Abstract
Objective
The objective of this article is to assess the effects of sumatriptan monotherapy, telcagepant monotherapy, and their combination on blood pressure (BP) in migraine patients during a headache-free period.
Methods
A double-blind, placebo-controlled, four-period, single-dose, randomized crossover study in 24 migraine patients was conducted. In each period, patients received a single oral dose of sumatriptan 100 mg alone, telcagepant 600 mg alone, sumatriptan 100 mg coadministered with telcagepant 600 mg, or placebo. Semi-recumbent BP was measured pre-dose and at seven post-dose timepoints over a period of six hours. Individual time-weighted averages in mean arterial pressure (MAP) were evaluated using a linear mixed-effects model. The pharmacokinetics of sumatriptan alone and in the presence of telcagepant were also evaluated using limited sampling times.
Results
The mean difference in time-weighted (0–2.5 h) MAP (90% confidence interval) was 1.2 mmHg (−0.2, 2.7) between telcagepant and placebo, 4.0 mmHg (2.5, 5.5) between sumatriptan and placebo, and 1.5 mmHg (0.0, 3.0) between telcagepant with sumatriptan vs sumatriptan alone. When coadministered with telcagepant, the AUC0–6h and Cmax of sumatriptan were increased by 23% and 24%, respectively. The small MAP increases observed after coadministration could possibly be associated with the slight elevations in sumatriptan levels.
Conclusion
Telcagepant does not elevate mean MAP, and coadministration of telcagepant with sumatriptan results in elevations in MAP similar to those observed following administration of sumatriptan alone in migraineurs during the interictal period. When coadministered, telcagepant slightly increases the plasma levels of sumatriptan, but without an apparent clinically meaningful effect.
Introduction
Migraine is a common neurovascular disorder characterized by attacks of severe headache that are highly disabling (1). Triptans, selective agonists of the serotonin receptor 5-HT1B/1D (2), are currently viewed as the most efficacious acute migraine-specific treatment. However, triptans can be associated with adverse events and their vasoconstrictor effects make them contraindicated in patients with substantial underlying cardiovascular disease, uncontrolled hypertension and certain migraine subtypes, including hemiplegic and basilar-type migraine (3,4).
Calcitonin gene-related peptide (CGRP) is a potent vasodilator and a neuropeptide that plays a key role in the pathophysiology of migraine (5). Elevated plasma levels of CGRP have been observed in the cranial circulation during a migraine attack (6) and the levels were normalized concomitantly with pain relief (7). Also, intravenous administration of CGRP to migraineurs induced a delayed migraine-like headache (8). CGRP receptors are found throughout the trigeminal pathways involved in migraine headache pain (9). These observations led to the conclusion that antagonism of the CGRP receptor might represent a novel therapeutic approach to treatment of migraine (10).
Clinical evidence for the utility of CGRP receptor antagonists for the acute treatment of migraine was initially obtained with olcegepant (BIBN4096BS) (11). This highly potent CGRP receptor antagonist (Ki = 10 pM) has shown compelling efficacy in a phase II clinical trial (12). However, the use of olcegepant is limited by intravenous administration. More recently, an orally available CGRP receptor antagonist telcagepant (MK-0974) (13) was shown to be effective for acute treatment of migraine with an efficacy comparable to zolmitriptan 5 mg but with fewer associated adverse effects (14,15). Importantly, CGRP receptor antagonists lack direct vasoconstrictor activity (16). Therefore, they may have the potential to treat migraine patients for whom vasoconstrictive agents are contraindicated.
In the present study, the cardiovascular effects of antimigraine therapy (i.e. triptans and CGRP receptor antagonists) were further evaluated. The goal was to understand whether telcagepant elevated mean arterial pressure (MAP) as compared to sumatriptan, and also to understand if there was a drug-drug interaction, possibly leading to an increased MAP effect, if the two drugs were coadministered. Preclinical data suggested that telcagepant may act as a weak inhibitor of monoamine oxidase B (MAO-B), an enzyme involved in the metabolism of sumatriptan. To that end, the MAP was measured in migraine patients during a headache-free period after administration of sumatriptan alone versus sumatriptan in combination with the oral CGRP receptor antagonist telcagepant and telcagepant alone versus placebo.
Methods
Full details of the study methods are provided in the study protocol which is available online as Supplementary Material.
