baseline migraine severity, and age. *Hypotheses are shown in the order in which they were tested. If one hypothesis in the sequence had been non-significant then the remaining hypotheses would have not been formally tested. All hypotheses were statistically significant at α = 0.05 under the pre-specified closed testing procedure.

Table 3.

Summary of efficacy for primary and secondary endpoints: observed percentage of patients (95% CI)

	Telcagepant 140 mg (N = 559)			Telcagepant 280 mg (N = 537)			Placebo/control^† (N = 542)
	m	% (95% CI)		m	% (95% CI)		m	% (95% CI)
Attack 1 co-primary endpoints
Pain freedom, 2 hours	556	21.9 (18.6, 25.6)	***	534	25.1 (21.5, 29.0)	***	539	10.2 (7.8, 13.1)
Pain relief, 2 hours	556	58.6 (54.4, 62.8)	***	534	56.7 (52.4, 61.0)	***	539	33.4 (29.4, 37.6)
No phonophobia, 2 hours	555	61.4 (57.2, 65.5)	***	534	59.4 (55.1, 63.6)	***	537	48.6 (44.3, 52.9)
No photophobia, 2 hours	554	52.3 (48.1, 56.6)	***	534	52.4 (48.1, 56.7)	***	539	40.6 (36.5, 44.9)
No nausea, 2 hours	553	72.9 (69.0, 76.5)	***	534	71.7 (67.7, 75.5)	***	538	62.8 (58.6, 66.9)
Consistency co-primary endpoints
Pain freedom consistency	493	9.3 (6.9, 12.2)	***	468	14.1 (11.1, 17.6)	***	485	2.7 (1.4, 4.5)
Pain relief consistency	469	41.8 (37.3, 46.4)	***	440	46.8 (42.1, 51.6)	***	452	22.3 (18.6, 26.5)
Attack 1 secondary endpoints
2–24-hour sustained pain freedom	553	15.6 (12.6, 18.8)	***	529	19.1 (15.8, 22.7)	***	537	6.5 (4.6, 8.9)
2–48-hour sustained pain freedom	552	13.4 (10.7, 16.5)	***	526	17.9 (14.7, 21.4)	***	536	6.2 (4.3, 8.5)
Total migraine freedom, 2 hours	556	19.4 (16.2, 23.0)	***	534	22.3 (18.8, 26.1)	***	539	9.5 (7.1, 12.3)
2–24-hour total migraine freedom	553	13.7 (11.0, 16.9)	***	531	17.1 (14.0, 20.6)	***	537	6.5 (4.6, 8.9)

CI = confidence interval. N = number of treated patients. m = number of patients in the endpoint-specific full-analysis-set (FAS) population (Attack 1) or modified FAS population (consistency endpoints). ^†For Attack 1 endpoints, control = placebo. For consistency endpoints, control includes patients assigned to treat three attacks with placebo and one attack (Attack 3 or Attack 4) with telcagepant 140 mg. ***p ≤ .001 for the telcagepant-placebo pair-wise comparison. P-values computed using a logistics model adjusting for baseline severity, geographic region and age.

Table 4.

Summary of efficacy for primary and secondary endpoints by attack: number of patients with response/number evaluable (%)

