pii: jc- 00084-15http://dx.doi.org/10.5664/jcsm.5382
S CI E NT IF IC IN VES TIGATIONS
Effects of Suvorexant, an Orexin Receptor Antagonist, on Respiration during Sleep In Patients with Obstructive Sleep Apnea Hong Sun, MD, PhD1; John Palcza, MS1; Deborah Card, MS1; Adrianna Gipson, MS1; Russell Rosenberg, PhD2; Meir Kryger, MD3; Christopher Lines, PhD1; John A. Wagner, MD, PhD1; Matthew D. Troyer, MD1 Merck & Co., Inc., Kenilworth, NJ; 2NeuroTrials Research, Atlanta, GA; 3Yale School of Medicine, New Haven, CT
1
Study Objectives: To investigate the respiratory effects of suvorexant, an orexin receptor antagonist for treating insomnia, in patients with obstructive sleep apnea (OSA). Methods: This was a randomized, double-blind, placebo-controlled, 2-period (4 days per period), crossover, sleep laboratory study. Twenty-six patients aged 18–65 years with mild (apnea-hypopnea index [AHI] ≥ 5 and < 15) to moderate (AHI ≥ 15 and < 30) OSA were randomized to receive suvorexant 40 mg or placebo in period-1 and then crossed over to the other treatment in period-2. Breathing during sleep was measured by AHI (primary endpoint) and oxygen saturation assessed by pulse oximetry (SpO2, secondary endpoint). The study was powered to rule out a mean increase in AHI between suvorexant and placebo of 5 or greater on Day 4. Results: There was a small increase in mean AHI (2.66) in OSA patients after multiple doses of suvorexant relative to placebo, with the upper 90% CI bound slightly exceeding 5.00 (0.22, 5.09). No increase in mean AHI was observed after a single dose of suvorexant versus placebo (mean difference = −0.47 [−3.20, 2.26]), and there was no treatment effect on mean SpO2 during total sleep time after single or multiple doses (Day 1: mean difference = −0.04 [−0.49, 0.42]; Day 4: mean difference = −0.06 [−0.45, 0.33]). There was inter- and intra-individual variability in suvorexant respiratory effects. Conclusions: Suvorexant 40 mg, twice the 20 mg maximum recommended dose for treating insomnia in the USA and Japan, does not appear to have clinically important respiratory effects during sleep in patients with mild to moderate OSA as assessed by mean AHI and SpO2. Due to inter- and intraindividual variability in respiratory effects, suvorexant should be used with caution in patients with compromised respiratory function, and at the lowest effective dose. Clinical Trial Registration: clinicaltrials.gov, NCT01300455. Keywords: suvorexant, MK-4305, orexin, respiration, obstructive sleep apnea, randomized trial Citation: Sun H, Palcza J, Card D, Gipson A, Rosenberg R, Kryger M, Lines C, Wagner JA, Troyer MD. Effects of suvorexant, an orexin receptor antagonist, on respiration during sleep in patients with obstructive sleep apnea. J Clin Sleep Med 2016;12(1):9–17.
I N T RO D U C T I O N
BRIEF SUMMARY
Current Knowledge/Study Rationale: Suvorexant is a first-in-class orexin receptor antagonist that is approved in the USA and Japan for the treatment of insomnia. Given the coexistence of insomnia and sleep apnea in many patients, it is important to examine the respiratory safety of any new insomnia medication in patients with sleep apnea. Study Impact: The findings of this study show that a nighttime 40 mg dose of suvorexant (twice the 20 mg maximum daily dose approved in the USA and Japan) does not have clinically meaningful effects on respiration during sleep in patients with mild to moderate obstructive sleep apnea as assessed by mean changes in number of apneas/hypopneas and oxygen saturation. Because there is inter- and intra-individual variability in respiratory effects, suvorexant should be used with caution in patients with compromised respiratory function, and at the lowest effective dose.
Sleep apnea and insomnia commonly coexist, especially in women.1–3 Sedative hypnotics represent the main pharmacologic therapy for insomnia, but there are concerns about administering these medications in patients who have untreated sleep apnea. Benzodiazepines used as sedative hypnotics bind to the benzodiazepine receptor at the GABA-A complex (e.g., triazolam, flurazepam) and might be associated with depression of central respiratory drive, blunting of the arousal response to hypoxia, and decreases in muscle tone in the upper airways.4–6 Limited data are available regarding the use of the newer nonbenzodiazepine benzodiazepine receptor agonists (e.g., zolpidem, zaleplon, zopiclone, and eszopiclone) in patients with sleep apnea, although some researchers have found no evidence of a significant effect on respiratory measures7 and others have even reported an improvement in aspects of respiration in apnea patients without marked hypoxemia.8 Given the coexistence of insomnia and sleep apnea in many patients and the speculated potential for hypnotic agents to negatively affect respiration, it is important to examine the respiratory safety of new sedative hypnotic drugs being investigated for the treatment of insomnia.
Orexin receptor antagonism represents a new approach to the treatment of insomnia.9–14 Orexin receptor antagonists appear to promote sleep by selectively blocking the brain’s orexin-mediated wake system thereby enabling the transition to sleep. Orexin neurons originate in the lateral hypothalamus and project throughout the brain, including to respiratory 9
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Standard Protocol Approvals, Registrations, and Patient Consents
centers in the brainstem, suggesting that orexin has a role in controlling respiration.15,16 Although limited data are available, there is no strong evidence to suggest that an orexin receptor antagonist would impair respiratory function. Studies in orexin knockout mice or rodents receiving an orexin receptor antagonist show an attenuation of the hypercapnic response (response to excess CO2 ) in the wake state but not in the sleep state.17,18 No difference in the respiratory response to CO2 was observed between narcolepsy patients with impaired orexin signaling and healthy controls.19 The orexin receptor antagonist suvorexant (MK-4305)20–22 has been shown to be effective for the treatment of insomnia in previous clinical trials at doses of 10, 20, or 40 mg in nonelderly patients and 15 or 30 mg in elderly patients.23–25 The maximum recommended dose approved in the USA and Japan is 20 mg once daily.26 Our group has recently shown that suvorexant does not significantly impair respiratory function in patients with mild to moderate chronic obstructive pulmonary disease (COPD).27 Here we report results from a study which assessed the effects of single and multiple doses of suvorexant 40 mg (twice the maximum recommended dose) on respiratory function during sleep in non-elderly adult patients with obstructive sleep apnea (OSA). The primary endpoint used to assess changes in breathing pattern was the apnea hypopnea index (AHI), a measure of the number of apneas and hypopneic episodes during an hour of sleep.
The study was conducted in accordance with principles of Good Clinical Practice and was approved by the appropriate institutional review committees and regulatory agency. After explanation of the study procedures, risks, and benefits, written informed consent was obtained from all patients. Patients were compensated for their participation. The study was registered at ClinicalTrials.gov (NCT01300455).
Study Design and Procedure
This multi-center, randomized, double-blind, placebo-controlled, 2-period (4 days per period) crossover study (Merck protocol 036) was performed at 6 sleep laboratories/clinical research units in the United States from April 2011 to July 2011. Following an initial screening visit, patients who met the inclusion/exclusion criteria underwent a screening nighttime PSG visit within approximately 3 weeks prior to initial dosing on Day 1 of Period 1. A sleep history diary was used to establish habitual median bedtime for ≥ 5 consecutive nights any time prior to the screening PSG visit. The median bedtime established during this period (± 1 hour) was used as the bedtime (“lights-off”) for the screening PSG visit and PSG collection on Day 1 and 4 in Periods 1 and 2. The screening PSG visit was also used to further define patient eligibility to exclude sleep disorders other than insomnia, and evaluate oxygen saturation. Following the screening PSG visit, eligible patients were admitted to the study site on Day 1 of Period 1 and were randomized to 1 of 2 treatment sequences. In Period 1, patients were administered a single 40 mg oral dose of suvorexant or matching placebo, for 4 consecutive days, before being crossed over to the other treatment in Period 2. A 40 mg dose of suvorexant, twice the maximum recommended 20 mg dose, was evaluated because it was the maximum dose investigated in phase 3 trials.24,25 At the time the OSA study was initiated, it was thought that 40 mg might be the maximum recommended dose. In each period, study drug was administered in the evening at approximately 0.5 h before bedtime (“lights-off”). On Days 1 and 4, study drug was administered following a 4-h fast. In both study periods, patients remained overnight in the sleep laboratory/clinic on Day 1 and Day 4 for PSG recording and O2 monitoring via finger pulse oximetry (SpO2 ). PSG recording commenced at the time of lights-off and continued for 8 hours. SpO2 monitoring commenced approximately 15 min prior to dosing and continued during PSG recording. Patients were discharged on the morning of Day 2 after all study procedures were completed and patients continued to take study drug at home. On Day 4, patients were readmitted to the sleep laboratory/clinic for evening study drug administration and remained overnight for PSG recording and SpO2 monitoring. There was ≥ 7 days washout between each treatment period. Sleep stage scoring was performed according to the American Academy of Sleep Medicine Manual for Scoring of Sleep and Associated Events,29 which maintained much of the Rechtschaffen and Kales framework for standardized scoring methods and criteria.30 Next-day residual effects were assessed the morning after PSG recording on nights 1 and 4, at approximately 9 h post dose, using Immediate and Delayed Word
METHODS Full details of the study procedures are in the study protocol which is available in the supplemental material.
Patients
Eligible patients were men and women between the ages of 18 to 65 years (inclusive) with an International Classification of Sleep Disorders diagnosis of OSA28 based on the investigator’s assessment and diagnostic interview along with a documented sleep study (i.e., nighttime polysomnography [PSG] in a sleep laboratory) within the past 5 years that confirmed the OSA diagnosis. The severity of OSA had to be mild (AHI between 5 and 14 inclusive) or moderate (AHI between 15 and 29 inclusive) based on the screening PSG. Patients were excluded if they had a screening PSG recording with O2 saturation < 80% for ≥ 5% of the total sleep time (TST), or > 10 periodic limb movements per hour associated with an arousal. Patients were excluded if they used a continuous positive airway pressure (CPAP) device or a dental appliance within the preceding 7 days prior to screening PSG, or were required to use CPAP or a dental appliance during the course of the study. Patients with other respiratory disorders were excluded. Patients with the following sleep disorders were excluded, but patients with insomnia could be included (patients were not required to have insomnia): narcolepsy, cataplexy (familial or idiopathic), circadian rhythm sleep disorder, parasomnia including nightmare disorder, sleep terror disorder, sleepwalking disorder, REM behavior disorder, periodic limb movement disorder, restless legs syndrome, primary hypersomnia. Journal of Clinical Sleep Medicine, Vol. 12, No. 1, 2016
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Recall,31 the Digit Symbol Substitution Test,32 Bond-Lader Visual Analog Scales,33 and Body Sway assessments.34
endpoints included PSG measures (LPS, WASO, TST, SEI, REM, and NREM), and endpoints assessing next morning residual effects (Immediate and Delayed Word Recall, Digit Symbol Substitution Test, Bond-Lader Visual Analog Scales, Body Sway). PSG measures were analyzed on the natural log scale with model based least squares means and confidence intervals back-transformed to the original scale to obtain geometric means and geometric mean ratios with corresponding confidence intervals. This was done to allow for a relative fold change comparison of these endpoints across treatments. Data were analyzed using SAS Version 9.2.