Patients
Patients were eligible for the study if they were nonsmoking, healthy males or females between 18 and 65 years of age with a body mass index between 18 and 32 kg/m2. Patients had to have a history of migraine with or without aura according to International Headache Society criteria (17) for at least six months. All patients had to discontinue all medication including nonacute antimigraine medication within approximately two weeks of study initiation. However, acute antimigraine and ergot derivative medications were allowed within up to three days of receiving the study medication. Anti-emetic medications were allowed up to 48 hours and medication containing codeine up to 24 hours of dosing in each treatment period.
Patients were required to be in good health based on medical history, physical examination, electrocardiogram (ECG), vital signs (i.e. blood pressure (BP), heart rate, oral temperature and respiration rate) and standard clinical laboratory tests (hematology, blood chemistry and urinalysis). Females were required to have a negative pregnancy test at screening and agreed to remain abstinent or use appropriate double-barrier contraception during the study. Patients with a history or clinical evidence of either cardiovascular disease or hypertension were excluded. Patients had to have a resting systolic BP (SBP) ≥ 90 mmHg and ≤140 mmHg, resting diastolic BP (DBP) ≥50 mmHg and ≤90 mmHg, and a resting heart rate ≥40 or ≤100 beats per minute after 10 minutes in a semi-recumbent position.
Protocol approvals and informed consent
The study was approved by the appropriate ethics committees and regulatory agencies. Prior to initiation of study procedures, each patient provided written informed consent. The study was conducted in accordance with the principles of Good Clinical Practice and local regulations. The study was registered at ClinicalTrial.gov: NCT00701389.
Study design
This was a multicenter, randomized, double-blind, placebo-controlled, four-period, single-dose crossover study to evaluate the safety, tolerability and effect on BP of oral doses of sumatriptan alone, sumatriptan in combination with telcagepant and telcagepant alone in 24 migraine patients. The study (Merck Protocol 026) was conducted at two sites between December 2007 and April 2008: at the Centre for Clinical Pharmacology, University Hospitals Leuven, Campus Gasthuisberg, Leuven, Belgium, Europe, and at the New Orleans Center for Clinical Research, University of Tennessee Medical Centre, Knoxville, TN, United States.
Patients who had met the study eligibility criteria at the screening visit received prior to randomization a single, oral dose of 100 mg sumatriptan to familiarize themselves with the effects that they may experience when administered sumatriptan during the treatment phase of the study.
During each treatment period, migraine patients were randomized to receive one of four different treatments in a blinded fashion according to an allocation schedule generated by a statistician at Merck: telcagepant 600 mg (given as 2 × 300 mg capsules with a placebo for sumatriptan tablet), telcagepant 600 mg coadministered with sumatriptan 100 mg (given as 2 × 300 mg telcagepant capsules with a sumatriptan tablet), sumatriptan 100 mg (given as a sumatriptan tablet with 2 × placebo for telcagepant capsules), and placebo (given as a placebo for sumatriptan tablet and 2 × placebo for telcagepant capsules). The patients were blindfolded at the time of dosing and the study drug was administered to the patients by a designated unblinded dosing administrator who ensured that the blindfold was appropriately placed on the patient and that the appropriate dose of study drug was administered. There was a minimum five-day wash-out interval between treatment periods.
The patients were free from migraine 24 hours prior to receiving the study dose in each period. During each period, study drug was administered under supervision with 240 ml of water and at approximately the same time of the day. This study used a nonmatching placebo for sumatriptan. Therefore, the study medication was administered to the blindfolded patient by a designated unblinded person who was not otherwise involved in the conduct of the study. Patients were in a fasting state for at least four hours prior to dosing and up to four hours postdose. Patients abstained from consuming caffeinated or alcoholic beverages 24 hours before dosing until six hours postdose after the last measurements.
Pharmacodynamics
DBP, SBP and heart rate were measured in duplicate at predose and at 30, 60, 90, 120 and 150 minutes and three and six hours after drug administration in each treatment period. Measurements were performed at the same arm throughout the study using an automated BP machine. Patients remained in a semi-recumbent position from predose baseline measurements until six hours after administration.
Pharmacokinetics
Plasma samples for pharmacokinetic analysis of sumatriptan were collected predose and at 30, 60, 90, 120 and 150 minutes and three and six hours after drug administration in each treatment period immediately following the previous BP/heart rate measurement.
