*Current affiliation: Shenox Pharmaceuticals, McLean, VA, USA
This 52-week, double-blind, randomized, Phase 3 study evaluated the long-term safety of esmirtazapine 1.5 mg and 3.0 mg in elderly outpatients (aged ≥65 years) with insomnia.
Participants were randomized to receive esmirtazapine 1.5 mg or 3.0 mg administered once nightly. Safety and tolerability (primary objectives) were assessed via adverse event (AE) reporting, routine clinical measurements [vital signs; electrocardiogram (ECG); laboratory parameters], and residual-effects assessments. Total sleep time (TST), wake time after sleep onset (WASO), and sleep latency (SL) were assessed (secondary objectives).
Of 259 randomized participants, 153 completed treatment. AEs and serious AEs were reported by 89.8% and 7.0%, respectively, of 1.5 mg recipients, and 88.5% and 3.8%, respectively, of 3.0 mg recipients. Discontinuations due to AEs were reported in 16.4% and 18.3% of participants receiving esmirtazapine 1.5 mg and 3.0 mg, respectively. The most frequent AEs (>10%) were nasopharyngitis, somnolence, dizziness, headache, dry mouth, weight increase, and fatigue. One participant died; the death was judged unrelated to treatment. Elevated eosinophil counts were noted, but not considered clinically significant. No remarkable or clinically relevant changes in laboratory parameters, vital signs, or ECG were observed. There was no evidence of residual effects; alertness at awakening increased by a median of 17 (1.5 mg) and 15 (3.0 mg) points from baseline, respectively, and ability to work/function by 12 points (both groups; all
Esmirtazapine was reasonably tolerated in elderly outpatients with insomnia. No significant safety signals were observed.
Insomnia is a highly prevalent disorder, characterized by either non-restorative sleep or difficulties initiating or maintaining sleep [
Currently, first-line pharmacotherapy for insomnia relies on the use of positive allosteric modulators of gamma-aminobutyric acid type A (GABAA) receptors, which induce sedation through the potentiation of the inhibitory signaling of GABAA receptors [
Safety concerns associated with GABAA modulators prompted the clinical development of sleep-promoting compounds that facilitate sleep via more specific and targeted mechanisms of action, and this was anticipated to translate into an improved side-effects profile. For example, orexin receptor antagonists (ORAs) have been developed to promote sleep by blocking physiological effects of the orexin compounds, which are key mediators in the maintenance of arousal and vigilance [
Treatment with low doses of sedating antidepressants may be a promising approach for those patients who are more likely to experience sleep-maintenance insomnia, such as the elderly. Antidepressants have relatively discrete activity and act by modulating neurotransmitters, such as histamine, serotonin, and norepinephrine [
Mirtazapine is an antidepressant with sleep-promoting properties [
Given the burden of insomnia and the high prevalence of sleep-aid use in the geriatric population, the current study was conducted in elderly outpatients (aged ≥65 years) with chronic primary insomnia. The primary objective was to investigate the safety and tolerability of long-term (52-week) treatment with esmirtazapine at doses of 1.5 mg and 3.0 mg. The secondary objective was to collect exploratory efficacy data with respect to sleep improvement.
This Phase 3 study (Merck & Co., Inc., Kenilworth, NJ, USA, Protocol Number 176005; NCT00561574) was part of the esmirtazapine clinical development program. Since this study was conducted, the sponsor (Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.) discontinued further development of esmirtazapine. The study was conducted between January 2008 and February 2010 in 32 centers across Canada, Denmark, Finland, Germany, the Netherlands, Sweden, and the U.S. The trial was carried out in compliance with the ethical principles of the Declaration of Helsinki and in accordance with the International Conference on Harmonisation guidelines for Good Clinical Practice, as well as applicable local regulatory requirements. The study was approved by the appropriate Institutional Ethics Committee or Review Board. Participants were required to sign an informed consent form after receiving an explanation of the scope and nature of the investigation.