Endpoints
The mean AHI score on Day 4 was the primary endpoint. AHI was measured as defined by the American Academy of Sleep Medicine.29 Effects on the AHI as measured by PSG, calculated by dividing the number of apneas and hypopneas by the total sleep time (in minutes) and multiplying by 60 (i.e., the average number of apneas and hypopneas per hour of sleep), were evaluated on Day 1 and Day 4. The mean oxygen saturation (SpO2 ) for TST on Day 1 and 4, as well as for each of the different sleep stages (awake, NREM, REM) on Day 1 and Day 4, were also compared. SpO2 data used for the analyses were rounded to the nearest integer. Exploratory endpoints included PSG measures of latency to persistent sleep (LPS), wake after sleep onset (WASO), sleep efficiency index (SEI), TST, REM, and NREM and scores on assessments of next-morning residual effects (Immediate and Delayed Word Recall, Digit Symbol Substitution Test, Bond-Lader Visual Analog Scales, Body Sway). Safety and tolerability were evaluated by clinical assessment of adverse experiences and other safety measurements (e.g., vital signs, ECGs, routine laboratory blood chemistry, hematology, and urinalysis measures). The following were prespecified as events of clinical interest in the protocol: cataplexy, sleep paralysis and sleep onset paralysis, hypnagogic or hypnopompic hallucinations, suicidal ideation and/or behaviors, complex sleep-related behaviors, falls, selected events associated with potential for abuse, and traffic/vehicle accidents.
Power
A mean difference between treatments in AHI > 5 was considered clinically meaningful. Assuming a true within-patient variance of 14.62 for AHI based on pooled data from 2 previous studies,7,35 a total of 24 patients completing the crossover study, and significance level α = 0.05 (one-sided), there was 0.92 probability that the upper bound of the 90% CI for the true mean difference in AHI (suvorexant − placebo) on Day 4 would be < 5, if the true difference is as high as 1.5. The true mean difference could be as high as 2.17 and still have 80% power to support the hypothesis. For the secondary endpoint of mean SpO2 during total sleep time, a 2% decrease in mean SpO2 during TST was considered a clinically meaningful change. SpO2 is typically lower at night during sleep than while awake. Assuming a true withinpatient variance of 0.763%2 for mean SpO2 as observed in a previous study,35 a total of 24 patients completing the crossover study, and significance level α = 0.05 (one-sided), there was 0.99 probability that the lower bound of the 90% CI for the true mean difference in mean SpO2 (suvorexant − placebo) on Day 4 would be greater than −2%, if the mean true difference is as low as −1%. The true difference could be as low as −1.35% and still have 80% power to support the hypothesis.
Statistical Analysis
The primary hypothesis was that multiple doses of suvorexant do not produce a clinically significant increase in AHI in patients with mild to moderate OSA as compared to placebo; specifically, the true mean AHI treatment difference (suvorexant − placebo) on Day 4 is less than 5. Individual AHI values on Day 4 were evaluated using a linear mixed-effects model appropriate for a 2-period crossover study. This model was used to adjust for key design elements by including fixed effects for treatment, period, and sequence, and a random effect for patient within sequence. Using an appropriate linear contrast, a two-sided 90% confidence interval (equivalent to a one-sided upper 95% CI) for the true mean difference (suvorexant − placebo) in AHI was calculated using the mean square error from the model and referencing a t-distribution. Results are reported as least squares means and confidence intervals obtained from the statistical model. If the upper bound of the CI was < 5, then the hypothesis that multiple oral doses of suvorexant do not produce a clinically significant increase in AHI in patients with mild to moderate OSA would be supported. Day 1 results were analyzed in a similar fashion as above. Additional secondary and other exploratory endpoints were analyzed using the same methods to estimate the effects of single and multiple dose administration of suvorexant. Secondary endpoints included mean SpO2 during total sleep time, mean SpO2 during REM, NREM, and awake stages, and the percentage of total sleep time when SpO2 was less than 90%, 85%, and 80% during the night. Exploratory
R ES U LT S
Patient Accounting and Characteristics
Twenty-six patients with mild to moderate OSA were enrolled in this study and 25 completed the study (Figure 1). One patient discontinued due to a scheduling conflict after completing Period 1 and before starting Period 2. Twenty-four patients had complete evaluable SpO2 data from both treatment periods. The patient who discontinued had data from only Period 1 (suvorexant), which were included in the statistical respiratory analyses. For another patient, Period 2/Day 1 (placebo) SpO2 data were missing due to malfunctioning equipment. Patient characteristics are shown in Table 1. Of the 26 enrolled patients, 12 had moderate OSA and 14 had mild OSA; 7 were women and 19 were men; 6 were black and 20 were white. The mean age was 49 years (range = 30 to 64 years). One patient was reported to have comorbid insomnia.
Respiratory Effects
Table 2 presents the results of the statistical analysis of respiratory safety endpoints (AHI and SpO2 ). The mean AHI 11
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treatment difference (suvorexant − placebo) and 90% CI on Day 4 was 2.66 (0.22, 5.09). Since the upper bound of the 90% CI did not lie below 5, the primary hypothesis that multiple doses of suvorexant do not produce a clinically significant increase in AHI in patients with mild to moderate OSA, as compared to placebo, was not supported. The AHI treatment difference
(suvorexant − placebo) and 90% CI on Day 1 was −0.47 (−3.20, 2.26). Since the upper bound of the 90% confidence interval lay below 5, the secondary hypothesis that a single dose of suvorexant does not produce a clinically significant increase in AHI in patients with mild to moderate OSA, as compared to placebo, was supported. Suvorexant differences from placebo for AHI in individual patients are shown in Figure 2. Consistent changes in individuals across days were not apparent. The number of patients who had an AHI difference greater than 5 was eight on Day 4 and six on Day 1. However, only one patient had an individual AHI difference greater than 5 on both Days (Day 1 = 8.8, Day 4 = 12.5). It is of note that the withinpatient variability observed in the present study (mean squared error of 25.34) was larger than that in 2 previous studies of hypnotics’ effect in OSA patients (pooled mean squared error of 14.62),7,35 which was used to calculate the power of the present study. Of 8 patients whose AHI difference following suvorexant compared to placebo was ≥ 5 on Day 4, five showed a difference in which their AHI during placebo exceeded that following suvorexant by ≥ 5 on Day 1. One patient showed particularly large day-to-day variability; on Day 4 the patient had
Figure 1—Study flowchart.
Table 1—Patient baseline characteristics (n = 26). Mean age, years (range) Gender, n (%) Female Male Race, n (%) White Black OSA category Mild (AHI ≥ 5 and < 15) Moderate (AHI ≥ 15 and < 30) Mean AHI (range) Mean height, cm (range) Mean weight, kg (range) Mean BMI, kg/m2 (range)
There were 4 days in each treatment period. *n = 26 for suvorexant, n = 24 for placebo on Day 1, and n = 25 for placebo on Day 4 (1 patient withdrew before receiving placebo and therefore did not provide Day 1 or Day 4 data, and 1 patient had missing data on Day 1 of the placebo period due to equipment malfunction).
49 (30 to 64) 7 (26.9%) 19 (73.1%) 20 (76.9%) 6 (23.1%) 14 (53.8%) 12 (46.2%) 15.2 (5.4 to 29.7) 174.3 (149.8 to 190.5) 92.1 (58.0 to 129.5) 30.2 (23.6 to 39.8)
OSA, obstructive sleep apnea; AHI, apnea-hypopnea index; BMI, body mass index.
Table 2—Respiratory endpoints following single (Day 1) and multiple (Day 4) dose administration of suvorexant 40 mg or placebo in mild and moderate OSA patients. Suvorexant (n = 26) Endpoint LS Mean (95% CI) Apnea and hypopnea index†,a 16.25 (12.65, 19.86) Mean SpO2 during TST (%) 94.12 (93.48, 94.75) Mean SpO2 during NREM (%) 94.12 (93.47, 94.76) Mean SpO2 during REM (%) 94.08 (93.34, 94.82) Mean SpO2 during wake (%) 94.42 (93.74, 95.11) Percentage of total sleep time that SpO2 is < 90% 3.31 (1.03, 5.58) Percentage of total sleep time that SpO2 is < 85% 0.48 (0.12, 0.85)
Day 1 Placebo (n = 24) LS Mean (95% CI) 16.72 (13.02, 20.42) 94.15 (93.50, 94.80) 94.07 (93.41, 94.73) 94.14 (93.38, 94.90) 94.94 (94.23, 95.65) 2.57 (0.22, 4.92) 0.24 (−0.14, 0.61)
Suvorexant − Placebo Difference (90% CI) −0.47 (−3.20, 2.26) −0.04 (−0.49, 0.42) 0.05 (−0.41, 0.50) −0.06 (−0.61, 0.49) −0.51 (−1.13, 0.10) 0.74 (−1.31, 2.79) 0.25 (−0.10, 0.59)
Suvorexant (n = 26) LS Mean (95% CI) 17.07 (13.30, 20.84) 94.15 (93.53, 94.78) 94.27 (93.64, 94.90) 93.96 (93.17, 94.76) 94.73 (94.11, 95.36) 2.16 (0.88, 3.45) 0.69 (0.16, 1.23)
Day 4 Placebo (n = 25) LS Mean (95% CI) 14.41 (10.61, 18.22) 94.21 (93.59, 94.84) 94.25 (93.62, 94.89) 93.83 (93.03, 94.63) 94.91 (94.28, 95.54) 1.95 (0.66, 3.25) 0.41 (−0.13, 0.95)
Suvorexant − Placebo Difference (90% CI) 2.66 (0.22, 5.09)a −0.06 (−0.45, 0.33) 0.02 (−0.40, 0.43) 0.13 (−0.24, 0.50) −0.18 (−0.61, 0.25) 0.21 (−0.59, 1.01) 0.28 (−0.09, 0.65)
Primary endpoint = treatment difference in AHI on Day 4; upper bound of 90% CI was greater than the difference of 5 prespecified as clinically significant. AHI at screening, mean = 15.18, SD = 6.11 (n = 26). Higher AHI values and lower SpO2 values associated with impairment. Percentage of total sleep time that SpO2 is < 80% was also a prespecified endpoint, but due to the small number of patients meeting the endpoint, a formal statistical analysis was not conducted. LS Mean, least squares mean (from mixed effects statistical model); SpO2, oxygen saturation; TST, total sleep time. a †
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Figure 2—Individual treatment differences (suvorexant − placebo) for AHI in OSA patients.
Figure 3—Individual treatment differences (suvorexant − placebo) for mean SpO2 (%) during total sleep time (TST) in OSA patients.
A mean difference of 5 or greater in AHI was prespecified as clinically significant.