Tolerability and safety
Tolerability and safety were assessed by adverse experiences monitoring and by physical examinations, vital signs, 12-lead ECGs and laboratory safety evaluation throughout the study.
Drug supplies
Telcagepant and corresponding placebo was supplied in a liquid-filled oral soft elastic (OSE) capsule formulation manufactured by Banner Pharmacaps Inc. The bulk drug used for telcagepant was telcagepant monopotassium salt, ethanolate supplied by Merck Research Laboratories. Sumatriptan (IMITREX™, sumatriptan succinate) was manufactured by GlaxoSmithKline. The placebo for sumatriptan was manufactured by Merck & Co. Inc.
Bioanalysis and pharmacokinetic calculations
Plasma samples were assayed for sumatriptan concentrations. A 250 µl sample aliquot was fortified with 100 µl of internal standard working solution and diluted with 250 µl of 100 mM ammonium formate, pH 9.0. Both analyte and internal standard were isolated from human plasma through solid-phase extraction using an Oasis HLB 96-well SPE plate. The eluate was evaporated and the remaining residue was reconstituted with 150 µl of 10 mM ammonium formate/acetonitrile, 70 : 30, volume to volume (v/v). The final extracts were analyzed by high-pressure liquid chromatography with tandem mass spectrometry detection. The lower limit of quantitation for sumatriptan was 0.200 ng/ml with a linear calibration curve range of 0.200 ng/ml to 100 ng/ml.
The area under the plasma concentration versus time curve to six hours (AUC0–6h) for sumatriptan was calculated using the linear trapezoidal method for ascending concentrations and the logarithmic trapezoidal method for descending concentrations. The maximum concentration observed (Cmax) and the time at which Cmax was observed (Tmax) were assessed by inspection of the plasma concentration data. The pharmacokinetic calculations were performed using WinNonlin Enterprise version 5.0.1.
Endpoints and statistical analysis
Pharmacodynamics
MAP was calculated using the following formula: MAP = DBP + (0.33 * PP) where PP = SBP–DBP. Individual time-weighted averages in MAP, calculated as the area under the measurement-time curve from predose through 2.5 hours of MAP divided by the time period over which measurements were made (i.e. AUC0–150 min/150 minutes), were evaluated using a linear mixed-effects model appropriate for a four-period crossover study (with fixed effects for period and treatment, and a random effect for patient). Replicate BP measurements at a given timepoint were averaged prior to calculation of the time-weighted averages.
To determine if the time-weighted average in MAP following sumatriptan with telcagepant is similar to sumatriptan alone, a two-sided 90% confidence interval (CI) (equivalent to a one-sided upper 95% CI) for the mean treatment difference (sumatriptan with telcagepant–sumatriptan alone) was calculated using the linear mixed-effects model. If the upper bound of the 90% CI is <5 mmHg, the hypothesis that the effect on semi-recumbent MAP, following telcagepant with sumatriptan, is similar to that following sumatriptan alone would be supported. Telcagepant versus placebo and sumatriptan alone versus placebo were analyzed in a similar fashion. Time-weighted SBP and time-weighted DBP were both analyzed in a similar fashion as time-weighted MAP.
Pharmacokinetics
Paired t tests were used to compare the pharmacokinetics of sumatriptan when administered alone and in combination with telcagepant. Prior to analysis, individual sumatriptan AUC0–6h values were natural log-transformed and analyzed with a linear mixed-effects model with treatment (sumatriptan alone; sumatriptan with telcagepant) as a fixed effect and patient as a random effect. Using the model, the 90% CI for the difference in means for log-transformed AUC0–6h (sumatriptan with telcagepant-sumatriptan alone) was calculated using the mean square error from the model and referencing a t distribution. These confidence limits were exponentiated to obtain the 90% CI for the AUC0–6h geometric mean ratio (sumatriptan with telcagepant/sumatriptan alone). Sumatriptan Cmax and C6h were analyzed in a similar fashion. Summary statistics were provided for Tmax.
Safety
Safety and tolerability were evaluated in migraine patients by the clinical assessment of adverse experiences and other safety measurements. Summary statistics were performed for laboratory analysis, vital signs and ECGs.
All statistical analyses were performed using SAS version 8 or later (SAS Institute, Cary, NC).