This was a randomized, double-blind, parallel-group (assignment to two doses of esmirtazapine), multisite study undertaken in elderly participants over a period of 52 weeks. The study design comprised a 14-day screening process during which participants’ eligibility for the study was ascertained based on prespecified inclusion criteria (
Eligible participants were aged ≥65 years at screening and had a normal bedtime within the 21:00–01:00-hours range, with variations not exceeding 2 h for five out of seven nights. Participants were required to demonstrate the ability to independently complete a sleep questionnaire in the week preceding randomization using the LogPad, a handheld electronic data-recording device that captures the sleep diary with respect to subjective drug-efficacy parameters and measures of drug residual effects. Further, participants had a documented diagnosis of chronic primary insomnia according to the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) criteria for primary insomnia (DSM-IV-TR 307.42) with a duration of ≥1 month, and met the following criteria based on medical or sleep history for at least 3 nights per week for at least 1 month: total sleep time (TST) ≤6.5 h; wake time after sleep onset (WASO) ≥60 min; and sleep latency (SL) ≥30 min.
Participants with other sleep disorders based on DSM-IVTR criteria, those presenting with sleep disturbances caused by significant medical or DSM-IV-TR psychiatric illness, and those who were currently, or within the last 2 years had been, diagnosed or treated for depression were excluded. Participants with signs of dementia or other serious cognitive impairment, defined as a score of <26 on the Mini-Mental State Examination, were also excluded.
The safety and tolerability analyses (primary objective) were performed in the all-participants-treated population, which was defined as all participants who received at least one dose of trial medication. Recording of AEs was performed from signing the informed consent form until 30 days after end of treatment. Clinical examinations evaluating vital signs and body weight were conducted at screening (Day -14) and at every visit, including the 7-day follow-up visit. Physical examinations were scheduled at screening (Day -14) and Week 52. In addition, electrocardiogram (ECG) was assessed at Days -14 and -7 and Weeks 2, 24, and 52, and laboratory parameters, including hematology, biochemistry, and urinalysis, were evaluated at screening and Weeks 2, 4, 12, 24, 36, and 52.
Residual effects (special safety measures) were assessed based on a sleep diary completed weekly on the LogPad from Day 1 until Week 52. The sleep diary captured participants’ ratings of alertness at awakening, energy level, and ability to work/ function during the day on visual analog scales (VAS) from 0–100 mm. Participants also reported their tendency to nap during the day (“Yes/No”) and indicated the napping time per day (in h and min).
Exploratory efficacy evaluations (secondary objective) were performed in the intent-to-treat population of all randomized participants who received at least one dose of trial medication and had at least one recorded post-baseline efficacy measurement on the weekly sleep diary. Efficacy measures included TST, WASO, SL, number of awakenings, and sleep quality based on weekly sleep diaries completed from Day 1 until Week 52. In addition, the extent of sleep difficulties was assessed on Day -7 and Weeks 2, 4, 12, 24, 36, and 52 using the insomnia severity index (ISI) based on participant ratings. The investigator global rating (IGR) scale was used by the clinician to rate insomnia symptom severity [IGR-severity (IGR-S)] and the therapeutic effect of the treatment regimen. These evaluations were completed at Day -7 (IGR-S score only) and Weeks 2, 4, 12, 24, 36, and 52.
Safety and efficacy parameters were evaluated using summary and descriptive statistics, respectively, with changes from baseline where appropriate. Continuous variables were analyzed by summary statistics. Paired t-statistics were used for testing the change from baseline by visit and by week as an exploratory analysis for efficacy endpoints. The ratings on the weekly sleep diary collected at Day 1 were used as baseline. No primary or secondary hypotheses for the testing of either efficacy or safety were performed. Categorical endpoints were summarized by treatment group, and summary statistics included sample size and percent for each response category. The denominator for percentage calculations was the total number of participants with non-missing values within each treatment group in that specific time point.
Data from weekly sleep diaries were analyzed using the last observation carried forward (LOCF) approach; sensitivity analyses were conducted based on observed case (OC) data. As the primary objective of this study was to assess long-term safety, the efficacy analysis is presented descriptively and with
The planned number of participants was based on the need to collect long-term safety data in elderly patients. Assuming a discontinuation rate of 50–80%, a sample size of 250 participants was considered sufficient. A sample size of 130 participants in each group would have an effect size of 1.1 to detect a difference in means of 86 min for TST duration, assuming the common standard deviation was 80 min using a two-sample t-test with a 5% two-sided significance level.