	Attack 1	Attack 2	Attack 3	Attack 4
Co-primary endpoints
Pain freedom, 2 hours
Telcagepant 140 mg	122/556 (21.9)	127/520 (24.4)	162/689 (23.5)	149/601 (24.8)
Telcagepant 280 mg	134/534 (25.1)	131/491 (26.7)	125/453 (27.6)	125/395 (31.6)
Placebo	55/539 (10.2)	54/490 (11.0)	26/217 (12.0)	29/181 (16.0)
Pain relief, 2 hours
Telcagepant 140 mg	326/556 (58.6)	298/520 (57.3)	386/689 (56.0)	305/601 (50.7)
Telcagepant 280 mg	303/534 (56.7)	286/491 (58.2)	265/453 (58.5)	241/395 (61.0)
Placebo	180/539 (33.4)	165/490 (33.7)	84/217 (38.7)	63/181 (34.8)
No phonophobia, 2 hours
Telcagepant 140 mg	341/555 (61.4)	315/520 (60.6)	376/689 (54.6)	314/601 (52.2)
Telcagepant 280 mg	317/534 (59.4)	277/491 (56.4)	270/453 (59.6)	232/395 (58.7)
Placebo	261/537 (48.6)	225/490 (45.9)	103/217 (47.5)	82/180 (45.6)
No photophobia, 2 hours
Telcagepant 140 mg	290/554 (52.3)	262/520 (50.4)	336/689 (48.8)	294/601 (48.9)
Telcagepant 280 mg	280/534 (52.4)	254/491 (51.7)	227/453 (50.1)	212/395 (53.7)
Placebo	219/539 (40.6)	188/490 (38.4)	94/217 (43.3)	70/180 (38.9)
No nausea, 2 hours
Telcagepant 140 mg	403/553 (72.9)	381/520 (73.3)	512/689 (74.3)	434/601 (72.2)
Telcagepant 280 mg	383/534 (71.7)	359/491 (73.1)	322/453 (71.1)	293/395 (74.2)
Placebo	338/538 (62.8)	322/490 (65.7)	150/217 (69.1)	118/181 (65.2)
Secondary endpoints
2–2-hour sustained pain freedom
Telcagepant 140 mg	86/553 (15.6)	89/516 (17.2)	122/681 (17.9)	119/597 (19.9)
Telcagepant 280 mg	101/529 (19.1)	104/487 (21.4)	91/445 (20.4)	99/389 (25.4)
Placebo	35/537 (6.5)	40/488 (8.2)	21/217 (9.7)	20/180 (11.1)
2–4-hour sustained pain freedom
Telcagepant 140 mg	74/552 (13.4)	83/515 (16.1)	108/677 (16.0)	108/596 (18.1)
Telcagepant 280 mg	94/526 (17.9)	96/486 (19.8)	83/445 (18.7)	92/388 (23.7)
Placebo	33/536 (6.2)	36/488 (7.4)	20/216 (9.3)	17/178 (9.6)
Total migraine freedom, 2 hours
Telcagepant 140 mg	108/556 (19.4)	110/520 (21.2)	141/689 (20.5)	133/601 (22.1)
Telcagepant 280 mg	119/534 (22.3)	118/491 (24.0)	107/453 (23.6)	109/395 (27.6)
Placebo	51/539 (9.5)	45/490 (9.2)	23/217 (10.6)	28/181 (15.5)
2–24-hour total migraine freedom
Telcagepant 140 mg	76/553 (13.7)	77/516 (14.9)	105/681 (15.4)	108/597 (18.1)
Telcagepant 280 mg	91/531 (17.1)	94/487 (19.3)	80/448 (17.9)	90/390 (23.1)
Placebo	35/537 (6.5)	35/489 (7.2)	16/217 (7.4)	19/180 (10.6)

Note: In this table, the data from the one attack in the control treatment sequence groups that was treated with telcagepant 140 mg (Attack 3 or Attack 4) is pooled with the data from the telcagepant 140 mg treatment sequence group (patients assigned to treat all four attacks with telcagepant 140 mg).

As shown in Tables 2 and 3, telcagepant was superior to control for the two primary consistency endpoints in the primary analysis using the MFAS population (see statistical analysis). A supportive analysis also looked at the consistency measures for those patients who treated four attacks. The results were similar to those shown for the primary analysis in Table 3 (pain-free consistency: telcagepant 140 mg = 41/410 [10.0%], telcagepant 280 mg = 63/393 [16.0%], control = 11/365 [3.0%]; pain-relief consistency: telcagepant 140 mg = 177/410 [43.2%], telcagepant 280 mg = 189/393 [48.1%], control = 91/365 [24.9%]). Telcagepant 280 mg was numerically more effective than the 140 mg dose on the consistency measures.