A mean difference of −2 percentage points or more in SpO2 was prespecified as clinically significant. SpO2 data used for the analyses were rounded to the nearest integer.
an AHI of 27 on placebo versus 47 on suvorexant, whereas the same patient’s AHI on Day 1 was 46 on placebo versus 26 on suvorexant. A sensitivity analysis excluding this patient found a mean treatment difference in AHI of 2.03 (90% CI: −0.23, 4.28) on Day 4, and 0.23 (90% CI: −2.28, 2.75) on Day 1. Thus when excluding this patient, the upper bound of the 90% CI lay below the prespecified bound of 5 on both days. The mean SpO2 (during TST) treatment difference (suvorexant − placebo) and 90% CI on Day 4 was −0.06% (−0.45%, 0.33%). Since the lower bound of the 90% CI interval was above −2%, the secondary hypothesis that multiple doses of suvorexant do not produce a clinically significant reduction of mean SpO2 during TST in patients with mild to moderate OSA, as compared to placebo, was supported. Similar findings were apparent for Day 1; the mean SpO2 (during total sleep time) treatment difference (suvorexant − placebo) and 90% CI on Day 1 was −0.04% (−0.49%, 0.42%). Suvorexant differences from placebo for SpO2 during TST in individual patients are shown in Figure 3. The mean treatment effects on SpO2 during NREM, REM, and awake as well as the percentage of TST that SpO2 was less than 90% and 85% were generally similar for suvorexant and placebo, on both Day 1 and Day 4 (Table 2). This was also the case when looking at mean SpO2 by hour of the night on Day 1 and Day 4 (Table S1, supplemental material).
(SEI). A statistically significant decrease in wake after sleep onset (WASO) for suvorexant relative to placebo was seen on Day 1. However, all results should be interpreted with caution as there was no multiplicity adjustment to account for the multiple endpoints and time points, and the false positive rate is inflated as a consequence. It should be noted that patients could be included in the study regardless of whether or not they had insomnia, but in practice only one patient was reported to have comorbid insomnia.
Next-Morning Residual Effects
Mean scores for suvorexant and placebo were generally similar on Immediate and Delayed Word Recall (Table S2, supplemental material), Digit Symbol Substitution Test (Table S2), Bond-Lader Visual Analog Scales (Table S2), and Body Sway assessments (Table S3, supplemental material) following both single and multiple doses.
Safety and Tolerability
Adverse events are summarized in Table 4. Eleven patients reported a total of 19 clinical adverse events, 11 of which were considered drug-related by the investigator. Of the 19 adverse events, 15 were rated mild in intensity; the remainder were rated as moderate in intensity. The most frequently reported adverse events were somnolence (19% of patients on suvorexant versus 0% on placebo) and nausea (8% of patients on placebo versus 0% on suvorexant). There were no serious adverse events, no deaths, and no discontinuations because of an adverse event. There were no prespecified events of clinical
PSG Effects
Results for the exploratory PSG endpoints are shown in Table 3. Statistically significant increases for suvorexant relative to placebo (i.e., ratios with confidence intervals not overlapping 1) were seen on both Days 1 and 4 for time in REM sleep and TST, and on Day 1 only for NREM sleep and sleep efficiency 13
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Table 3—Exploratory PSG endpoints following single (Day 1) and multiple (Day 4) dose administration of suvorexant 40 mg or placebo in mild and moderate OSA patients. Endpoint LPS (min)
NREM (min)
REM (min)
SEI (%)
TST (min)
WASO (min)
Geometric Mean (95% CI)* 15.80 (9.33, 26.76) 14.41 (8.70, 23.86) 13.55 (8.30, 22.13) 14.66 (9.03, 23.78)
Geometric Mean Ratio − Suvorexant/Placebo (90% CI)*
Day 1
Treatment Placebo Suvorexant
N 24 26
Arithmetic Mean (SD) 21.42 (20.24) 24.39 (17.97)
4
Placebo Suvorexant
25 26
22.22 (20.39) 25.50 (28.75)
1
Placebo Suvorexant
24 26
311.67 (49.68) 322.04 (37.76)
308.57 (290.45, 327.81) 319.72 (301.16, 339.43)
1.04 (1.01, 1.07)
4
Placebo Suvorexant
25 26
314.72 (40.21) 317.08 (41.50)
311.93 (294.14, 330.80) 314.01 (296.21, 332.87)
1.01 (0.98, 1.04)
1
Placebo Suvorexant
24 26
72.73 (27.75) 98.44 (29.40)
66.27 (56.04, 78.36) 94.36 (80.31, 110.86)
1.42 (1.22, 1.67)
4
Placebo Suvorexant
25 26
78.64 (22.91) 93.35 (32.46)
75.22 (66.00, 85.73) 88.59 (77.93, 100.71)
1.18 (1.03, 1.34)
1
Placebo Suvorexant
24 26
80.08 (11.14) 87.62 (5.43)
79.56 (76.20, 83.07) 87.45 (83.90, 91.16)
1.10 (1.06, 1.14)
4
Placebo Suvorexant
25 26
82.21 (10.42) 85.50 (8.19)
81.56 (77.70, 85.61) 85.08 (81.13, 89.21)
1.04 (0.99, 1.10)
1
Placebo Suvorexant
24 26
384.40 (53.46) 420.48 (25.96)
381.90 (365.78, 398.73) 419.69 (402.64, 437.47)
1.10 (1.06, 1.14)
4
Placebo Suvorexant
25 26
393.36 (49.98) 410.42 (39.29)
390.25 (371.88, 409.53) 408.38 (389.51, 428.16)
1.05 (1.00, 1.10)
1
Placebo Suvorexant
24 26
76.38 (51.02) 41.83 (25.03)
55.17 (43.20, 70.46) 35.53 (27.98, 45.13)
0.64 (0.54, 0.76)
4
Placebo Suvorexant
25 26
58.24 (32.64) 52.04 (28.58)
50.20 (40.28, 62.56) 44.95 (36.19, 55.82)
0.90 (0.74, 1.08)
0.91 (0.54, 1.55) 1.08 (0.74, 1.57)
*Geometric mean and geometric mean ratio with corresponding confidence intervals obtained from back-transformed least squares means on the natural log scale obtained from the mixed effects statistical model. LPS, latency to persistent sleep; SEI, sleep efficiency index; TST, total sleep time; WASO, wake after sleep onset; REM, rapid eye movement sleep; NREM, Non-rapid eye movement sleep.
Table 4—Number (%) of OSA patients with clinical adverse events. Patients with ≥ 1 adverse event Somnolence Diarrhoea Sinusitis Pain in extremity Dizziness Insomnia Nausea Headache Nasal congestion Sneezing
interest. There were no consistent treatment-related changes in laboratory, vital signs or ECG safety parameters.
Suvorexant 40 mg (n = 26) Placebo (n = 26) n (%) n (%) 8 (30.8) 4 (15.4) 5 (19.2) 0 (0.0) 1 (3.8) 0 (0.0) 1 (3.8) 0 (0.0) 1 (3.8) 0 (0.0) 1 (3.8) 0 (0.0) 1 (3.8) 1 (3.8) 0 (0.0) 2 (7.7) 0 (0.0) 1 (3.8) 0 (0.0) 1 (3.8) 0 (0.0) 1 (3.8)
D I SCUS S I O N In this study we assessed the effects of single and multiple 40mg doses of the orexin receptor antagonist suvorexant on AHI during sleep in patients with mild to moderate OSA. The maximum recommended dose approved in the USA and Japan is 20 mg once daily. Consequently, the 40 mg dose of suvorexant included in this study is twice the maximum dose to be used by insomnia patients in the USA and Japan. Suvorexant plasma exposures increase approximately 75% with a doubling of dose from 20 mg to 40 mg. A mean increase in AHI of 5 is the minimum change that was considered clinically meaningful based on findings from longitudinal population-based studies which suggest that an elevation in mean AHI of 5–10 is associated with increased risks of developing hypertension and type 2 diabetes.36,37 This conservative AHI criterion (mean increase
Although a patient may have had 2 or more clinical adverse experiences, the patient is counted only once within a category. The same patient may appear in different categories.
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of 5) was used in a recent OSA study with ramelteon.35 Another OSA study defined a clinically significant difference as an increase of 8.7 The results showed that there was a small increase in AHI (mean 2.66) following once-daily administration for 4 consecutive days of suvorexant relative to placebo, with the upper 90% CI bound slightly exceeding 5 (5.09). No statistically significant mean treatment difference between suvorexant and placebo was observed on Day 1 after single dose of suvorexant however. As there is minimal accumulation (accumulation ratio 1.2 to 1.4) of suvorexant following once-daily multiple-dose administration, significant differences between AHI on Day 1 and 4 would not be anticipated based upon pharmacokinetics alone. Another factor to consider when interpreting the results is that the within-patient variability was larger than reported in two published studies of the respiratory effects of hypnotics in OSA patients (mean squared error of 25.34 in this study vs. 14.62 pooled from two previously published studies).7,35 In particular, one patient’s AHI was 27 on placebo versus 47 on suvorexant on Day 4, whereas the same patient’s AHI was 46 on placebo versus 26 on suvorexant on Day 1. The fact that the large treatment differences for this patient were in opposite directions over the course of just a few days suggests that this patient may not have been representative of the population and may have unduly affected the overall results of the statistical analysis, as supported by the results of the sensitivity analysis excluding this patient. Relatively high night-to-night variability on AHI has been reported in previous studies of OSA patients with mechanisms that are not clearly understood.38,39 Previous studies in mild-moderate COPD patients using the same doses and dosing regimes as evaluated here, or single doses of 40 mg and 140 mg in healthy subjects, found minimal or no effects of suvorexant on AHI.27,40 The mean oxygen saturation (SpO2 ) during TST was the secondary endpoint in the current study. A 2-percentage point drop in mean SpO2 was considered clinically meaningful. The mean SpO2 is typically in the range of ~92% to 94% in mild to moderate OSA patients during sleep,41 and a 2% drop from 92% could result in hypoxemia (SpO2 < 90%). Oxygen saturation has been used as an endpoint in other respiratory safety studies with hypnotics.7,35 Ventilation is lower during all stages of sleep in patients with OSA due to disappearance of the influence of wakefulness and change in respiratory center activity. The reduction in ventilation is particularly more pronounced during REM sleep, resulting in increased potential for oxygen desaturation in respiratory function compromised patients. Thus, when assessing potential respiratory effects of a drug, it is important to compare mean SpO2 in each sleep/wake stage as well as during total sleep time. The mean SpO2 was similar between suvorexant and placebo in all comparisons after single and multiple doses of suvorexant. The mean SpO2 for each of the different sleep stages (awake, NREM, and REM) and the percentage of night with SpO2 < 90% and < 85% following suvorexant dosing were compared and did not reveal any clinically meaningful or statistically significant differences between suvorexant and placebo. Suvorexant 40 mg was generally well tolerated in men and women with mild to moderate OSA. No serious clinical
adverse events were reported and no patients discontinued because of an adverse event. All adverse events were rated mild or moderate in intensity. The most frequently reported adverse event with suvorexant was somnolence, in line with findings from clinical trials in insomnia patients,23–25 although this occurred in only 5/26 patients (19%). Exploratory assessments of residual effects performed the morning after dosing did not suggest that suvorexant resulted in impairments. However, these endpoints were exploratory and the study was not designed or powered to assess them. There are a number of limitations to interpretation of the present findings. Firstly, the study was of relatively short duration. Suvorexant has a half-life of approximately 8 to 10 hours in non-elderly subjects, and steady-state plasma concentration is achieved after 3–4 days dosing with minimal accumulation. Therefore, the Day 4 assessment in the present study evaluated the effects of suvorexant at steady-state, and it is unlikely that the results would be different if the evaluation period had been longer, although we cannot exclude the possibility. A second limitation is that we studied patients with mild to moderate OSA who did not have evidence of hypoxemia/hypoventilation on their screening PSG. Further studies are necessary to determine the respiratory safety of suvorexant in patients with severe OSA. Another limitation is that our conclusions are based on measurement of AHI and SpO2 , which do not constitute a full assessment of all aspects of respiration. Finally, we did not include a comparator agent so we cannot directly compare our findings with an orexin receptor antagonist to other classes of insomnia treatments such as benzodiazepine receptor agonists. In conclusion, these findings suggest that a nighttime 40 mg dose of suvorexant (twice the 20 mg maximum daily dose approved in the USA and Japan) does not have clinically meaningful effects on respiration during sleep in patients with mild to moderate OSA as assessed by mean changes in AHI and SpO2. These data support previous findings of a lack of respiratory effect of suvorexant 40 mg in mild-moderate COPD patients27 and in healthy subjects at doses of 40 mg and 150 mg.40 There is currently no clinical experience with suvorexant in patients with severe OSA, in patients treated with positive airway pressure therapy, or in patients with OSA-COPD overlap syndrome. Furthermore, there is inter- and intra-individual variability in respiratory effects. Therefore, suvorexant should be used with caution in patients with compromised respiratory function, and at the lowest effective dose. R E FE R E N CES 1. Krakow B, Melendrez D, Ferreira E, et al. Prevalence of insomnia symptoms in patients with sleep-disordered breathing. Chest 2001;120:1923–9. 2. Smith S, Sullivan K, Hopkins W, Douglas J. Frequency of insomnia report in patients with obstructive sleep apnoea hypopnea syndrome (OSAHS). Sleep Med 2004;5:449–56. 3. Shepertycky MR, Banno K, Kryger MH. Differences between men and women in the clinical presentation of patients diagnosed with obstructive sleep apnea syndrome. Sleep 2005;28:309–14. 4. Guilleminault C. Benzodiazepines, breathing, and sleep. Am J Med 1990;88:25S–28S. 5. Berry RB, Kouchi KG, Bower JL, Light RW. Effect of upper airway anesthesia on obstructive sleep apnea. Am J Respir Crit Care Med 1995;151:1857–61.