Of the 348 participants screened for this trial, 259 were randomized and treated, with 128 participants allocated to the 1.5-mg esmirtazapine treatment group and 131 participants assigned to the 3.0-mg treatment group (
The majority of participants were female (62.5%), white (97.7%), and of non-Hispanic/Latino descent (97.7%), with a mean (standard deviation) age of 70.9 (±5.2) years, and a mean body mass index (BMI) of 26.9 (±3.8) kg/m2. The most reported BMI category was overweight (43.2%) (
A total of 231 participants experienced at least one AE during the in-treatment period, including 115 participants (89.8%) in the 1.5-mg group and 116 participants (88.5%) in the 3.0-mg group (
One participant in the 1.5-mg treatment group died due to narcotic intoxication. The autopsy report indicated a history of asthma, heroin abuse, recent depression, and remote hand injuries. Toxicological studies were positive for ethanol and morphine. Based on these findings, the cause of death was described as morphine toxicity with arteriosclerotic cardiovascular disease listed as a contributing condition. The death was judged as unlikely to be related to study drug by the investigator and the sponsor.
During the in-treatment period, a total of 13 serious AEs (SAEs) were reported in nine participants (7.0%) in the 1.5-mg group, and seven SAEs were reported in five participants (3.8%) in the 3.0-mg group. In the 1.5-mg group, one participant with a history of arterial hypertension experienced two SAEs (cardiac failure and hypertensive heart disease), which the investigator judged to be possibly drug-related, whereas the sponsor deemed these SAEs unlikely to be related to the study drug. Another participant in the 1.5-mg group experienced three SAEs (contusion, dizziness, and fall) that were judged by the investigator as unlikely to be related to the study drug; however, the sponsor considered these events to be possibly related to the study drug. The remaining SAEs were considered by both the sponsor and the investigator to be either not related or unlikely related to the study drug. Except for the deceased participant, and one participant who recovered from cardiac events but also experienced intervertebral disc protrusion and recovered with sequelae (paraparesis of both legs), all participants in the 1.5-mg and 3.0-mg groups recovered or were still recovering from their SAEs at trial completion. During the post-treatment period (2 days after the 30-day follow-up period), one participant treated with 3.0 mg esmirtazapine reported an SAE (hernia) that was not considered to be treatment-related.
There were no clinically meaningful changes in hematology parameters over the course of the study, with the exception of notable increases from baseline in both the percentage of eosinophils, which increased by a median of 16.7% and 20.4% with esmirtazapine 1.5 mg and 3.0 mg, respectively, and absolute eosinophil counts, which increased by a median of 20.0% and 14.3% with esmirtazapine 1.5 mg and 3.0 mg, respectively, over the course of the study. However, none of the abnormally high values were considered to be clinically significant. Although there were no clinically significant changes in mean or median values for biochemical parameters between baseline and the last measurement, there were some differences observed among treatment groups: higher median percentages of change from baseline were observed with the 3.0-mg vs. the 1.5-mg dose for alanine aminotransferase (1.5 mg: 0.0%; 3.0 mg: 5.4%), aspartate aminotransferase (1.5 mg: 0.0%; 3.0 mg: 2.0%), total bilirubin (1.5 mg: 4.9%; 3.0 mg: 6.3%), and glucose (1.5 mg: 3.9%; 3.0 mg: 10.3%), and lower for gamma-glutamyl transferase (1.5 mg: 5.3%; 3.0 mg: 0.0%). There were no clinically relevant changes in urinalysis, vital signs, or ECG parameters.
Based on the daytime functioning questionnaire in the weekly diary, no residual effects were noted for either treatment group (
Exploratory efficacy measures were determined by comparison of subjective sleep parameters (TST, WASO, and SL) recorded on Day 1 with those recorded at end of treatment (
At baseline, the median TST per night was 300.0 min for the 1.5-mg and 3.0-mg dose groups (
The median ISI total score at baseline was 18 for both the 1.5-mg and 3.0-mg esmirtazapine treatment groups. An improvement in ISI score from baseline to endpoint was observed for both treatment groups. At Week 52 (Visit 18), the median change from baseline in ISI was -9 and -11 for the 1.5-mg and 3.0-mg treatment groups, respectively; at end of treatment, the median change from baseline in ISI was -8 for both treatment groups. Changes from baseline in ISI total score by visit/week are shown in
Overall, the magnitude of change in the subjective efficacy variables was generally consistent throughout the 52 weeks of treatment, and no apparent difference between the 1.5-mg and 3.0-mg treatment groups was observed.