Power calculations
Pharmacodynamics
Sumatriptan with telcagepant versus sumatriptan alone
The power calculations for time-weighted MAP were based on an assumed true within-subject standard deviation of 2.83 mmHg for the 100 mg sumatriptan group (18). With at least 20 migraine patients completing the study, alpha = 0.05 (one-sided), there was 0.99 probability that the upper limit of the 90% CI for the treatment difference (sumatriptan with telcagepant–sumatriptan alone) would lie below 5 mmHg, given that the true difference is 0. The true difference could be as high as 2.75 mmHg and still would have had 80% power to support the hypothesis.
Telcagepant versus placebo
The precision of the estimate of the effect of telcagepant on MAP compared to placebo was assessed by calculating the half-width of the 90% CI expected for the given sample size and assumed variability. The following precision estimate was based on an assumed within-subject standard deviation of 2.83 mmHg for the 100 mg sumatriptan group. With at least 20 patients completing the study, the half width of the 90% CI for the treatment difference (telcagepant–placebo) would be 1.50 mmHg. Thus, for example, if the observed treatment difference was 0, the 90% CI would be (−1.50, 1.50).
Safety
If an adverse experience occurs at a rate of 1% or 10%, then the chance of observing such an adverse event among at least 20 migraine patients completing the study was 18% or 88%, respectively. At the end of the study, for a particular adverse event, if none were observed in any of the 20 migraine patients, then the true incidence is less than 8% with 80% confidence (less than 11% with 90% confidence).
Results
Patient demographics
Subject baseline demographics.
Pharmacodynamics
Table 2 summarizes the statistics of time-weighted MAP, SBP and DBP (0–150 minutes), including the corresponding 90% CI following single-dose administration of 600 mg telcagepant alone, 100 mg sumatriptan alone, 600 mg telcagepant with 100 mg sumatriptan, or placebo. The mean change from baseline (±SD) over time for MAP is presented in the Figure 1.
Mean (±SD) change from baseline for the time-weighted mean arterial pressure (0–150 minutes) (a), for the time-weighted mean systolic blood pressure (0–150 minutes) (b) and for the time-weighted mean diastolic blood pressure (0–150 minutes) (c) following single-dose administration of 600 mg telcagepant alone, 600 mg telacagepant with 100 mg sumatriptan, 100 mg sumatriptan alone or placebo to migraine patients. Statistical summary of the time-weighted mean arterial pressure (0–150 minutes), of the time-weighted mean systolic blood pressure (0–150 minutes) and of the time-weighted mean diastolic blood pressure (0–150 minutes) following single-dose administration of 600 mg telcagepant alone, 600 mg telcagepant with 100 mg sumatriptan, 100 mg sumatriptan alone or placebo to migraine patients. Area under the curve (AUC)0–150 min/150. bCalculated from analysis of variance model (ANOVA). cCI: confidence interval; LS mean: least squares mean; MAP: mean arterial pressure; SBP: systolic blood pressure; DBP: diastolic blood pressure. dN: 22 (Two subjects vomited during sumatriptan alone treatment: data excluded).
The mean difference in time-weighted MAP (0–150 minutes) between sumatriptan and placebo was 4.0 mmHg and the upper bound of the 90% CI was 5.5 mmHg (i.e. above the predefined upper bound of <5 mmHg), thereby confirming the well-documented increase in BP caused by sumatriptan. Telcagepant, however, did not result in a significant increase in BP when administered alone (mean difference versus placebo of 1.2 mmHg (90% CI: −0.2, 2.7)). Furthermore, the combination of telcagepant plus sumatriptan did not result in a significant increase in BP beyond that expected from sumatriptan alone (mean difference versus sumatriptan of 1.5 mmHg (90% CI: 0.0, 3.0)). Both SBP and DBP were increased to the same extent following sumatriptan administration alone or with telcagepant.
Pharmacokinetics of sumatriptan
Summary of sumatriptan pharmacokinetic results following single-dose administration of 100 mg sumatriptan alone and with 600 mg telcagepant to migraine patients.
AUC: area under the curve. aGeometric mean computed from least squares estimate from a mixed-effects model performed on the natural-log transformed values (% CV). bMSE: Mean square error arising from mixed-effects model performed on the log-scale. cMedian (Min, Max) reported for Tmax. dN = 22 (Two subjects vomited during sumatriptan alone treatment: data excluded).
