Trial Outcomes & Findings for Dose-Finding Safety and Efficacy Trial of Org 50081 (Esmirtazapine) in the Treatment of Vasomotor Symptoms (177001/P06472/MK-8265-013) (NCT NCT00535288)

NCT ID: NCT00535288

Last Updated: 2019-04-02

Results Overview

Participants recorded the frequency (number) of vasomotor symptoms (hot flushes) on an electronic diary card (LogPad®) on a daily basis during screening and treatment. Frequency Score A was based on the number of moderate hot flushes + the number of severe hot flushes in one day. Baseline average was derived from, at most, 7 completely observed pre-treatment days. Weekly averages during treatment were calculated if at least 4 days with non-missing data were completely observed; if less than 4 days were completely observed, the averages of the previous week were carried forward (last observation carried forward, or LOCF). If the number of days observed in Week 1 were not sufficient, baseline values were carried forward.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 946 participants
• Primary outcome timeframe: Baseline and Week 4
• Results posted on: 2019-04-02

Participant Flow

946 participants were randomly assigned in this study, however, one participant assigned to placebo never received treatment and one participant assigned to placebo actually received esmirtazapine 18 mg and is included in that group for all study analyses.

Participant milestones

Measure	Placebo Participants receive encapsulated tablets, orally, once daily (QD) for up to 12 weeks.	Esmirtazapine 2.25 mg Participants receive esmirtazapine, 2.25 mg, encapsulated tablets, orally QD for up to 12 weeks.	Esmirtazapine 4.5 mg Participants receive esmirtazapine, 4.5 mg, encapsulated tablets, orally QD for up to 12 weeks.	Esmirtazapine 9 mg Participants receive esmirtazapine, 9 mg, encapsulated tablets, orally QD for up to 12 weeks.	Esmirtazapine 18 mg Participants receive esmirtazapine, 18 mg, encapsulated tablets, orally QD for up to 12 weeks.
Overall Study STARTED	314	162	160	151	158
Overall Study COMPLETED	260	130	127	122	116
Overall Study NOT COMPLETED	54	32	33	29	42

Reasons for withdrawal

Measure	Placebo Participants receive encapsulated tablets, orally, once daily (QD) for up to 12 weeks.	Esmirtazapine 2.25 mg Participants receive esmirtazapine, 2.25 mg, encapsulated tablets, orally QD for up to 12 weeks.	Esmirtazapine 4.5 mg Participants receive esmirtazapine, 4.5 mg, encapsulated tablets, orally QD for up to 12 weeks.	Esmirtazapine 9 mg Participants receive esmirtazapine, 9 mg, encapsulated tablets, orally QD for up to 12 weeks.	Esmirtazapine 18 mg Participants receive esmirtazapine, 18 mg, encapsulated tablets, orally QD for up to 12 weeks.
Overall Study Adverse Event	20	19	25	20	30
Overall Study Lost to Follow-up	0	3	0	0	0
Overall Study Lack of Efficacy	26	3	4	4	7
Overall Study Unwilling to cooperate	6	6	3	3	4
Overall Study Other	2	1	1	2	1

Baseline Characteristics

Dose-Finding Safety and Efficacy Trial of Org 50081 (Esmirtazapine) in the Treatment of Vasomotor Symptoms (177001/P06472/MK-8265-013)

Baseline characteristics by cohort

Measure	Placebo n=314 Participants Participants receive encapsulated tablets, orally, QD for up to 12 weeks.	Esmirtazapine 2.25 mg n=162 Participants Participants receive esmirtazapine, 2.25 mg, encapsulated tablets, orally QD for up to 12 weeks.	Esmirtazapine 4.5 mg n=160 Participants Participants receive esmirtazapine, 4.5 mg, encapsulated tablets, orally QD for up to 12 weeks.	Esmirtazapine 9 mg n=151 Participants Participants receive esmirtazapine, 9 mg, encapsulated tablets, orally QD for up to 12 weeks.	Esmirtazapine 18 mg n=158 Participants Participants receive esmirtazapine, 18 mg, encapsulated tablets, orally QD for up to 12 weeks.	Total n=945 Participants Total of all reporting groups
Age, Continuous	53.5 Years STANDARD_DEVIATION 4.9 • n=5 Participants	53.8 Years STANDARD_DEVIATION 5.0 • n=7 Participants	53.7 Years STANDARD_DEVIATION 4.8 • n=5 Participants	54.7 Years STANDARD_DEVIATION 4.6 • n=4 Participants	53.5 Years STANDARD_DEVIATION 4.7 • n=21 Participants	53.8 Years STANDARD_DEVIATION 4.8 • n=8 Participants
Sex: Female, Male Female	314 Participants n=5 Participants	162 Participants n=7 Participants	160 Participants n=5 Participants	151 Participants n=4 Participants	158 Participants n=21 Participants	945 Participants n=8 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants

PRIMARY outcome

Timeframe: Baseline and Week 4

Population: The Intent-to-Treat (ITT) population, defined as all randomized participants who had at least one pre-baseline and at least one post-baseline average of the number of hot flushes in a week.