The current study examined the long-term safety of esmirtazapine in elderly patients with a diagnosis of chronic insomnia. The efficacy assessments were exploratory in nature, as no placebo comparator was included. The results indicate reasonable tolerability of both investigated doses of esmirtazapine (1.5 mg and 3.0 mg) administered before bedtime for the long-term treatment of elderly patients with insomnia. The exploratory efficacy data demonstrated a marked improvement from baseline in subjective sleep diary measures (i.e., TST, WASO, SL). Similarly, improvements from baseline were also noted in the ISI and IGR-S. These improvements from baseline were sustained over the 52-week treatment period and did not exhibit apparent differences between the two dose groups. The percentage of participants completing the current study (59.1%) was comparable with the completion rate (65.4%) of a 1-year, open-label, extension phase of two randomized trials of zaleplon [
The safety of 1.5-mg, 3.0-mg, and 4.5-mg doses of esmirtazapine was previously examined for a shorter duration of treatment and in a younger population of adult patients with insomnia (aged ≤65 years) [
The fall rate observed in this study was relatively low: three participants (2.3%) receiving a dose of 1.5 mg esmirtazapine reported a fall. While treatment of insomnia symptoms in elderly patients frequently leads to the prescription of GABAA receptor modulators [
Discontinuation due to insufficient therapeutic effect appeared to occur more frequently in the 3.0-mg group than the 1.5-mg group. Although the small sample size limits the ability to draw conclusions regarding this finding, and a definitive explanation is therefore unclear, greater residual effects at the higher dose, which may have diminished participants’ interpretations of efficacy, may have contributed. This may be supported by the observation that approximately twice the number of participants in the 3.0-mg group reported somnolence and dizziness compared with the 1.5-mg group. Lack of compliance with taking medication per protocol could be another contributing factor; however, cumulative compliance in this study was 95.8% for the 3.0-mg group and 97.6% for the 1.5-mg group, and is unlikely to fully explain the difference.
The observation that both doses of esmirtazapine showed no apparent deleterious effects on measures of alertness at awakening, energy level, and ability to work/function (as captured with the sleep diary) is consistent with data from previous studies that have assessed the potential for next-day hangover effects from esmirtazapine in non-elderly adults with insomnia [
Previous reports on the efficacy of esmirtazapine in non-elderly adult patients with primary insomnia have indicated sustained beneficial effects on objective and subjective patient-reported measures of sleep onset and maintenance over the study period [
The apparent sleep-promoting properties of esmirtazapine should be considered in the context of long-term efficacy data of other pharmacological treatments for insomnia. While benzodiazepines have established short-term benefits with regard to improvement in sleep initiation and maintenance, their longterm efficacy has not been established [
Several limitations should be considered when interpreting the findings of this study. The study design did not include a non-active (placebo) treatment arm and participants were only blinded to the dose of treatment they received, which limits efficacy evaluation. The contribution of factors other than drug activity to the frequency of AEs and reported therapeutic effect cannot, therefore, be excluded. Also, the sample size of the study was not determined by power analysis for detecting a significant difference at a fixed, Type I error rate. As a result, there was no formal hypothesis formulation and testing in this study. The study was only designed to assess within-group statistical differences relative to baseline values—not differences between the dose groups. Although there were no apparent differences between the two dose groups with regard to exploratory efficacy outcomes, dose–response measurements were not collected for this study, so only a tentative statement regarding the lack of apparent dose–response effects of esmirtazapine in improving insomnia sleep parameters long-term can be made. Finally, co-occurrence of insomnia with anxiety and/or depression is prevalent in the elderly population, and patients with such comorbidities were excluded from this study. This limits the generalizability of the findings and warrants further research efforts in patients with comorbid insomnia to establish the safety and efficacy of esmirtazapine in these subpopulations.
Our findings suggest that esmirtazapine doses of 1.5 mg and 3.0 mg nightly are reasonably tolerated in elderly outpatients with insomnia as long-term treatment (up to 1 year) without evidence of significant residual effects. Despite the lack of placebo and the limited power of the analysis, the persistent improvements in sleep parameters throughout this year-long study in elderly patients are encouraging, especially when considering tolerance issues associated with the long-term use of many hypnotics.
The online-only Data Supplement is available with this article at
Funding for this research was provided by Organon, a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. The study sponsor was involved in the: design of the study; collection, analysis, and interpretation of the data; preparation of the manuscript; and decision to submit the manuscript for publication. Medical writing support, under the direction of the authors, was provided by Hicham Naimy, PhD, and Adele Blair, PhD, of CMC AFFINITY, McCann Health Medical Communications, funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, in accordance with Good Publication Practice (GPP3) guidelines. The authors would like to thank Armin Szegedi, Thomas Roth, and Bernhard Slaap for contributions to the study design and for helpful discussion.