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H Sun, J Palcza, D Card et al. Suvorexant in Obstructive Sleep Apnea 6. George CF. Perspectives on the management of insomnia in patients with chronic respiratory disorders. Sleep 2000;23(Suppl 1):S31–5. 7. Rosenberg R, Roach JM, Scharf M, Amato DA. A pilot study evaluating acute use of eszopiclone in patients with mild to moderate obstructive sleep apnea syndrome. Sleep Med 2007;8:464–70. 8. Eckert DJ, Owens RL, Kehlmann GB, et al. Eszopiclone increases the respiratory arousal threshold and lowers the apnoea/hypopnoea index in obstructive sleep apnoea patients with a low arousal threshold. Clin Sci (Lond) 2011;120:505–14. 9. Kilduff TS, Peyron C. The hypocretin/orexin ligand-receptor system: implications for sleep and sleep disorders. Trends Neurosci 2000;23:359–65. 10. Brisbare-Roch C, Dingemanse J, Koberstein R, et al. Promotion of sleep by targeting the orexin system in rats, dogs and humans. Nat Med 2007;13:150–5. 11. Sakurai T. The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness. Nat Rev Neurosci 2007;8:171–81. 12. Baumann CR, Bassetti CL. Hypocretins (orexins) and sleep-wake disorders. Lancet Neurol 2005;4:673–82. 13. Scammell TE, Winrow CJ. Orexin receptors: pharmacology and therapeutic opportunities. Annu Rev Pharmacol Toxicol 2011;51:243–66. 14. Mieda M, Sakurai T. Orexin (hypocretin) receptor agonists and antagonists for treatment of sleep disorders: rationale for development and current status. CNS Drugs 2013;27:83–90. 15. Peyron C, Tighe DK, van den Pol AN, et al. Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci 1998;18:9996–10015. 16. Kuwaki T. Orexinergic modulation of breathing across vigilance states. Respir Physiol Neurobiol 2008;164:204–12. 17. Deng BS, Nakamura A, Zhang W, Yanagisawa M, Fukuda Y, Kuwaki T. Contribution of orexin in hypercapnic chemoreflex: evidence from genetic and pharmacological disruption and supplementation studies in mice. J Appl Physiol 2007;103:1772–9. 18. Li A, Nattie E. Antagonism of rat orexin receptors by almorexant attenuates central chemoreception in wakefulness in the active period of the diurnal cycle. J Physiol 2010;588:2935–44. 19. Han F, Mignot E, Wei YC, et al. Ventilatory chemoresponsiveness, narcolepsycataplexy and human leukocyte antigen DQB1*0602 status. Eur Respir J 2010;36:577–83. 20. Cox CD, Breslin MJ, Whitman DB, et al. Discovery of the dual orexin receptor antagonist[(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (MK-4305) for the treatment of insomnia. J Med Chem 2010;53:5320–32. 21. Winrow CJ, Gotter AL, Cox CD, et al. Promotion of sleep by MK-4305 - a novel dual orexin receptor antagonist. J Neurogenetics 2011;25:52–61. 22. Sun H, Kennedy WP, Wilbraham D, et al. Effects of suvorexant, an orexin receptor antagonist, on sleep parameters as measured by polysomnography in healthy men. Sleep 2013;36:259–67. 23. Herring WJ, Snyder E, Budd K, et al. Orexin receptor antagonism for treatment of insomnia: a randomized clinical trial of suvorexant. Neurology 2012;79:2265–74. 24. Michelson D, Snyder E, Paradis E, et al. Safety and efficacy of suvorexant during 1-year treatment of insomnia with subsequent abrupt treatment discontinuation: a phase 3 randomised, double-blind, placebo-controlled trial. Lancet Neurol 2014;13:461–71. 25. Herring WJ, Connor KM, Ivgy-May N, et al. Suvorexant in patients with insomnia: results from two 3-month randomized controlled clinical trials. Biol Psychiatry 2014 Oct 23. [Epub ahead of print]. 26. Merck & Co. Inc. FDA approves BELSOMRA (suvorexant) for the treatment of insomnia. Press release, Aug 13, 2014. http://www.mercknewsroom. com/news-release/prescription-medicine-news/fda-approves-belsomrasuvorexant-treatment-insomnia. Accessed October 17, 2014. 27. Sun H, Palcza J, Rosenberg R, et al. Effects of suvorexant, an orexin receptor antagonist, on breathing during sleep in patients with chronic obstructive pulmonary disease. Respir Med 2015;109:416–26. 28. American Academy of Sleep Medicine. International classification of sleep disorders, revised: Diagnostic and coding manual. Chicago, IL: American Academy of Sleep Medicine, 2001.
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29. Iber C, Ancoli-Israel S, Chesson AL, Quan SF. The AASM manual for the scoring of sleep and associated events: rules, terminology, and technical specifications. 1st ed. Westchester, IL: American Academy of Sleep Medicine, 2007. 30. Rechtschaffen A, Kales A. A manual of standardized terminology, techniques and scoring system for sleep stages of human subjects. Washington DC: National Institute of Health, Publication 204. Government Printing Office, 1968. 31. Rey A. L’examen clinique en psychologie. Paris, France: Presses Universitaires de France, 1964. 32. Wechsler D. WAIS-R manual. New York, NY: The Psychological Corporation, 1981. 33. Bond A, Lader M. The use of analogue scales in rating subjective feelings. Br J Psychol 1974;47:211–8 34. Norris V, Baisley K, Calder N, van Troostenburg AR, Warrington S. Assessment of the AccuSwayPLUS system in measuring the effect of lorazepam on body sway in healthy volunteers. Int J Pharm Med 2005;19:233–8. 35. Kyrger M, Wang-Weigand S, Roth T. Safety of ramelteon in individuals with mild to moderate obstructive sleep apnea. Sleep Breath 2007;11:159–64. 36. Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 2000;342:1378–84. 37. Punjabi NM, Shahar E, Redline S, Gottlieb DJ, Givelber R, Resnick HE. Sleepdisordered breathing, glucose intolerance, and insulin resistance: the Sleep Heart Health Study. Am J Epidemiol 2004;160:521–30. 38. Bliwise DL, Benkert RE, Ingham RH. Factors associated with nightly variability in sleep disordered breathing in the elderly. Chest 1991;100:973–6. 39. Chediak AD, Acevedo-Crespo JC, Seiden DJ, Kim HH, Kiel MH. Sleep disordered breathing: nightly variability in the indices of sleep-disordered breathing in men being evaluated for impotence with consecutive night polysomnograms. Sleep 1996;19:589–92. 40. Uemura N, McCrea J, Sun H, et al. Effects of the orexin receptor antagonist suvorexant on respiration during sleep in healthy subjects. J Clin Pharmacol 2015;55:1093–100. 41. Valipour A, Lothaller H, Rauscher H, Zwick H, Burghuber OC, Lavie P. Gender related differences in symptoms of patients with suspected breathing disorders in sleep: a clinical population study using the Sleep Disorders Questionnaire. Sleep 2007:30:312–9.
ACK N O W L E D G M E N T S The authors thank Chantal Mahon and Kate Mostoller from Merck & Co., Inc., for their contributions to running the study and Sheila Erespe from Merck & Co., Inc., for assistance in formatting the article. Investigators: Mardik Donikyan, Clinilabs, Inc., New York, NY; Russell Rosenberg, NeuroTrials Research, Atlanta, GA; David Seiden, Broward Research Group, Pembroke Pines, FL; Timothy Grant, Miami Research Associates, Miami, FL; Meir Kryger, Gaylord Sleep Medicine, Wallingford, CT.