Participants recorded the frequency (number) of vasomotor symptoms (hot flushes) on an electronic diary card (LogPad®) on a daily basis during screening and treatment. Frequency Score A was based on the number of moderate hot flushes + the number of severe hot flushes in one day. Baseline average was derived from, at most, 7 completely observed pre-treatment days. Weekly averages during treatment were calculated if at least 4 days with non-missing data were completely observed; if less than 4 days were completely observed, the averages of the previous week were carried forward (last observation carried forward, or LOCF). If the number of days observed in Week 1 were not sufficient, baseline values were carried forward.

Outcome measures

Measure	Placebo n=283 Participants Participants receive encapsulated tablets, orally, once daily (QD) for up to 12 weeks.	Esmirtazapine 2.25 mg n=146 Participants Participants receive esmirtazapine, 2.25 mg, encapsulated tablets, orally QD for up to 12 weeks.	Esmirtazapine 4.5 mg n=144 Participants Participants receive esmirtazapine, 4.5 mg, encapsulated tablets, orally QD for up to 12 weeks.	Esmirtazapine 9 mg n=134 Participants Participants receive esmirtazapine, 9 mg, encapsulated tablets, orally QD for up to 12 weeks.	Esmirtazapine 18 mg n=138 Participants Participants receive esmirtazapine, 18 mg, encapsulated tablets, orally, QD for up to 12 weeks
Change From Baseline in Average Daily Frequency of Moderate/Severe Vasomotor Symptoms (Frequency Score A) at Week 4 Baseline	12.1 Events per day Standard Deviation 5.1	12.2 Events per day Standard Deviation 5.1	12.6 Events per day Standard Deviation 4.7	12.3 Events per day Standard Deviation 4.4	11.5 Events per day Standard Deviation 4.7
Change From Baseline in Average Daily Frequency of Moderate/Severe Vasomotor Symptoms (Frequency Score A) at Week 4 Week 4	-3.8 Events per day Standard Deviation 4.5	-5.1 Events per day Standard Deviation 4.1	-5.7 Events per day Standard Deviation 4.8	-5.3 Events per day Standard Deviation 3.8	-5.6 Events per day Standard Deviation 4.4

PRIMARY outcome

Timeframe: Baseline and Week 4

Population: The ITT population, defined as all randomized participants who had at least one pre-baseline and at least one post-baseline average of the number of hot flushes in a week.

Participants recorded the severity of hot flushes on a LogPad on a daily basis during screening and treatment. The severity of hot flushes was defined as: mild (sensation of heat without sweating); moderate (sensation of heat with sweating, able to continue activity); and severe (sensation of heat with sweating, causing cessation of activity). Severity Score A was calculated as the number of moderate hot flushes x 2 + the number of severe hot flushes x 3, divided by the total number of moderate and severe hot flushes per week. If no hot flushes were experienced, this was to be recorded as 'no sensation of heat'. Baseline values were based on, at most, 7 completely observed pre-treatment days. If less than 4 days were completely observed during treatment, the averages of the previous week were carried forward (LOCF). If the number of days observed in Week 1 were not sufficient, baseline values were carried forward.

Outcome measures

Measure	Placebo n=283 Participants Participants receive encapsulated tablets, orally, once daily (QD) for up to 12 weeks.	Esmirtazapine 2.25 mg n=146 Participants Participants receive esmirtazapine, 2.25 mg, encapsulated tablets, orally QD for up to 12 weeks.	Esmirtazapine 4.5 mg n=144 Participants Participants receive esmirtazapine, 4.5 mg, encapsulated tablets, orally QD for up to 12 weeks.	Esmirtazapine 9 mg n=134 Participants Participants receive esmirtazapine, 9 mg, encapsulated tablets, orally QD for up to 12 weeks.	Esmirtazapine 18 mg n=138 Participants Participants receive esmirtazapine, 18 mg, encapsulated tablets, orally, QD for up to 12 weeks
Change From Baseline in Average Daily Severity of Moderate/Severe Vasomotor Symptoms (Severity Score A) at Week 4 Baseline	2.45 Severity score Standard Deviation 0.30	2.45 Severity score Standard Deviation 0.30	2.45 Severity score Standard Deviation 0.32	2.46 Severity score Standard Deviation 0.30	2.40 Severity score Standard Deviation 0.27
Change From Baseline in Average Daily Severity of Moderate/Severe Vasomotor Symptoms (Severity Score A) at Week 4 Week 4	-0.07 Severity score Standard Deviation 0.20	-0.14 Severity score Standard Deviation 0.23	-0.13 Severity score Standard Deviation 0.23	-0.15 Severity score Standard Deviation 0.24	-0.15 Severity score Standard Deviation 0.23

PRIMARY outcome

Timeframe: Baseline and Week 12

Population: The ITT population, defined as all randomized participants who had at least one pre-baseline and at least one post-baseline average of the number of hot flushes in a week.