NI-M, QC, and AP are current or former employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and may own stock and/or stock options in Merck & Co., Inc., Kenilworth, NJ, USA. AW received research funding and personal fees from Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA for the conduct of the study at UConn Health, Farmington, CT, USA.
Conceptualization: Neely Ivgy-May, Qing Chang. Data curation: Andrew Winokur. Formal analysis: Neely Ivgy-May, Annpey Pong. Investigation: Andrew Winokur. Methodology: Neely Ivgy-May, Qing Chang. Supervision: Neely Ivgy-May. Writing—original draft: Neely Ivgy-May, Qing Chang, Annpey Pong, Andrew Winokur. Writing—review & editing: Neely Ivgy-May, Qing Chang, Annpey Pong, Andrew Winokur.
Study design.
Participant disposition. *participants took at least one dose of trial medication, †information as per End of Trial Form, ‡one participant in the 1.5-mg group discontinued due to lack of compliance with study diary. AE: adverse event, SAE: serious AE.
Mean change from baseline for weekly TST (A), WASO (B), and SL (C) in the intent-to-treat population (last observation carried forward). SL: sleep latency, TST: total sleep time, WASO: wake time after sleep onset.
Participant demographics at screening
Variables | Esmirtazapine 1.5 mg (n=128) | Esmirtazapine 3.0 mg (n=131) | Total (n=259) |
---|---|---|---|
Age (years) | |||
Median (range) | 69.0 (65.0-86.0) | 70.0 (65.0-87.0) | 69.0 (65.0-87.0) |
Mean (SD) | 70.7 (5.2) | 71.1 (5.1) | 70.9 (5.2) |
Height (cm) | |||
Median (range) | 165.0 (139.7-198.1) | 166.4 (144.0-188.0) | 166.0 (139.7-198.1) |
Mean (SD) | 167.3 (10.5) | 167.4 (9.7) | 167.4 (10.1) |
Weight (kg) | |||
Median (range) | 73.7 (48.6-124.3) | 75.0 (45.3-107.0) | 73.9 (45.3-124.3) |
Mean (SD) | 76.1 (15.8) | 75.5 (13.2) | 75.8 (14.5) |
Gender, n (%) | |||
Female | 83 (64.8) | 79 (60.3) | 162 (62.5) |
Male | 45 (35.2) | 52 (39.7) | 97 (37.5) |
Race, n (%) | |||
Black or African-American | 4 (3.1) | 2 (1.5) | 6 (2.3) |
White | 124 (96.9) | 129 (98.5) | 253 (97.7) |
Ethnicity, n (%) | |||
Hispanic or Latino | 2 (1.6) | 4 (3.1) | 6 (2.3) |
Not Hispanic or Latino | 126 (98.4) | 127 (96.9) | 253 (97.7) |
BMI (kg/m2) | |||
Median (range) | 26.3 (17.9-35.8) | 26.6 (19.2-35.4) | 26.5 (17.9-35.8) |
Mean (SD) | 27.0 (4.0) | 26.9 (3.7) | 26.9 (3.8) |
BMI category, n (%) | |||
Underweight (BMI<18.5) | 1 (0.8) | 0 (0.0) | 1 (0.4) |
Normal range (18.5≤BMI<25) | 43 (33.6) | 43 (32.8) | 86 (33.2) |