Tolerability and safety

Adverse events occurring up to 48 hours after dosing over the study period are summarized in Table 5. Telcagepant was generally well tolerated in the acute treatment of up to four migraine attacks (with the use of an optional second dose for Attack 1 in some patients). The percentage of patients with adverse events was higher for telcagepant 140 mg and 280 mg compared with placebo (patients treated up to three attacks with placebo). Among the most common specific adverse events (incidence ≥2% in at least one of the treatment groups), the following showed a numerical increase compared to placebo for at least one dose of telcagepant: upper abdominal pain, diarrhea, dry mouth, nausea, vomiting, fatigue, dizziness and somnolence. Of these, only somnolence and vomiting had an incidence at least twice that of placebo, and they were experienced by only a small number of patients. The majority of adverse events occurred during the first 48 hours after dosing and the tolerability profile in a supportive analysis looking at adverse events occurring up to 14 days after dosing was similar to that described above for adverse events occurring within 48 hours (Supplementary Table S1). Because the comparison of telcagepant to placebo over all attacks involved a different number of treated attacks (four for telcagepant groups and three for placebo), data for the first attack were also analyzed. The pattern of findings was generally similar to that described above, although there were fewer adverse events overall (Supplementary Table S2).

Table 5.

Summary of number (%) of patients reporting adverse events within 48 hours post-dose over all attacks

Treatment sequence group	Telcagepant 140 mg^†		Telcagepant 280 mg^†		Control^‡
Treatment	Telcagepant 140 mg (N = 573)		Telcagepant 280 mg (N = 543)		Placebo (N = 561)		Telcagepant 140 mg (N = 422)
	n	(%)	n	(%)	n	(%)	n	(%)
Any adverse event	260	(45.4)	237	(43.6)	218	(38.9)	68	(16.1)
Serious adverse event	1	(0.2)	2	(0.4)	0	(0.0)	0	(0.0)
Discontinued due to adverse event	1	(0.2)	2	(0.4)	3	(0.5)	0	(0.0)
Specific adverse events with incidence ≥2% in any group
Nausea	43	(7.5)	45	(8.3)	31	(5.5)	4	(0.9)
Dry mouth	59	(10.3)	42	(7.7)	51	(9.1)	19	(4.5)
Dizziness	36	(6.3)	41	(7.6)	35	(6.2)	8	(1.9)
Fatigue	47	(8.2)	32	(5.9)	24	(4.3)	8	(1.9)
Somnolence	34	(5.9)	31	(5.7)	13	(2.3)	3	(0.7)
Vomiting	6	(1.0)	16	(2.9)	8	(1.4)	4	(0.9)
Diarrhea	13	(2.3)	15	(2.8)	10	(1.8)	1	(0.2)
Upper abdominal pain	14	(2.4)	13	(2.4)	9	(1.6)	2	(0.5)

†

Includes patients assigned to treatment sequences involving four migraine attacks treated with telcagepant 140 or 280 mg. ^‡Includes patients assigned to control treatment sequences involving three migraine attacks treated with placebo and one attack (Attack 3 or 4) treated with telcagepant 140 mg. Note: In both telcagepant treatment sequence groups, adverse event counts are cumulative from all four attacks, whereas the control placebo group counts represent cumulative adverse events from three placebo-treated attacks and the control telcagepant 140 mg group counts represent adverse events from a single telcagepant-treated attack.

No patients died during the study. A total of 14 patients who received telcagepant reported serious adverse events during or after the study; three within 48 hours of study medication (Table 5), an additional five within 14 days of study medication, and a further six more than 14 days after study medication. None of the 14 was classified as drug-related by the investigators (while blinded to treatment). The serious adverse events within 48 hours of telcagepant dosing were pneumonia (one patient), palpitations and dizziness (one patient) and pulmonary embolism and deep vein thrombosis (one patient). The deep vein thrombosis and subsequent pulmonary embolism occurred in a patient with positive lupus anticoagulant, who did not complete the treatment diary and thus the relationship to dosing time was unknown. Based on a pre-specified imputation rule, the dosing time was conservatively imputed to the day of onset of the adverse event. Only one dose of study medication was missing when the study medication was returned. This serious vascular event was confirmed by the independent adjudication committee. The only other confirmed vascular event occurring after dosing with telcagepant was unstable angina which occurred 42 days after dosing in a 67-year-old man with history of hypertension. A total of 12 patients who took study treatment discontinued due to an adverse event (Figure 1); seven of these were last treated with telcagepant and five were treated with placebo. For the three patients who discontinued due to an adverse event occurring within 48 hours of telcagepant (Table 5), the adverse events were somnolence (one patient), chest discomfort (one patient) and deep vein thrombosis (one patient, already described above).