SUBM I SSI O N & CO R R ESPO NDENCE I NFO R M ATI O N Submitted for publication February, 2015 Submitted in final revised form May, 2015 Accepted for publication June, 2015 Address correspondence to: Dr. Christopher Lines, Merck & Co., Inc., Kenilworth , NJ, USA; Tel: (267) 305-7870; Fax: (267) 305-6425; Email: [email protected]
D I SCLO S U R E S TAT E M E N T This study was funded by Merck & Co., Inc., Kenilworth, 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. 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
16
H Sun, J Palcza, D Card et al. Suvorexant in Obstructive Sleep Apnea content. All authors provided final approval of the version to be published. Dr. Sun, Mr. Palcza, Ms. Card, Ms. Gipson, Dr. Lines, Dr. Wagner, and Dr. Troyer are current or former employees of Merck and own or owned stock/stock options in Merck. Dr. Sun is a current employee of Amgen, Thousand Oaks, CA. Dr. Wagner is a current employee of Takeda, Boston, MA. Dr. Troyer is a current employee of Medivation, San Francisco, CA. Dr. Rosenberg has received research funding from
and/or acted as a consultant for Merck, Teva, Pfizer, Jazz Pharmaceuticals, Eisai, and Respironics. Dr. Kryger has received research funding from and/or acted as consultant for Merck, Pfizer, Medtronic, and Inspire. These data were previously presented at the 27th annual meeting of the Associated Professional Sleep Societies, June 1–5, 2013, Baltimore, MD
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S CI E NT IF IC IN VES TIGATIONS
Effects of Suvorexant, an Orexin Receptor Antagonist, on Respiration during Sleep In Patients with Obstructive Sleep Apnea Hong Sun, MD, PhD1; John Palcza, MS1; Deborah Card, MS1; Adrianna Gipson, MS1; Russell Rosenberg, PhD2; Meir Kryger, MD3; Christopher Lines, PhD1; John A. Wagner, MD, PhD1; Matthew D. Troyer, MD1 Merck & Co., Inc., Kenilworth, NJ; 2NeuroTrials Research, Atlanta, GA; 3Yale School of Medicine, New Haven, CT
1
Study Objectives: To investigate the respiratory effects of suvorexant, an orexin receptor antagonist for treating insomnia, in patients with obstructive sleep apnea (OSA). Methods: This was a randomized, double-blind, placebo-controlled, 2-period (4 days per period), crossover, sleep laboratory study. Twenty-six patients aged 18–65 years with mild (apnea-hypopnea index [AHI] ≥ 5 and < 15) to moderate (AHI ≥ 15 and < 30) OSA were randomized to receive suvorexant 40 mg or placebo in period-1 and then crossed over to the other treatment in period-2. Breathing during sleep was measured by AHI (primary endpoint) and oxygen saturation assessed by pulse oximetry (SpO2, secondary endpoint). The study was powered to rule out a mean increase in AHI between suvorexant and placebo of 5 or greater on Day 4. Results: There was a small increase in mean AHI (2.66) in OSA patients after multiple doses of suvorexant relative to placebo, with the upper 90% CI bound slightly exceeding 5.00 (0.22, 5.09). No increase in mean AHI was observed after a single dose of suvorexant versus placebo (mean difference = −0.47 [−3.20, 2.26]), and there was no treatment effect on mean SpO2 during total sleep time after single or multiple doses (Day 1: mean difference = −0.04 [−0.49, 0.42]; Day 4: mean difference = −0.06 [−0.45, 0.33]). There was inter- and intra-individual variability in suvorexant respiratory effects. Conclusions: Suvorexant 40 mg, twice the 20 mg maximum recommended dose for treating insomnia in the USA and Japan, does not appear to have clinically important respiratory effects during sleep in patients with mild to moderate OSA as assessed by mean AHI and SpO2. Due to inter- and intraindividual variability in respiratory effects, suvorexant should be used with caution in patients with compromised respiratory function, and at the lowest effective dose. Clinical Trial Registration: clinicaltrials.gov, NCT01300455. Keywords: suvorexant, MK-4305, orexin, respiration, obstructive sleep apnea, randomized trial Citation: Sun H, Palcza J, Card D, Gipson A, Rosenberg R, Kryger M, Lines C, Wagner JA, Troyer MD. Effects of suvorexant, an orexin receptor antagonist, on respiration during sleep in patients with obstructive sleep apnea. J Clin Sleep Med 2016;12(1):9–17.
I N T RO D U C T I O N
BRIEF SUMMARY
Current Knowledge/Study Rationale: Suvorexant is a first-in-class orexin receptor antagonist that is approved in the USA and Japan for the treatment of insomnia. Given the coexistence of insomnia and sleep apnea in many patients, it is important to examine the respiratory safety of any new insomnia medication in patients with sleep apnea. Study Impact: The findings of this study show that a nighttime 40 mg dose of suvorexant (twice the 20 mg maximum daily dose approved in the USA and Japan) does not have clinically meaningful effects on respiration during sleep in patients with mild to moderate obstructive sleep apnea as assessed by mean changes in number of apneas/hypopneas and oxygen saturation. Because there is inter- and intra-individual variability in respiratory effects, suvorexant should be used with caution in patients with compromised respiratory function, and at the lowest effective dose.
Sleep apnea and insomnia commonly coexist, especially in women.1–3 Sedative hypnotics represent the main pharmacologic therapy for insomnia, but there are concerns about administering these medications in patients who have untreated sleep apnea. Benzodiazepines used as sedative hypnotics bind to the benzodiazepine receptor at the GABA-A complex (e.g., triazolam, flurazepam) and might be associated with depression of central respiratory drive, blunting of the arousal response to hypoxia, and decreases in muscle tone in the upper airways.4–6 Limited data are available regarding the use of the newer nonbenzodiazepine benzodiazepine receptor agonists (e.g., zolpidem, zaleplon, zopiclone, and eszopiclone) in patients with sleep apnea, although some researchers have found no evidence of a significant effect on respiratory measures7 and others have even reported an improvement in aspects of respiration in apnea patients without marked hypoxemia.8 Given the coexistence of insomnia and sleep apnea in many patients and the speculated potential for hypnotic agents to negatively affect respiration, it is important to examine the respiratory safety of new sedative hypnotic drugs being investigated for the treatment of insomnia.
Orexin receptor antagonism represents a new approach to the treatment of insomnia.9–14 Orexin receptor antagonists appear to promote sleep by selectively blocking the brain’s orexin-mediated wake system thereby enabling the transition to sleep. Orexin neurons originate in the lateral hypothalamus and project throughout the brain, including to respiratory 9
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Standard Protocol Approvals, Registrations, and Patient Consents
centers in the brainstem, suggesting that orexin has a role in controlling respiration.15,16 Although limited data are available, there is no strong evidence to suggest that an orexin receptor antagonist would impair respiratory function. Studies in orexin knockout mice or rodents receiving an orexin receptor antagonist show an attenuation of the hypercapnic response (response to excess CO2 ) in the wake state but not in the sleep state.17,18 No difference in the respiratory response to CO2 was observed between narcolepsy patients with impaired orexin signaling and healthy controls.19 The orexin receptor antagonist suvorexant (MK-4305)20–22 has been shown to be effective for the treatment of insomnia in previous clinical trials at doses of 10, 20, or 40 mg in nonelderly patients and 15 or 30 mg in elderly patients.23–25 The maximum recommended dose approved in the USA and Japan is 20 mg once daily.26 Our group has recently shown that suvorexant does not significantly impair respiratory function in patients with mild to moderate chronic obstructive pulmonary disease (COPD).27 Here we report results from a study which assessed the effects of single and multiple doses of suvorexant 40 mg (twice the maximum recommended dose) on respiratory function during sleep in non-elderly adult patients with obstructive sleep apnea (OSA). The primary endpoint used to assess changes in breathing pattern was the apnea hypopnea index (AHI), a measure of the number of apneas and hypopneic episodes during an hour of sleep.
The study was conducted in accordance with principles of Good Clinical Practice and was approved by the appropriate institutional review committees and regulatory agency. After explanation of the study procedures, risks, and benefits, written informed consent was obtained from all patients. Patients were compensated for their participation. The study was registered at ClinicalTrials.gov (NCT01300455).
Study Design and Procedure
This multi-center, randomized, double-blind, placebo-controlled, 2-period (4 days per period) crossover study (Merck protocol 036) was performed at 6 sleep laboratories/clinical research units in the United States from April 2011 to July 2011. Following an initial screening visit, patients who met the inclusion/exclusion criteria underwent a screening nighttime PSG visit within approximately 3 weeks prior to initial dosing on Day 1 of Period 1. A sleep history diary was used to establish habitual median bedtime for ≥ 5 consecutive nights any time prior to the screening PSG visit. The median bedtime established during this period (± 1 hour) was used as the bedtime (“lights-off”) for the screening PSG visit and PSG collection on Day 1 and 4 in Periods 1 and 2. The screening PSG visit was also used to further define patient eligibility to exclude sleep disorders other than insomnia, and evaluate oxygen saturation. Following the screening PSG visit, eligible patients were admitted to the study site on Day 1 of Period 1 and were randomized to 1 of 2 treatment sequences. In Period 1, patients were administered a single 40 mg oral dose of suvorexant or matching placebo, for 4 consecutive days, before being crossed over to the other treatment in Period 2. A 40 mg dose of suvorexant, twice the maximum recommended 20 mg dose, was evaluated because it was the maximum dose investigated in phase 3 trials.24,25 At the time the OSA study was initiated, it was thought that 40 mg might be the maximum recommended dose. In each period, study drug was administered in the evening at approximately 0.5 h before bedtime (“lights-off”). On Days 1 and 4, study drug was administered following a 4-h fast. In both study periods, patients remained overnight in the sleep laboratory/clinic on Day 1 and Day 4 for PSG recording and O2 monitoring via finger pulse oximetry (SpO2 ). PSG recording commenced at the time of lights-off and continued for 8 hours. SpO2 monitoring commenced approximately 15 min prior to dosing and continued during PSG recording. Patients were discharged on the morning of Day 2 after all study procedures were completed and patients continued to take study drug at home. On Day 4, patients were readmitted to the sleep laboratory/clinic for evening study drug administration and remained overnight for PSG recording and SpO2 monitoring. There was ≥ 7 days washout between each treatment period. Sleep stage scoring was performed according to the American Academy of Sleep Medicine Manual for Scoring of Sleep and Associated Events,29 which maintained much of the Rechtschaffen and Kales framework for standardized scoring methods and criteria.30 Next-day residual effects were assessed the morning after PSG recording on nights 1 and 4, at approximately 9 h post dose, using Immediate and Delayed Word
METHODS Full details of the study procedures are in the study protocol which is available in the supplemental material.
Patients
Eligible patients were men and women between the ages of 18 to 65 years (inclusive) with an International Classification of Sleep Disorders diagnosis of OSA28 based on the investigator’s assessment and diagnostic interview along with a documented sleep study (i.e., nighttime polysomnography [PSG] in a sleep laboratory) within the past 5 years that confirmed the OSA diagnosis. The severity of OSA had to be mild (AHI between 5 and 14 inclusive) or moderate (AHI between 15 and 29 inclusive) based on the screening PSG. Patients were excluded if they had a screening PSG recording with O2 saturation < 80% for ≥ 5% of the total sleep time (TST), or > 10 periodic limb movements per hour associated with an arousal. Patients were excluded if they used a continuous positive airway pressure (CPAP) device or a dental appliance within the preceding 7 days prior to screening PSG, or were required to use CPAP or a dental appliance during the course of the study. Patients with other respiratory disorders were excluded. Patients with the following sleep disorders were excluded, but patients with insomnia could be included (patients were not required to have insomnia): narcolepsy, cataplexy (familial or idiopathic), circadian rhythm sleep disorder, parasomnia including nightmare disorder, sleep terror disorder, sleepwalking disorder, REM behavior disorder, periodic limb movement disorder, restless legs syndrome, primary hypersomnia. Journal of Clinical Sleep Medicine, Vol. 12, No. 1, 2016
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Recall,31 the Digit Symbol Substitution Test,32 Bond-Lader Visual Analog Scales,33 and Body Sway assessments.34
endpoints included PSG measures (LPS, WASO, TST, SEI, REM, and NREM), and endpoints assessing next morning residual effects (Immediate and Delayed Word Recall, Digit Symbol Substitution Test, Bond-Lader Visual Analog Scales, Body Sway). PSG measures were analyzed on the natural log scale with model based least squares means and confidence intervals back-transformed to the original scale to obtain geometric means and geometric mean ratios with corresponding confidence intervals. This was done to allow for a relative fold change comparison of these endpoints across treatments. Data were analyzed using SAS Version 9.2.