Overweight (25≤BMI<30) | 55 (43.0) | 57 (43.5) | 112 (43.2) |
Obese (BMI≥30) | 29 (22.7) | 31 (23.7) | 60 (23.2) |
BMI: body mass index, SD: standard deviation
Safety profile of esmirtazapine
Esmirtazapine 1.5 mg (n=128; n, %) | Esmirtazapine 3.0 mg (n=131; n, %) | |||
---|---|---|---|---|
Overall safety profile | ||||
Participants with AEs | 115 (89.8) | 116 (88.5) | ||
Deaths |
1 (0.8) | 0 (0.0) | ||
Participants with SAEs |
9 (7.0) | 5 (3.8) | ||
Participants who discontinued due to AEs | 21 (16.4) | 24 (18.3) | ||
Participants with drug-related AEs |
74 (57.8) | 88 (67.2) | ||
Participants with severe AEs | 13 (10.2) | 14 (10.7) | ||
AEs occurring in ≥2.5% of participants in any treatment group | Related | Total | Related | Total |
Somnolence | 15 (11.7) | 15 (11.7) | 33 (25.2) | 35 (26.7) |
Weight increased | 11 (8.6) | 11 (8.6) | 18 (13.7) | 20 (15.3) |
Dizziness | 8 (6.3) | 12 (9.4) | 14 (10.7) | 19 (14.5) |
Nasopharyngitis | 0 (0.0) | 21 (16.4) | 0 (0.0) | 17 (13.0) |
Fatigue | 15 (11.7) | 17 (13.3) | 11 (8.4) | 15 (11.5) |
Dry mouth | 9 (7.0) | 10 (7.8) | 12 (9.2) | 14 (10.7) |
Headache | 7 (5.5) | 13 (10.2) | 3 (2.3) | 12 (9.2) |
Increased appetite | 5 (3.9) | 5 (3.9) | 12 (9.2) | 12 (9.2) |
Back pain | 0 (0.0) | 8 (6.3) | 0 (0.0) | 8 (6.1) |
Hypertension | 0 (0.0) | 3 (2.3) | 1 (0.8) | 11 (8.4) |
Urinary tract infection | 0 (0.0) | 2 (1.6) | 1 (0.8) | 10 (7.6) |
Diarrhea | 1 (0.8) | 7 (5.5) | 4 (3.1) | 9 (6.9) |
Arthralgia | 0 (0.0) | 6 (4.7) | 1 (0.8) | 9 (6.9) |
Restless legs syndrome | 3 (2.3) | 3 (2.3) | 6 (4.6) | 8 (6.1) |
Influenza | 0 (0.0) | 4 (3.1) | 0 (0.0) | 5 (3.8) |
Nightmare | 3 (2.3) | 3 (2.3) | 5 (3.8) | 6 (4.6) |
Nausea | 1 (0.8) | 3 (2.3) | 3 (2.3) | 6 (4.6) |
Pain in extremity | 0 (0.0) | 2 (1.6) | 1 (0.8) | 6 (4.6) |
Upper respiratory tract infection | 0 (0.0) | 3 (2.3) | 0 (0.0) | 4 (3.1) |
Insomnia | 0 (0.0) | 4 (3.1) | 1 (0.8) | 4 (3.1) |
Oropharyngeal pain | 0 (0.0) | 3 (2.3) | 0 (0.0) | 4 (3.1) |
Sinusitis | 0 (0.0) | 4 (3.1) | 0 (0.0) | 3 (2.3) |
Constipation | 1 (0.8) | 2 (1.6) | 4 (3.1) | 4 (3.1) |
Hepatic enzyme increased | 0 (0.0) | 0 (0.0) | 2 (1.5) | 4 (3.1) |
Cough | 1 (0.8) | 8 (6.3) | 0 (0.0) | 3 (2.3) |
Sedation | 4 (3.1) | 4 (3.1) | 2 (1.5) | 2 (1.5) |
Abnormal dreams | 6 (4.7) | 6 (4.7) | 1 (0.8) | 1 (0.8) |
Upper abdominal pain | 2 (1.6) | 4 (3.1) | 0 (0.0) | 1 (0.8) |
One participant had an SAE 2 days after the 30-day follow-up period; this participant is not counted in the table.