Laboratory abnormalities during the study were uncommon and no clinically relevant differences were seen between treatment groups. Other assessments, including the percentage of patients who exceeded pre-defined levels of change on laboratory parameters, vital sign measurements, ECG measurements and physical examinations, indicated no clinically meaningful differences between treatment groups. None of the patients on telcagepant 140 mg or 280 mg demonstrated an elevation in hepatic transaminases (ALT and AST) ≥3 times above the upper limit of normal.

Discussion

The results from this large phase 3 trial showed that the tablet formulation of the CGRP receptor antagonist telcagepant was effective in treating migraine symptoms. The characteristics of patients included were typical of those recruited to migraine trials, with most being women and the mean age being approximately 40 years. Approximately 75% of those patients who treated the first attack went on to treat all four attacks.

The trial demonstrated that telcagepant 140 mg and 280 mg tablets were significantly more consistently effective than control for intermittent treatment of up to four migraine attacks. Assessment of consistency of response is important to fully characterize the efficacy profile of acute migraine treatments (12,13). Two types of consistency can be defined: (i) population consistency, also sometimes referred to as “reproducibility” (18), which examines the mean response across attacks in the population of patents (mean response rate for Attack 1, Attack 2, etc.), and (ii) intra-individual consistency which examines the consistency of response within individual patients (e.g. the proportion of patients who respond in at least three out of four attacks) (19). A number of study designs have been utilized to evaluate consistency over a number of attacks (18). A parallel placebo-controlled design has limitations due to potential unblinding and consequent differential drop-out rates, as well as ethical concerns about depriving patients of treatment for too many attacks. Cross-over designs can be complicated to implement, and may be difficult to interpret due to carry-over effects. A design in which each patient receives placebo once over the course of the study (random-insertion-of-placebo design) (20) does not allow for the formal testing of within-patient consistency.

For these reasons a modified parallel design with the insertion of an active-treated attack into placebo treatment sequence groups (e.g. three attacks treated with placebo, one treated with active treatment) was developed for the present study. Most notably, this design does allow for the formal testing of within-patient consistency, as conducted between different treatment sequences. The successful application of this design to assess the consistency of response to telcagepant 140 mg and 280 mg versus a control group demonstrates the utility of this approach for future migraine treatment studies.

A drawback of the present design is that the inclusion of the control treatment sequences, where patients received placebo for three attacks, may have had the effect of creating an expectation among patients that they would receive placebo for all four attacks (since the design was transparent to patients when they provided informed consent). This expectation may have been further heightened by the placebo-like tolerability profile of telcagepant. This differs from the random-insertion-of-placebo design where patients know that they will receive placebo for at most only one attack. As a consequence, it is not appropriate to compare the present consistency findings with results from other multiple attack studies which used random-insertion-of-placebo designs. Future studies with active comparators using the modified parallel design are necessary to inform a comparison of consistency of response between telcagepant and other treatments.

In the Attack 1 analyses, telcagepant 140 mg and 280 mg tablets were significantly more effective than placebo on all primary and secondary endpoints. The efficacy of the 140 mg and 280 tablets for Attack 1 was similar to the efficacy of the 150 mg and 300 mg capsules used in the previous phase 3 studies (8,9). Since the study was not designed to assess the treatment difference between the active dose arms, there is limited ability to draw any firm conclusions about the relative efficacy between the 140 mg and 280 mg dose arms. With that caveat, however, two-hour pain freedom, as well as all of the secondary endpoints which measured the sustained effectiveness of telcagepant over 24 or 48 hours, did suggest a dose-response relationship.

Telcagepant was generally well tolerated for the intermittent treatment of up to four attacks in this study with an adverse event profile similar to that of placebo for the intermittent treatment of up to three attacks. Specific common adverse events that had a slightly higher incidence for either dose of telcagepant than placebo in this study were upper abdominal pain, diarrhea, dry mouth, nausea, vomiting, fatigue, dizziness and somnolence. Of these, only somnolence and vomiting showed a greater than two times increase versus placebo, and they were experienced by only a small number of patients. No clinically relevant changes in laboratory measures, including transaminase levels, were seen, although these were assessed up to seven days or more after dosing. A separate study (NCT00797667) looking at the use of telcagepant for migraine prophylaxis, where patients took telcagepant 140 mg or 280 mg tablets twice daily for up to three months, was recently terminated due observation of symptomatic transaminase elevation in two patients (21). The relevance of the increased transaminase levels observed in the prophylaxis study for the use of telcagepant as an intermittent acute treatment is being evaluated.