Endpoints
The mean AHI score on Day 4 was the primary endpoint. AHI was measured as defined by the American Academy of Sleep Medicine.29 Effects on the AHI as measured by PSG, calculated by dividing the number of apneas and hypopneas by the total sleep time (in minutes) and multiplying by 60 (i.e., the average number of apneas and hypopneas per hour of sleep), were evaluated on Day 1 and Day 4. The mean oxygen saturation (SpO2 ) for TST on Day 1 and 4, as well as for each of the different sleep stages (awake, NREM, REM) on Day 1 and Day 4, were also compared. SpO2 data used for the analyses were rounded to the nearest integer. Exploratory endpoints included PSG measures of latency to persistent sleep (LPS), wake after sleep onset (WASO), sleep efficiency index (SEI), TST, REM, and NREM and scores on assessments of next-morning residual effects (Immediate and Delayed Word Recall, Digit Symbol Substitution Test, Bond-Lader Visual Analog Scales, Body Sway). Safety and tolerability were evaluated by clinical assessment of adverse experiences and other safety measurements (e.g., vital signs, ECGs, routine laboratory blood chemistry, hematology, and urinalysis measures). The following were prespecified as events of clinical interest in the protocol: cataplexy, sleep paralysis and sleep onset paralysis, hypnagogic or hypnopompic hallucinations, suicidal ideation and/or behaviors, complex sleep-related behaviors, falls, selected events associated with potential for abuse, and traffic/vehicle accidents.
Power
A mean difference between treatments in AHI > 5 was considered clinically meaningful. Assuming a true within-patient variance of 14.62 for AHI based on pooled data from 2 previous studies,7,35 a total of 24 patients completing the crossover study, and significance level α = 0.05 (one-sided), there was 0.92 probability that the upper bound of the 90% CI for the true mean difference in AHI (suvorexant − placebo) on Day 4 would be < 5, if the true difference is as high as 1.5. The true mean difference could be as high as 2.17 and still have 80% power to support the hypothesis. For the secondary endpoint of mean SpO2 during total sleep time, a 2% decrease in mean SpO2 during TST was considered a clinically meaningful change. SpO2 is typically lower at night during sleep than while awake. Assuming a true withinpatient variance of 0.763%2 for mean SpO2 as observed in a previous study,35 a total of 24 patients completing the crossover study, and significance level α = 0.05 (one-sided), there was 0.99 probability that the lower bound of the 90% CI for the true mean difference in mean SpO2 (suvorexant − placebo) on Day 4 would be greater than −2%, if the mean true difference is as low as −1%. The true difference could be as low as −1.35% and still have 80% power to support the hypothesis.
Statistical Analysis
The primary hypothesis was that multiple doses of suvorexant do not produce a clinically significant increase in AHI in patients with mild to moderate OSA as compared to placebo; specifically, the true mean AHI treatment difference (suvorexant − placebo) on Day 4 is less than 5. Individual AHI values on Day 4 were evaluated using a linear mixed-effects model appropriate for a 2-period crossover study. This model was used to adjust for key design elements by including fixed effects for treatment, period, and sequence, and a random effect for patient within sequence. Using an appropriate linear contrast, a two-sided 90% confidence interval (equivalent to a one-sided upper 95% CI) for the true mean difference (suvorexant − placebo) in AHI was calculated using the mean square error from the model and referencing a t-distribution. Results are reported as least squares means and confidence intervals obtained from the statistical model. If the upper bound of the CI was < 5, then the hypothesis that multiple oral doses of suvorexant do not produce a clinically significant increase in AHI in patients with mild to moderate OSA would be supported. Day 1 results were analyzed in a similar fashion as above. Additional secondary and other exploratory endpoints were analyzed using the same methods to estimate the effects of single and multiple dose administration of suvorexant. Secondary endpoints included mean SpO2 during total sleep time, mean SpO2 during REM, NREM, and awake stages, and the percentage of total sleep time when SpO2 was less than 90%, 85%, and 80% during the night. Exploratory
R ES U LT S
Patient Accounting and Characteristics
Twenty-six patients with mild to moderate OSA were enrolled in this study and 25 completed the study (Figure 1). One patient discontinued due to a scheduling conflict after completing Period 1 and before starting Period 2. Twenty-four patients had complete evaluable SpO2 data from both treatment periods. The patient who discontinued had data from only Period 1 (suvorexant), which were included in the statistical respiratory analyses. For another patient, Period 2/Day 1 (placebo) SpO2 data were missing due to malfunctioning equipment. Patient characteristics are shown in Table 1. Of the 26 enrolled patients, 12 had moderate OSA and 14 had mild OSA; 7 were women and 19 were men; 6 were black and 20 were white. The mean age was 49 years (range = 30 to 64 years). One patient was reported to have comorbid insomnia.
Respiratory Effects
Table 2 presents the results of the statistical analysis of respiratory safety endpoints (AHI and SpO2 ). The mean AHI 11
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treatment difference (suvorexant − placebo) and 90% CI on Day 4 was 2.66 (0.22, 5.09). Since the upper bound of the 90% CI did not lie below 5, the primary hypothesis that multiple doses of suvorexant do not produce a clinically significant increase in AHI in patients with mild to moderate OSA, as compared to placebo, was not supported. The AHI treatment difference
(suvorexant − placebo) and 90% CI on Day 1 was −0.47 (−3.20, 2.26). Since the upper bound of the 90% confidence interval lay below 5, the secondary hypothesis that a single dose of suvorexant does not produce a clinically significant increase in AHI in patients with mild to moderate OSA, as compared to placebo, was supported. Suvorexant differences from placebo for AHI in individual patients are shown in Figure 2. Consistent changes in individuals across days were not apparent. The number of patients who had an AHI difference greater than 5 was eight on Day 4 and six on Day 1. However, only one patient had an individual AHI difference greater than 5 on both Days (Day 1 = 8.8, Day 4 = 12.5). It is of note that the withinpatient variability observed in the present study (mean squared error of 25.34) was larger than that in 2 previous studies of hypnotics’ effect in OSA patients (pooled mean squared error of 14.62),7,35 which was used to calculate the power of the present study. Of 8 patients whose AHI difference following suvorexant compared to placebo was ≥ 5 on Day 4, five showed a difference in which their AHI during placebo exceeded that following suvorexant by ≥ 5 on Day 1. One patient showed particularly large day-to-day variability; on Day 4 the patient had
Figure 1—Study flowchart.
Table 1—Patient baseline characteristics (n = 26). Mean age, years (range) Gender, n (%) Female Male Race, n (%) White Black OSA category Mild (AHI ≥ 5 and < 15) Moderate (AHI ≥ 15 and < 30) Mean AHI (range) Mean height, cm (range) Mean weight, kg (range) Mean BMI, kg/m2 (range)
There were 4 days in each treatment period. *n = 26 for suvorexant, n = 24 for placebo on Day 1, and n = 25 for placebo on Day 4 (1 patient withdrew before receiving placebo and therefore did not provide Day 1 or Day 4 data, and 1 patient had missing data on Day 1 of the placebo period due to equipment malfunction).
49 (30 to 64) 7 (26.9%) 19 (73.1%) 20 (76.9%) 6 (23.1%) 14 (53.8%) 12 (46.2%) 15.2 (5.4 to 29.7) 174.3 (149.8 to 190.5) 92.1 (58.0 to 129.5) 30.2 (23.6 to 39.8)
OSA, obstructive sleep apnea; AHI, apnea-hypopnea index; BMI, body mass index.
Table 2—Respiratory endpoints following single (Day 1) and multiple (Day 4) dose administration of suvorexant 40 mg or placebo in mild and moderate OSA patients. Suvorexant (n = 26) Endpoint LS Mean (95% CI) Apnea and hypopnea index†,a 16.25 (12.65, 19.86) Mean SpO2 during TST (%) 94.12 (93.48, 94.75) Mean SpO2 during NREM (%) 94.12 (93.47, 94.76) Mean SpO2 during REM (%) 94.08 (93.34, 94.82) Mean SpO2 during wake (%) 94.42 (93.74, 95.11) Percentage of total sleep time that SpO2 is < 90% 3.31 (1.03, 5.58) Percentage of total sleep time that SpO2 is < 85% 0.48 (0.12, 0.85)
Day 1 Placebo (n = 24) LS Mean (95% CI) 16.72 (13.02, 20.42) 94.15 (93.50, 94.80) 94.07 (93.41, 94.73) 94.14 (93.38, 94.90) 94.94 (94.23, 95.65) 2.57 (0.22, 4.92) 0.24 (−0.14, 0.61)
Suvorexant − Placebo Difference (90% CI) −0.47 (−3.20, 2.26) −0.04 (−0.49, 0.42) 0.05 (−0.41, 0.50) −0.06 (−0.61, 0.49) −0.51 (−1.13, 0.10) 0.74 (−1.31, 2.79) 0.25 (−0.10, 0.59)
Suvorexant (n = 26) LS Mean (95% CI) 17.07 (13.30, 20.84) 94.15 (93.53, 94.78) 94.27 (93.64, 94.90) 93.96 (93.17, 94.76) 94.73 (94.11, 95.36) 2.16 (0.88, 3.45) 0.69 (0.16, 1.23)
Day 4 Placebo (n = 25) LS Mean (95% CI) 14.41 (10.61, 18.22) 94.21 (93.59, 94.84) 94.25 (93.62, 94.89) 93.83 (93.03, 94.63) 94.91 (94.28, 95.54) 1.95 (0.66, 3.25) 0.41 (−0.13, 0.95)
Suvorexant − Placebo Difference (90% CI) 2.66 (0.22, 5.09)a −0.06 (−0.45, 0.33) 0.02 (−0.40, 0.43) 0.13 (−0.24, 0.50) −0.18 (−0.61, 0.25) 0.21 (−0.59, 1.01) 0.28 (−0.09, 0.65)
Primary endpoint = treatment difference in AHI on Day 4; upper bound of 90% CI was greater than the difference of 5 prespecified as clinically significant. AHI at screening, mean = 15.18, SD = 6.11 (n = 26). Higher AHI values and lower SpO2 values associated with impairment. Percentage of total sleep time that SpO2 is < 80% was also a prespecified endpoint, but due to the small number of patients meeting the endpoint, a formal statistical analysis was not conducted. LS Mean, least squares mean (from mixed effects statistical model); SpO2, oxygen saturation; TST, total sleep time. a †
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Figure 2—Individual treatment differences (suvorexant − placebo) for AHI in OSA patients.
Figure 3—Individual treatment differences (suvorexant − placebo) for mean SpO2 (%) during total sleep time (TST) in OSA patients.
A mean difference of 5 or greater in AHI was prespecified as clinically significant.