Safety
There were no serious adverse experiences. No patients discontinued the study because of an adverse experience. All clinical adverse experiences were mild to moderate in intensity. Twenty of the 24 patients enrolled reported one or more clinical adverse experiences. The most common adverse experience following administration of 600 mg telcagepant was nausea (n = 3). The most common adverse experiences following administration of 100 mg sumatriptan were nausea (n = 2), vomiting (n = 2), headache (n = 2) and migraine (n = 4). The most common adverse experience following coadministration of 100 mg sumatriptan with 600 mg telcagepant was migraine (n = 3). The most common adverse experience following placebo was migraine (n = 5).
There were no laboratory adverse experiences of clinical importance except for two subjects in whom bilirubin increased. One subject experienced an elevation in bilirubin of two times the upper normal limit and one subject of three times the upper normal limit at several post-treatment measurements throughout the study. Both subjects exhibited elevated bilirubin prior to dosing with telcagepant. Elevated bilirubin was not accompanied by elevations in hepatic transaminases or symptoms of hepatic injury.
No clinically meaningful findings were observed for physical examinations, heart rate or ECGs as a function of treatment. Sumatriptan treatment was associated with elevated BP consistent with known effects of triptans.
Discussion
CGRP receptor antagonists represent a new treatment approach for acute migraine headache with a reported incidence of adverse events similar to that of placebo (19). Furthermore, although CGRP itself is a potent vasodilator, CGRP receptor antagonists appear not to exhibit vasoconstrictor activity. As migraine patients may combine several medications to relieve migraine headache, the potential to use both a triptan and a CGRP receptor antagonist exists. The present study was conducted to evaluate the impact of a small-molecule CGRP receptor antagonist (MK-0974, telcagepant) on the vascular effects of a triptan (sumatriptan) by assessing the effect on BP of each compound alone as well as the combination of both. In this pharmacodynamic drug-interaction study with sumatriptan, we found that the oral CGRP receptor antagonist telcagepant did not significantly increase MAP when administered as monotherapy to migraineurs during the interictal period. Coadministration with sumatriptan resulted in an increased MAP, comparable to the increase reported after the intake of sumatriptan alone.
Triptans are selective 5-HT1B/1D receptor agonists used for the treatment of migraine and cluster headache. Although as a class the triptans are effective and generally well-tolerated drugs, a major limitation for their use is their cardiovascular side effect profile (20). Because of the activation of vascular 5-HT1B receptors, triptans exhibit vasoconstrictor properties resulting in an elevated BP in humans. Therefore, triptans are contraindicated in patients with vascular disease and patients at increased risk for acute cardiovascular events. The most common, and highest, clinical oral dose of sumatriptan used is 100 mg (21). In previous studies evaluating the effects of sumatriptan on cardiovascular hemodynamics, effects were observed at doses ranging from 25 to 100 mg (22). For this study, a 100 mg dose was selected for sumatriptan. The dose used for telcagepant was based on a dose-finding phase II study and a pivotal phase III study, in which it was demonstrated that a 300 mg dose of telcagepant has an efficacy comparable with that of the triptans for the treatment of acute migraine headache (14,23). As the anticipated clinical dose of telcagepant was a single 300 mg dose, with an optional second 300 mg dose two hours later if needed for pain relief, a dose of 600 mg of telcagepant was used in this study. A single 600 mg dose achieves pharmacokinetic exposures slightly higher than those anticipated after two 300 mg doses administered two hours apart. Based on pharmacodynamic/pharmacokinetic modeling results in healthy men from a capsaicin-induced dermal vasodilation assay, which is a biomarker for peripheral blockade of CGRP receptor binding, a 300 mg dose of telcagepant is predicted to inhibit on average 90% of the capsaicin-induced dermal vasodilation response for about four hours shortly following oral administration (24).
Prior triptan studies describing cardiovascular effects have used invasive (25) and sophisticated noninvasive techniques (21,26) to assess BP, as well as standard sphygmomanometry (27,28). In this study, oscillometric sphygmomanometry was used. In a previous study oscillometric BP measurement appeared to be a sensitive technique to detect sumatriptan-induced vascular effects (29). Although BP was measured over a six-hour period following treatment, time-weighted average MAP over 2.5 hours was calculated. That is around the expected time to reach maximal plasma concentrations after oral sumatriptan (±1.5 hours) and telcagepant (±1 to 2 hours) and thus around the maximal potential effect on MAP. The population used was migraine patients as they are the target population for both telcagepant and sumatriptan and they are known to have alterations in arterial function (30).