Although CGRP itself is a potent vasodilator (22), CGRP receptor antagonists are not direct vasoconstrictors and therefore might, in theory, be safe for use in patients with known cardiovascular disease. No significant drug-related cardiovascular events were observed in the present study, in which patients with stable cardiovascular disease were not excluded. However, only a small percentage of such patients were enrolled. A dedicated out-patient study in patients with both migraine and stable cardiovascular disease (NCT00662818) may help to further inform the appropriate use of telcagepant in this population.

Study investigators

Australia: Negar Amanat, Australian Clinical Research Centre, Caringbah, New South Wales; Stephen Hall, Emeritus Research, Malvern, Victoria; Jeff Karrasch, Peninsula Specialist Centre, Kippa Ring, Queensland; Maureen McKeirnan, Brisbane South Clinical Research Centre, Carina Heights, Queensland. Austria: Christian Woeber, Allgemeines Krankenhaus Wein, Vienna; Werner Poewe, Universitat Innsbruck, Innsbruck; Susanne Groblschegg, ClinPharm International GMBH & Co, Vienna. Canada: Michel Aube, Montreal Neurological Institute and Hospital, Montreal, Quebec; Werner John Becker, Foothills Medical Centre, Calgary, Alberta; Guy Boudreau, Clinique Medical St-Urbain, Montreal, Quebec; Suzanne Christie, Ottawa Headache Center, Ottawa, Ontario; Jacques de Lean, Hopital de l’Enfant-Jesus, Quebec; Marek Gawel, Stroyan Research, Toronto, Ontario; Rosella Giammarco, Charlton Medical Centre, Hamilton, Ontario; Stephane Ledoux, Clinique de la Migraine, Montreal, Quebec; Valdemar Martinho, Ottawa; Allan Purdy, Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia; Gary Shapero, Markham Headache and Pain Treatment Centre, Markham, Ontario. Colombia: Felipe Pretelt, Hospital Universitario San Ignacio, Bogota; Sergio F. Ramirez, Fundacion Universitaria Sanitas, Bogota. Czech Republic: Stanislav Bartek, Odborny lekar neurologie, Prerov I Mesto; Ivan Rektor, Fakultni Nemocnice u svate Anny v Brne, Brno; Danuse Roubcova, Odborny Lekar Neurologie, Ostrava; Monika Zahumenska, Lekarsky dum Ormiga Neurologicka, Zlin. Denmark: Konstantinos Kakulidis, Aalborg; Michael Gronbech-Jensen, Denmark; Messoud Ashina, Glostrup Hospital, Glostrup. France: Dominique Valade, Hopital Lariboisiere, Paris; Michel Lanteri-Minet, Hopital Pasteur, Nice; Christian Lucas, Hopital Roger Salengro, Lille. Germany: Bettina Bergtholdt, Emovis GmbH, Berlin; Peter Emrich, Hamburg; Stefan Evers, Universitatsklinikum Munster, Munster; Hartmut Goebel, Universitatsklinikum Kiel, Kiel; Reiner Lehmann, Krankenhaus Berlin-Buch, Berlin; Arne May, Universitatsklinikum Hamburg-Eppendorf, Hamburg; Claudio Padovan, Munchen; Volker Pfaffenrath, Munchen; Gunther Schumann, Praxis fur Neurologie and Psychiatrie, Bochum. Israel: Amnon Mosek, Tel Aviv Sourasky Medical Center, Tel Aviv; Yaron River, Bnei Zion Medical Center, Haifa; Arieh Kuritzky, Rabin Medical Center, Petah-Tikva; Gal Ifergane, Soroka Medical Center, Beer Sheva; Yelena Feingold, Chaim Sheba Medical Center, Tel Hashomer; Bella Gross, Nahariya-Western Galilee Hospital, Nahariya. Italy: Piero Barbanti, Istituto di Ricovero e Cura a Carattere, Roma; Giorgio G. Bono, Ospedale di Circolo e Foundazione Macchi, Varese; Paolo Martelletti, Ospedale Sant’Andrea, Roma; Grazia Sances, Foundazione Instituto Neurologico Casimiro; Pavia; Giorgio Zanchin, Universita di Padova, Clinica Neurologica, Padova. Netherlands: Paul H.M. Pop, VieCuri Medisch Centrum, Venray, Kimburg; P.J.J. Koehler, Atrium Medisch Centrum, Heerlen, Limburg; Yuriy M. Nemchenko, City Clinical Hospital, Ekaterinburg; Jan Van den Berg, Isala Klinieken, Zwoole, Overijssel.