A mean difference of −2 percentage points or more in SpO2 was prespecified as clinically significant. SpO2 data used for the analyses were rounded to the nearest integer.
an AHI of 27 on placebo versus 47 on suvorexant, whereas the same patient’s AHI on Day 1 was 46 on placebo versus 26 on suvorexant. A sensitivity analysis excluding this patient found a mean treatment difference in AHI of 2.03 (90% CI: −0.23, 4.28) on Day 4, and 0.23 (90% CI: −2.28, 2.75) on Day 1. Thus when excluding this patient, the upper bound of the 90% CI lay below the prespecified bound of 5 on both days. The mean SpO2 (during TST) treatment difference (suvorexant − placebo) and 90% CI on Day 4 was −0.06% (−0.45%, 0.33%). Since the lower bound of the 90% CI interval was above −2%, the secondary hypothesis that multiple doses of suvorexant do not produce a clinically significant reduction of mean SpO2 during TST in patients with mild to moderate OSA, as compared to placebo, was supported. Similar findings were apparent for Day 1; the mean SpO2 (during total sleep time) treatment difference (suvorexant − placebo) and 90% CI on Day 1 was −0.04% (−0.49%, 0.42%). Suvorexant differences from placebo for SpO2 during TST in individual patients are shown in Figure 3. The mean treatment effects on SpO2 during NREM, REM, and awake as well as the percentage of TST that SpO2 was less than 90% and 85% were generally similar for suvorexant and placebo, on both Day 1 and Day 4 (Table 2). This was also the case when looking at mean SpO2 by hour of the night on Day 1 and Day 4 (Table S1, supplemental material).
(SEI). A statistically significant decrease in wake after sleep onset (WASO) for suvorexant relative to placebo was seen on Day 1. However, all results should be interpreted with caution as there was no multiplicity adjustment to account for the multiple endpoints and time points, and the false positive rate is inflated as a consequence. It should be noted that patients could be included in the study regardless of whether or not they had insomnia, but in practice only one patient was reported to have comorbid insomnia.
Next-Morning Residual Effects
Mean scores for suvorexant and placebo were generally similar on Immediate and Delayed Word Recall (Table S2, supplemental material), Digit Symbol Substitution Test (Table S2), Bond-Lader Visual Analog Scales (Table S2), and Body Sway assessments (Table S3, supplemental material) following both single and multiple doses.
Safety and Tolerability
Adverse events are summarized in Table 4. Eleven patients reported a total of 19 clinical adverse events, 11 of which were considered drug-related by the investigator. Of the 19 adverse events, 15 were rated mild in intensity; the remainder were rated as moderate in intensity. The most frequently reported adverse events were somnolence (19% of patients on suvorexant versus 0% on placebo) and nausea (8% of patients on placebo versus 0% on suvorexant). There were no serious adverse events, no deaths, and no discontinuations because of an adverse event. There were no prespecified events of clinical
PSG Effects
Results for the exploratory PSG endpoints are shown in Table 3. Statistically significant increases for suvorexant relative to placebo (i.e., ratios with confidence intervals not overlapping 1) were seen on both Days 1 and 4 for time in REM sleep and TST, and on Day 1 only for NREM sleep and sleep efficiency 13
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Table 3—Exploratory PSG endpoints following single (Day 1) and multiple (Day 4) dose administration of suvorexant 40 mg or placebo in mild and moderate OSA patients. Endpoint LPS (min)
NREM (min)
REM (min)
SEI (%)
TST (min)
WASO (min)
Geometric Mean (95% CI)* 15.80 (9.33, 26.76) 14.41 (8.70, 23.86) 13.55 (8.30, 22.13) 14.66 (9.03, 23.78)
Geometric Mean Ratio − Suvorexant/Placebo (90% CI)*
Day 1
Treatment Placebo Suvorexant
N 24 26
Arithmetic Mean (SD) 21.42 (20.24) 24.39 (17.97)
4
Placebo Suvorexant
25 26
22.22 (20.39) 25.50 (28.75)
1
Placebo Suvorexant
24 26
311.67 (49.68) 322.04 (37.76)
308.57 (290.45, 327.81) 319.72 (301.16, 339.43)
1.04 (1.01, 1.07)
4
Placebo Suvorexant
25 26
314.72 (40.21) 317.08 (41.50)
311.93 (294.14, 330.80) 314.01 (296.21, 332.87)
1.01 (0.98, 1.04)
1
Placebo Suvorexant
24 26
72.73 (27.75) 98.44 (29.40)
66.27 (56.04, 78.36) 94.36 (80.31, 110.86)
1.42 (1.22, 1.67)
4
Placebo Suvorexant
25 26
78.64 (22.91) 93.35 (32.46)
75.22 (66.00, 85.73) 88.59 (77.93, 100.71)
1.18 (1.03, 1.34)
1
Placebo Suvorexant
24 26
80.08 (11.14) 87.62 (5.43)
79.56 (76.20, 83.07) 87.45 (83.90, 91.16)
1.10 (1.06, 1.14)
4
Placebo Suvorexant
25 26
82.21 (10.42) 85.50 (8.19)
81.56 (77.70, 85.61) 85.08 (81.13, 89.21)
1.04 (0.99, 1.10)
1
Placebo Suvorexant
24 26
384.40 (53.46) 420.48 (25.96)
381.90 (365.78, 398.73) 419.69 (402.64, 437.47)
1.10 (1.06, 1.14)
4
Placebo Suvorexant
25 26
393.36 (49.98) 410.42 (39.29)
390.25 (371.88, 409.53) 408.38 (389.51, 428.16)
1.05 (1.00, 1.10)
1
Placebo Suvorexant
24 26
76.38 (51.02) 41.83 (25.03)
55.17 (43.20, 70.46) 35.53 (27.98, 45.13)
0.64 (0.54, 0.76)
4
Placebo Suvorexant
25 26
58.24 (32.64) 52.04 (28.58)
50.20 (40.28, 62.56) 44.95 (36.19, 55.82)
0.90 (0.74, 1.08)
0.91 (0.54, 1.55) 1.08 (0.74, 1.57)
*Geometric mean and geometric mean ratio with corresponding confidence intervals obtained from back-transformed least squares means on the natural log scale obtained from the mixed effects statistical model. LPS, latency to persistent sleep; SEI, sleep efficiency index; TST, total sleep time; WASO, wake after sleep onset; REM, rapid eye movement sleep; NREM, Non-rapid eye movement sleep.
Table 4—Number (%) of OSA patients with clinical adverse events. Patients with ≥ 1 adverse event Somnolence Diarrhoea Sinusitis Pain in extremity Dizziness Insomnia Nausea Headache Nasal congestion Sneezing
interest. There were no consistent treatment-related changes in laboratory, vital signs or ECG safety parameters.
Suvorexant 40 mg (n = 26) Placebo (n = 26) n (%) n (%) 8 (30.8) 4 (15.4) 5 (19.2) 0 (0.0) 1 (3.8) 0 (0.0) 1 (3.8) 0 (0.0) 1 (3.8) 0 (0.0) 1 (3.8) 0 (0.0) 1 (3.8) 1 (3.8) 0 (0.0) 2 (7.7) 0 (0.0) 1 (3.8) 0 (0.0) 1 (3.8) 0 (0.0) 1 (3.8)
D I SCUS S I O N In this study we assessed the effects of single and multiple 40mg doses of the orexin receptor antagonist suvorexant on AHI during sleep in patients with mild to moderate OSA. The maximum recommended dose approved in the USA and Japan is 20 mg once daily. Consequently, the 40 mg dose of suvorexant included in this study is twice the maximum dose to be used by insomnia patients in the USA and Japan. Suvorexant plasma exposures increase approximately 75% with a doubling of dose from 20 mg to 40 mg. A mean increase in AHI of 5 is the minimum change that was considered clinically meaningful based on findings from longitudinal population-based studies which suggest that an elevation in mean AHI of 5–10 is associated with increased risks of developing hypertension and type 2 diabetes.36,37 This conservative AHI criterion (mean increase
Although a patient may have had 2 or more clinical adverse experiences, the patient is counted only once within a category. The same patient may appear in different categories.
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of 5) was used in a recent OSA study with ramelteon.35 Another OSA study defined a clinically significant difference as an increase of 8.7 The results showed that there was a small increase in AHI (mean 2.66) following once-daily administration for 4 consecutive days of suvorexant relative to placebo, with the upper 90% CI bound slightly exceeding 5 (5.09). No statistically significant mean treatment difference between suvorexant and placebo was observed on Day 1 after single dose of suvorexant however. As there is minimal accumulation (accumulation ratio 1.2 to 1.4) of suvorexant following once-daily multiple-dose administration, significant differences between AHI on Day 1 and 4 would not be anticipated based upon pharmacokinetics alone. Another factor to consider when interpreting the results is that the within-patient variability was larger than reported in two published studies of the respiratory effects of hypnotics in OSA patients (mean squared error of 25.34 in this study vs. 14.62 pooled from two previously published studies).7,35 In particular, one patient’s AHI was 27 on placebo versus 47 on suvorexant on Day 4, whereas the same patient’s AHI was 46 on placebo versus 26 on suvorexant on Day 1. The fact that the large treatment differences for this patient were in opposite directions over the course of just a few days suggests that this patient may not have been representative of the population and may have unduly affected the overall results of the statistical analysis, as supported by the results of the sensitivity analysis excluding this patient. Relatively high night-to-night variability on AHI has been reported in previous studies of OSA patients with mechanisms that are not clearly understood.38,39 Previous studies in mild-moderate COPD patients using the same doses and dosing regimes as evaluated here, or single doses of 40 mg and 140 mg in healthy subjects, found minimal or no effects of suvorexant on AHI.27,40 The mean oxygen saturation (SpO2 ) during TST was the secondary endpoint in the current study. A 2-percentage point drop in mean SpO2 was considered clinically meaningful. The mean SpO2 is typically in the range of ~92% to 94% in mild to moderate OSA patients during sleep,41 and a 2% drop from 92% could result in hypoxemia (SpO2 < 90%). Oxygen saturation has been used as an endpoint in other respiratory safety studies with hypnotics.7,35 Ventilation is lower during all stages of sleep in patients with OSA due to disappearance of the influence of wakefulness and change in respiratory center activity. The reduction in ventilation is particularly more pronounced during REM sleep, resulting in increased potential for oxygen desaturation in respiratory function compromised patients. Thus, when assessing potential respiratory effects of a drug, it is important to compare mean SpO2 in each sleep/wake stage as well as during total sleep time. The mean SpO2 was similar between suvorexant and placebo in all comparisons after single and multiple doses of suvorexant. The mean SpO2 for each of the different sleep stages (awake, NREM, and REM) and the percentage of night with SpO2 < 90% and < 85% following suvorexant dosing were compared and did not reveal any clinically meaningful or statistically significant differences between suvorexant and placebo. Suvorexant 40 mg was generally well tolerated in men and women with mild to moderate OSA. No serious clinical
adverse events were reported and no patients discontinued because of an adverse event. All adverse events were rated mild or moderate in intensity. The most frequently reported adverse event with suvorexant was somnolence, in line with findings from clinical trials in insomnia patients,23–25 although this occurred in only 5/26 patients (19%). Exploratory assessments of residual effects performed the morning after dosing did not suggest that suvorexant resulted in impairments. However, these endpoints were exploratory and the study was not designed or powered to assess them. There are a number of limitations to interpretation of the present findings. Firstly, the study was of relatively short duration. Suvorexant has a half-life of approximately 8 to 10 hours in non-elderly subjects, and steady-state plasma concentration is achieved after 3–4 days dosing with minimal accumulation. Therefore, the Day 4 assessment in the present study evaluated the effects of suvorexant at steady-state, and it is unlikely that the results would be different if the evaluation period had been longer, although we cannot exclude the possibility. A second limitation is that we studied patients with mild to moderate OSA who did not have evidence of hypoxemia/hypoventilation on their screening PSG. Further studies are necessary to determine the respiratory safety of suvorexant in patients with severe OSA. Another limitation is that our conclusions are based on measurement of AHI and SpO2 , which do not constitute a full assessment of all aspects of respiration. Finally, we did not include a comparator agent so we cannot directly compare our findings with an orexin receptor antagonist to other classes of insomnia treatments such as benzodiazepine receptor agonists. In conclusion, these findings suggest that a nighttime 40 mg dose of suvorexant (twice the 20 mg maximum daily dose approved in the USA and Japan) does not have clinically meaningful effects on respiration during sleep in patients with mild to moderate OSA as assessed by mean changes in AHI and SpO2. These data support previous findings of a lack of respiratory effect of suvorexant 40 mg in mild-moderate COPD patients27 and in healthy subjects at doses of 40 mg and 150 mg.40 There is currently no clinical experience with suvorexant in patients with severe OSA, in patients treated with positive airway pressure therapy, or in patients with OSA-COPD overlap syndrome. Furthermore, there is inter- and intra-individual variability in respiratory effects. Therefore, suvorexant should be used with caution in patients with compromised respiratory function, and at the lowest effective dose. R E FE R E N CES 1. Krakow B, Melendrez D, Ferreira E, et al. Prevalence of insomnia symptoms in patients with sleep-disordered breathing. Chest 2001;120:1923–9. 2. Smith S, Sullivan K, Hopkins W, Douglas J. Frequency of insomnia report in patients with obstructive sleep apnoea hypopnea syndrome (OSAHS). Sleep Med 2004;5:449–56. 3. Shepertycky MR, Banno K, Kryger MH. Differences between men and women in the clinical presentation of patients diagnosed with obstructive sleep apnea syndrome. Sleep 2005;28:309–14. 4. Guilleminault C. Benzodiazepines, breathing, and sleep. Am J Med 1990;88:25S–28S. 5. Berry RB, Kouchi KG, Bower JL, Light RW. Effect of upper airway anesthesia on obstructive sleep apnea. Am J Respir Crit Care Med 1995;151:1857–61.