irrespective of time point of death,
including the fatal SAE,
relationship specified by the investigator as “Definite,” “Probable,” “Possible.” AE: adverse event, SAE: serious AE
Summary statistics for residual effects parameters (allparticipants-treated population; last observation carried forward)
Statistic | Change from baseline to end of treatment |
|
---|---|---|
Esmirtazapine 1.5 mg (n=128) | Esmirtazapine 3.0 mg (n=131) | |
Alertness at awakening | ||
n | 123 | 128 |
Median (range) | 17 (-71 to 97) | 15 (-46 to 88) |
Mean (SD) | 18.3 (29.2) | 16.2 (24.9) |
|
<0.0001 | <0.0001 |
Feeling full of energy the past 7 days | ||
n | 123 | 128 |
Median (range) | 13 (-87 to 95) | 11 (-58 to 83) |
Mean (SD) | 16.1 (27.7) | 13.6 (24.3) |
|
<0.0001 | <0.0001 |
VAS rating on ability to work/function | ||
n | 123 | 128 |
Median (range) | 12 (-77 to 94) | 12 (-50 to 88) |
Mean (SD) | 14.7 (26.7) | 14.6 (23.1) |
|
<0.0001 | <0.0001 |
Total nap time (min) | ||
n | 25 | 25 |
Median (range) | -1 (-45.0 to 40.0) | 5 (-120.0 to 30.0) |
Mean (SD) | -2.8 (16.7) | -0.9 (27.4) |
|
0.4174 | 0.8737 |
SD: standard deviation, VAS: visual analog scale
Summary statistics of SL, WASO, and TST at baseline and end of treatment (intent-to-treat population; last observation carried forward)
Sleep characteristic (min) | Time point | Esmirtazapine 1.5 mg (n=128) |
Esmirtazapine 3.0 mg (n=129) |
||
---|---|---|---|---|---|
Mean (SD) | Median (range) | Mean (SD) | Median (range) | ||
Sleep duration | |||||
TST | n | 127 | 127 | 128 | 128 |
Baseline | 294.0 (71.0) | 300.0 (150.0 to 666.0) | 293.5 (67.3) | 300.0 (0.0 to 436.0) | |
n | 124 | 124 | 129 | 129 | |
End of treatment | 381.0 (82.5) | 390.0 (120.0 to 510.0) | 380.4 (99.1) | 390.0 (6.0 to 660.0) | |
Sleep maintenance | |||||
WASO | n | 127 | 127 | 128 | 128 |
Baseline | 109.4 (86.4) | 90.0 (0.0 to 660.0) | 102.4 (71.0) | 90.0 (13.0 to 540.0) | |
n | 124 | 124 | 129 | 129 | |
End of treatment | 47.5 (53.9) | 30.0 (0.0 to 360.0) | 52.1 (67.4) | 25.0 (0.0 to 360.0) | |
Sleep induction | |||||
SL | n | 127 | 127 | 128 | 128 |
Baseline | 88.6 (72.5) | 60.0 (9.0 to 480.0) | 91.4 (77.7) | 70.0 (4.0 to 360.0) | |
n | 124 | 124 | 129 | 129 | |
End of treatment | 60.8 (81.4) | 30.0 (5.0 to 445.0) | 69.3 (85.7) | 30.0 (3.0 to 450.0) |
SD: standard deviation, SL: sleep latency, TST: total sleep time, WASO: wake time after sleep onset
Change from baseline for ISI total score by visit (intent-to-treat population; observed cases)
Statistic | Change in total ISI score from baseline |
|
---|---|---|
Esmirtazapine 1.5 mg (n=128) | Esmirtazapine 3.0 mg (n=129) | |
Visit 5 (week 2) | ||
n | 118 | 117 |
Median (range) | -4 (-21 to 6) | -5 (-20 to 7) |
Mean (SD) | -4.7 (5.0) | -5.6 (5.4) |
|
<0.0001 | <0.0001 |
Visit 6 (week 4) | ||
n | 110 | 112 |
Median (range) | -7 (-17 to 4) | -7 (-21 to 6) |
Mean (SD) | -6.5 (4.9) | -7.0 (5.7) |
|
<0.0001 | <0.0001 |
Visit 8 (week 12) | ||
n | 110 | 100 |
Median (range) | -7 (-19 to 5) | -9 (-22 to 6) |
Mean (SD) | -7.7 (6.0) | -8.6 (5.9) |
|
<0.0001 | <0.0001 |
Visit 11 (week 24) | ||
n | 96 | 91 |
Median (range) | -9 (-21 to 4) | -9 (-25 to 7) |
Mean (SD) | -8.5 (5.9) | -8.8 (6.4) |
|
<0.0001 | <0.0001 |
Visit 14 (week 36) | ||
n | 81 | 77 |
Median (range) | -10 (-20 to 2) | -9 (-22 to 4) |
Mean (SD) | -9.4 (5.5) | -8.9 (5.9) |
|
<0.0001 | <0.0001 |
Visit 18 (week 52) | ||
n | 70 | 68 |
Median (range) | -9 (-22 to 6) | -11 (-21 to 4) |
Mean (SD) | -8.9 (6.4) | -10.3 (5.8) |
|
<0.0001 | <0.0001 |
Endpoint | ||
n | 122 | 123 |
Median (range) | -8 (-22 to 6) | -8 (-25 to 7) |
Mean (SD) | -7.5 (6.6) | -7.5 (6.9) |
|
<0.0001 | <0.0001 |