Norway: Hans Olav Hoivik, Hedmark Medisinski Senter AS, Hamar; Sigbjorn Elle, Elverum Legesenter AS, Elverum; Anne Christine Poole, Sjolyst Medisinski Senter AS, Oslo; Andreas Tandberg, Bekkestua Legesenter, Bekkestua; Arne Skag, Bergen Medisinske Senter AS, Bergen; Vidar Moldegard, Gjovik Legesenter, Gjovik. Russian Federation: Guzyal R. Tabeeva, I.M. Sechenov Moscow Medical Academy, Moscow; Larisa I. Volkova, Regional Clinical Hospital, Ekaterinburg; Elena Filatova, Semashko Railway Hospital, Moscow; Andrey B. Danilov, I.M. Schenov Moscow Medical Academy, Moscow; Alexander V. Amelin, Pavlov State Medical University, Saint Petersburg. Spain: Salvador Tranche-Iparraguirre, Centros de Atencion Primaria El Cristo, Oviedo, Asturias; Valentin Mateos-Marcos, Hospital Central de Asturias, Oviedo, Astruias; Silvia Narejos-Perez, CAP Centelles, Centelles, Barcelona; Marc Tarruella Plandolit, CAP Poble Sec-Les Hortes, Barcelona; Santiago Alvarez-Montero, Centro de Salud Torrelodones, Torrelodones, Madrid. Sweden: Lars Edvinsson, Klinisk forskningsenhet, Lund; Carl Dahlof, Lakarhuset, Goteborg; Mattias Linde, Goteborg; Carin Muhr, Akademiska Sjikhuset, Uppsala; Gert Malmqvist, Helsingborg Hospital, Helsingborg. Switzerland: Peter Sandor, Universitaetsspital Zuerich, Zurich; Reto Agosti, Hirslanden Clinic, Zollikon; Hans Jorg Graf, Schaffhausen; Lidia Bernasconi-Savi, Lugano. United Kingdom: Ravi Pawa/Omobolanle Ojo, Lancashire Clinical Research Centre, Chorley, Lancashire; Rex Alamar Sarmiento, Birmingham Research Park, Edgbaston; Hilary Shaw, Thames Valley Clinical Research Centre, Reading, Berkshire; Essam Edlin Ahmed Abdullhakim, Merseyside Clinical Research Centre, Liverpool, Merseyside; Naren Savani, Mount Vernon Hospital, Northwood. United States: Sheena K. Aurora, Swedish Pain and Headache Center, Seattle, WA; Mira Baron, Rapid Medical Research, Inc., Cleveland, OH; Harold E. Bays, L-MARC Research Center, Louisville, KY; Nathan L. Bennett, Preferred Primary Care Physicians, Pittsburgh, PA; Gary D. Berman, Clinical Research Institute, Minneapolis, MN; Roger K. Cady, ClinVest, Springfield, MO; Kenneth Carnes, Raleigh Neurology Associates PA, Raleigh, NC; Harry Collins, Anderson and Collins Clinical Research, Inc., Edison, NJ; Brandon Essink/Kevin Ahlers, Meridian Clinical Research, Omaha, NE; Carol A. Foster, Carol A. Foster, MD, PC/Research, Phoenix, AZ; Itzhak Christopher Haimovic, Neurological Specialties of Long Island, Great Neck, NY; Constance J. Johnson, Neurological Medicine, Clarksville, TN; David B. Kudrow, California Medical Clinic for Headaches, Santa Monica, CA; Hubert A. Leonard, Oregon Clinic, Portland, OR; Thomas Willard Littlejohn III, Piedmont Medical Research, Winston-Salem, NJ; Ninan T. Mathew, Houston Headache Clinic, Houston, TX; Alexander Mauskop, New York Headache Center, New York, NY; Loretta L. Mueller, University of Medicine and Dentristry of NJ, Stratford, NJ; Michael J. Noss, Radiant Research, Cincinnati, OH; Anthony D. Puopolo, Milford Emergency Associates, Milford, MA; George J. Rederich, Redondo Beach, CA; Marcia Ribeiro, Mid-Atlantic Headache Institute, Inc., Pikesville, MD; Christopher Rocco, Community Clinical Research Centers, Anderson, IN; Dana M. Winegarner, MidAmerica Neuroscience Institute, Lenexa, KS; Joel R. Saper, Michigan Head Pain, Ann Arbor, MI; Larry S. Seidman, Philadelphia Clinical Research, LLC, Philadelphia, PA; Stephan C. Sharp, Clinical Research Associates, Inc., Nashville, TN; Thomas Shiovitz, California Neuroscience, Sherman Oaks, CA; Timothy Robert Smith, Mercy Health Research, Saint Louis, MO; Egilius L.H. Spierings, MedVadis Research, Wellesley Hills, MA; Cynthia Becher Strout, Coastal Carolina Research Center, Mount Pleasant, SC; Michael M. Tuchman, Palm Beach Neurological Center, Palm Beach Gardens, FL; Lynn R. Webster, Lifetree Clinical Research, Salt Lake City, UT.