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H Sun, J Palcza, D Card et al. Suvorexant in Obstructive Sleep Apnea 6. George CF. Perspectives on the management of insomnia in patients with chronic respiratory disorders. Sleep 2000;23(Suppl 1):S31–5. 7. Rosenberg R, Roach JM, Scharf M, Amato DA. A pilot study evaluating acute use of eszopiclone in patients with mild to moderate obstructive sleep apnea syndrome. Sleep Med 2007;8:464–70. 8. Eckert DJ, Owens RL, Kehlmann GB, et al. Eszopiclone increases the respiratory arousal threshold and lowers the apnoea/hypopnoea index in obstructive sleep apnoea patients with a low arousal threshold. Clin Sci (Lond) 2011;120:505–14. 9. Kilduff TS, Peyron C. The hypocretin/orexin ligand-receptor system: implications for sleep and sleep disorders. Trends Neurosci 2000;23:359–65. 10. Brisbare-Roch C, Dingemanse J, Koberstein R, et al. Promotion of sleep by targeting the orexin system in rats, dogs and humans. Nat Med 2007;13:150–5. 11. Sakurai T. The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness. Nat Rev Neurosci 2007;8:171–81. 12. Baumann CR, Bassetti CL. Hypocretins (orexins) and sleep-wake disorders. Lancet Neurol 2005;4:673–82. 13. Scammell TE, Winrow CJ. Orexin receptors: pharmacology and therapeutic opportunities. Annu Rev Pharmacol Toxicol 2011;51:243–66. 14. Mieda M, Sakurai T. Orexin (hypocretin) receptor agonists and antagonists for treatment of sleep disorders: rationale for development and current status. CNS Drugs 2013;27:83–90. 15. Peyron C, Tighe DK, van den Pol AN, et al. Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci 1998;18:9996–10015. 16. Kuwaki T. Orexinergic modulation of breathing across vigilance states. Respir Physiol Neurobiol 2008;164:204–12. 17. Deng BS, Nakamura A, Zhang W, Yanagisawa M, Fukuda Y, Kuwaki T. Contribution of orexin in hypercapnic chemoreflex: evidence from genetic and pharmacological disruption and supplementation studies in mice. J Appl Physiol 2007;103:1772–9. 18. Li A, Nattie E. Antagonism of rat orexin receptors by almorexant attenuates central chemoreception in wakefulness in the active period of the diurnal cycle. J Physiol 2010;588:2935–44. 19. Han F, Mignot E, Wei YC, et al. Ventilatory chemoresponsiveness, narcolepsycataplexy and human leukocyte antigen DQB1*0602 status. Eur Respir J 2010;36:577–83. 20. Cox CD, Breslin MJ, Whitman DB, et al. Discovery of the dual orexin receptor antagonist[(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (MK-4305) for the treatment of insomnia. J Med Chem 2010;53:5320–32. 21. Winrow CJ, Gotter AL, Cox CD, et al. Promotion of sleep by MK-4305 - a novel dual orexin receptor antagonist. J Neurogenetics 2011;25:52–61. 22. Sun H, Kennedy WP, Wilbraham D, et al. Effects of suvorexant, an orexin receptor antagonist, on sleep parameters as measured by polysomnography in healthy men. Sleep 2013;36:259–67. 23. Herring WJ, Snyder E, Budd K, et al. Orexin receptor antagonism for treatment of insomnia: a randomized clinical trial of suvorexant. Neurology 2012;79:2265–74. 24. Michelson D, Snyder E, Paradis E, et al. Safety and efficacy of suvorexant during 1-year treatment of insomnia with subsequent abrupt treatment discontinuation: a phase 3 randomised, double-blind, placebo-controlled trial. Lancet Neurol 2014;13:461–71. 25. Herring WJ, Connor KM, Ivgy-May N, et al. Suvorexant in patients with insomnia: results from two 3-month randomized controlled clinical trials. Biol Psychiatry 2014 Oct 23. [Epub ahead of print]. 26. Merck & Co. Inc. FDA approves BELSOMRA (suvorexant) for the treatment of insomnia. Press release, Aug 13, 2014. http://www.mercknewsroom. com/news-release/prescription-medicine-news/fda-approves-belsomrasuvorexant-treatment-insomnia. Accessed October 17, 2014. 27. Sun H, Palcza J, Rosenberg R, et al. Effects of suvorexant, an orexin receptor antagonist, on breathing during sleep in patients with chronic obstructive pulmonary disease. Respir Med 2015;109:416–26. 28. American Academy of Sleep Medicine. International classification of sleep disorders, revised: Diagnostic and coding manual. Chicago, IL: American Academy of Sleep Medicine, 2001.
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29. Iber C, Ancoli-Israel S, Chesson AL, Quan SF. The AASM manual for the scoring of sleep and associated events: rules, terminology, and technical specifications. 1st ed. Westchester, IL: American Academy of Sleep Medicine, 2007. 30. Rechtschaffen A, Kales A. A manual of standardized terminology, techniques and scoring system for sleep stages of human subjects. Washington DC: National Institute of Health, Publication 204. Government Printing Office, 1968. 31. Rey A. L’examen clinique en psychologie. Paris, France: Presses Universitaires de France, 1964. 32. Wechsler D. WAIS-R manual. New York, NY: The Psychological Corporation, 1981. 33. Bond A, Lader M. The use of analogue scales in rating subjective feelings. Br J Psychol 1974;47:211–8 34. Norris V, Baisley K, Calder N, van Troostenburg AR, Warrington S. Assessment of the AccuSwayPLUS system in measuring the effect of lorazepam on body sway in healthy volunteers. Int J Pharm Med 2005;19:233–8. 35. Kyrger M, Wang-Weigand S, Roth T. Safety of ramelteon in individuals with mild to moderate obstructive sleep apnea. Sleep Breath 2007;11:159–64. 36. Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 2000;342:1378–84. 37. Punjabi NM, Shahar E, Redline S, Gottlieb DJ, Givelber R, Resnick HE. Sleepdisordered breathing, glucose intolerance, and insulin resistance: the Sleep Heart Health Study. Am J Epidemiol 2004;160:521–30. 38. Bliwise DL, Benkert RE, Ingham RH. Factors associated with nightly variability in sleep disordered breathing in the elderly. Chest 1991;100:973–6. 39. Chediak AD, Acevedo-Crespo JC, Seiden DJ, Kim HH, Kiel MH. Sleep disordered breathing: nightly variability in the indices of sleep-disordered breathing in men being evaluated for impotence with consecutive night polysomnograms. Sleep 1996;19:589–92. 40. Uemura N, McCrea J, Sun H, et al. Effects of the orexin receptor antagonist suvorexant on respiration during sleep in healthy subjects. J Clin Pharmacol 2015;55:1093–100. 41. Valipour A, Lothaller H, Rauscher H, Zwick H, Burghuber OC, Lavie P. Gender related differences in symptoms of patients with suspected breathing disorders in sleep: a clinical population study using the Sleep Disorders Questionnaire. Sleep 2007:30:312–9.
ACK N O W L E D G M E N T S The authors thank Chantal Mahon and Kate Mostoller from Merck & Co., Inc., for their contributions to running the study and Sheila Erespe from Merck & Co., Inc., for assistance in formatting the article. Investigators: Mardik Donikyan, Clinilabs, Inc., New York, NY; Russell Rosenberg, NeuroTrials Research, Atlanta, GA; David Seiden, Broward Research Group, Pembroke Pines, FL; Timothy Grant, Miami Research Associates, Miami, FL; Meir Kryger, Gaylord Sleep Medicine, Wallingford, CT.
SUBM I SSI O N & CO R R ESPO NDENCE I NFO R M ATI O N Submitted for publication February, 2015 Submitted in final revised form May, 2015 Accepted for publication June, 2015 Address correspondence to: Dr. Christopher Lines, Merck & Co., Inc., Kenilworth , NJ, USA; Tel: (267) 305-7870; Fax: (267) 305-6425; Email: [email protected]
D I SCLO S U R E S TAT E M E N T This study was funded by Merck & Co., Inc., Kenilworth, 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. 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
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H Sun, J Palcza, D Card et al. Suvorexant in Obstructive Sleep Apnea content. All authors provided final approval of the version to be published. Dr. Sun, Mr. Palcza, Ms. Card, Ms. Gipson, Dr. Lines, Dr. Wagner, and Dr. Troyer are current or former employees of Merck and own or owned stock/stock options in Merck. Dr. Sun is a current employee of Amgen, Thousand Oaks, CA. Dr. Wagner is a current employee of Takeda, Boston, MA. Dr. Troyer is a current employee of Medivation, San Francisco, CA. Dr. Rosenberg has received research funding from
and/or acted as a consultant for Merck, Teva, Pfizer, Jazz Pharmaceuticals, Eisai, and Respironics. Dr. Kryger has received research funding from and/or acted as consultant for Merck, Pfizer, Medtronic, and Inspire. These data were previously presented at the 27th annual meeting of the Associated Professional Sleep Societies, June 1–5, 2013, Baltimore, MD
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