In accordance with previously reported studies (21,26,28), sumatriptan alone resulted in a statistically significant and clinically meaningful increase in MAP that demonstrates assay sensitivity. The addition of telcagepant did not significantly change the BP effects of sumatriptan alone: the time-weighted average MAP over 2.5 hours following the coadministration of telcagepant and sumatriptan was similar to that following administration of sumatriptan alone. Importantly, telcagepant alone, at a high clinical dose used in this study (i.e. 600 mg), did not show any effect on MAP: the change in MAP was statistically not different from placebo. This observation is consistent with the findings from recent studies showing that CGRP receptor antagonists prevent vasodilation but are devoid of vasoconstrictor activity. Petersen at al. demonstrated that olcegepant, the first CGRP receptor antagonist developed by Boehringer-Ingelheim, did not produce any change in systemic or cerebral rat or human circulation (16). Clinical studies with high doses of telcagepant, i.e. 560 and 600 mg, daily for up to eight days demonstrated no clinically significant effects on 24-hour mean ambulatory BP or heart rate (31). Furthermore, our group showed that telcagepant had no significant influence on the vasodilatory response of healthy male volunteers to therapeutic doses of sublingual nitroglycerin (32).
Pharmacokinetic sampling through six hours after drug administration was used to estimate sumatriptan exposure during this study. It appears that coadministration of telcagepant with sumatriptan may result in slightly elevated sumatriptan levels. Sumatriptan is primarily metabolized by oxidative deamination to the inactive indole acetic acid via the enzyme MAO-A (33,34). The increases in AUC and Cmax (23% and 24%, respectively) are consistent with in vitro findings suggesting that telcagepant may be a weak inhibitor of MAO-A with an IC50 ∼ 19 µM. This slight elevation in sumatriptan levels appeared not to result in a clinically meaningful change in time-weighted MAP. No statistically significant increase in mean MAP was observed for sumatriptan plus telcagepant compared to sumatriptan alone; however, small changes in mean MAP associated with the slight elevation in sumatriptan levels cannot be excluded.
Telcagepant was generally well tolerated in this study, alone and in combination with sumatriptan. There were no serious adverse experiences. All clinical adverse experiences were mild to moderate in intensity. There were no consistent treatment-related changes in heart rate, laboratory or ECG safety parameters. In conclusion, administration of telcagepant alone does not elevate MAP while coadministration with sumatriptan results in elevations in MAP similar to that following administration of sumatriptan alone in migraineurs during the interictal period. Therefore, coadministration of telcagepant with sumatriptan appears to be generally well tolerated with no additional clinically relevant effect on the sumatriptan-induced vascular effects.
A limitation of this study is that BP effects of the telcagepant-sumatriptan combination were assessed in cardiovascularly healthy patients outside a migraine attack. It is possible that different results may have been obtained had BP been measured during an attack. It is also possible that different results may be obtained in cardiovascularly impaired patients or under conditions of cardiac stress, although the contraindication of triptans in those with cardiovascular disease would make it difficult to perform such a study.
Clinical implications
Triptans are effective acute migraine treatments but are contraindicated in patients with cardiovascular disease because of potential vasoconstrictor effects. Calcitonin gene-related peptide (CGRP) receptor antagonists are investigational acute migraine treatments that appear to lack direct vasoconstrictor activity. The present study compared the effects of a triptan (sumatriptan), a CGRP receptor antagonist (telcagepant), and their combination on blood pressure (BP) in migraine patients during a headache-free period. As expected, sumatriptan monotherapy increased BP while telcagepant monotherapy did not. The combination of telcagepant plus sumatriptan did not result in a significant additional increase in BP beyond that due to sumatriptan alone. These data suggest that coadministration of a CGRP receptor antagonist with a triptan has no additional clinically relevant effect on triptan-induced vascular effects.
Footnotes
Acknowledgments
The authors would like to thank Gertrude Noonan and Christopher Lines from Merck for their assistance in drafting and revising the paper and Sheila Erespe from Merck for assistance in formatting the paper.
Funding
This study was funded by Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA. 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.
Conflicts of interest
CM, JP, MOB, IL, TH, DP, RB, JAC and MGM are current or former employees of Merck and own or owned stock/stock options in Merck; MD, WBS and JNH have received research funding from Merck.
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.