Competing interests

APH, JTK, SF, HL, CRL and TWH are employees of Merck and own stock/stock options in Merck. They were members of the scientific advisory committee for this study.

CGHD is or has been a consultant/scientific advisor in advisory boards, clinical trials, investigator-initiated trials and/or speaker for Allergan, Almirall Prodesfarma, AstraZeneca, Bayer, Bristol-Myers Squibb, Coherex, Eisai, GlaxoSmithKline, Janssen-Cilag, Johnson & Johnson, Merck, Lilly, Lundbeck, NMT Medical, Novartis, Nycomed, Ortho-McNeil Pharmaceutical, Pharmacia, Pharmnovo, Pfizer, Pierre Fabre St. Jude Medical, Takeda and Vernalis. He has no ownership interest and does not own stocks of any pharmaceutical company. He was a member of the scientific advisory committee for this study. He also served on the independent safety monitoring board for selected telcagepant studies in the clinical development program (not including the present study).

SDS has proprietary interest (speaker/advisory board/grants) in the following commercial, health care–related businesses: Abbott, AdvancedBionics, Advanced NeurModulation System, AGA, Allergan, AstraZeneca, Endo, GSK, Lilly, Medtronic, Merck, Ortho-McNeil, Pfizer, Pozen, ProEthic, Valeant and Vernalis. He was a member of the scientific advisory committee for this study.

JRS has received honoraria for speaking from GlaxoSmithKline, Merck & Co., Abbott Laboratories, Elan Corporation, AstraZeneca Pharmaceuticals, Pfizer, Ortho-McNeil Pharmaceuticals, Bristol-Myers Squibb, Medtronic, Endo Pharmaceuticals, Advanced Bionics, Pozen and Penwest Pharmaceuticals. He holds stock in Pozen. He has received research support from Novartis, Ortho-McNeil Pharmaceuticals, Merck & Co., GlaxoSmithKline, Allergan, Eisai, AstraZeneca Pharmaceuticals, Abbott, Advanced Bionics, Medtronic, Renovis and Pozen. He was a member of the scientific advisory committee for this study.

MA has received grant support and honoraria for lecturing from Merck, and honoraria for lecturing from Pfizer, GlaxoSmithKline and AstraZeneca, and he is a consultant and/or scientific adviser for Merck and BTG International. He was an investigator in this study.

Footnotes

Acknowledgements

This study was funded by Merck Research Laboratories. The funding organization was involved in the following: design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review and approval of the manuscript.

All authors are responsible for the work described in this paper. All authors were involved in at least one of the following: conception, design, acquisition, analysis, statistical analysis, interpretation of data; and drafting the manuscript and/or revising the manuscript for important intellectual content. All authors provided final approval of the version to be published.

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