Participants recorded the frequency (number) of vasomotor symptoms (hot flushes) on a LogPad on a daily basis during screening and treatment. Frequency Score A was based on the number of moderate hot flushes + the number of severe hot flushes in one day. Baseline average was derived from, at most, 7 completely observed pre-treatment days. Weekly averages during treatment were calculated if at least 4 days with non-missing data were completely observed; if less than 4 days were completely observed, the averages of the previous week were carried forward (LOCF). If the number of days observed in Week 1 were not sufficient, baseline values were carried forward.

Outcome measures

Measure	Placebo n=283 Participants Participants receive encapsulated tablets, orally, once daily (QD) for up to 12 weeks.	Esmirtazapine 2.25 mg n=146 Participants Participants receive esmirtazapine, 2.25 mg, encapsulated tablets, orally QD for up to 12 weeks.	Esmirtazapine 4.5 mg n=144 Participants Participants receive esmirtazapine, 4.5 mg, encapsulated tablets, orally QD for up to 12 weeks.	Esmirtazapine 9 mg n=134 Participants Participants receive esmirtazapine, 9 mg, encapsulated tablets, orally QD for up to 12 weeks.	Esmirtazapine 18 mg n=138 Participants Participants receive esmirtazapine, 18 mg, encapsulated tablets, orally, QD for up to 12 weeks
Change From Baseline in Average Daily Frequency of Moderate/Severe Vasomotor Symptoms (Frequency Score A) at Week 12 Baseline	12.1 Events per day Standard Deviation 5.1	12.2 Events per day Standard Deviation 5.1	12.6 Events per day Standard Deviation 4.7	12.3 Events per day Standard Deviation 4.4	11.5 Events per day Standard Deviation 4.7
Change From Baseline in Average Daily Frequency of Moderate/Severe Vasomotor Symptoms (Frequency Score A) at Week 12 Week 12	-4.2 Events per day Standard Deviation 5.3	-5.2 Events per day Standard Deviation 4.6	-6.0 Events per day Standard Deviation 4.9	-5.8 Events per day Standard Deviation 4.3	-6.0 Events per day Standard Deviation 4.6

PRIMARY outcome

Timeframe: Baseline and Week 12

Population: The ITT population, defined as all randomized participants who had at least one pre-baseline and at least one post-baseline average of the number of hot flushes in a week.

Participants recorded the severity of hot flushes on a LogPad on a daily basis during screening and treatment. The severity of hot flushes was defined as: mild (sensation of heat without sweating); moderate (sensation of heat with sweating, able to continue activity); and severe (sensation of heat with sweating, causing cessation of activity). Severity Score A was calculated as the number of moderate hot flushes x 2 + the number of severe hot flushes x 3, divided by the total number of moderate and severe hot flushes per week. If no hot flushes were experienced, this was to be recorded as 'no sensation of heat'. Baseline values were based on, at most, 7 completely observed pre-treatment days. If less than 4 days were completely observed during treatment, the averages of the previous week were carried forward (LOCF). If the number of days observed in Week 1 were not sufficient, baseline values were carried forward.

Outcome measures

Measure	Placebo n=283 Participants Participants receive encapsulated tablets, orally, once daily (QD) for up to 12 weeks.	Esmirtazapine 2.25 mg n=146 Participants Participants receive esmirtazapine, 2.25 mg, encapsulated tablets, orally QD for up to 12 weeks.	Esmirtazapine 4.5 mg n=144 Participants Participants receive esmirtazapine, 4.5 mg, encapsulated tablets, orally QD for up to 12 weeks.	Esmirtazapine 9 mg n=134 Participants Participants receive esmirtazapine, 9 mg, encapsulated tablets, orally QD for up to 12 weeks.	Esmirtazapine 18 mg n=138 Participants Participants receive esmirtazapine, 18 mg, encapsulated tablets, orally, QD for up to 12 weeks
Change From Baseline in Average Daily Severity of Moderate/Severe Vasomotor Symptoms (Severity Score A) at Week 12 Baseline	2.45 Severity score Standard Deviation 0.30	2.45 Severity score Standard Deviation 0.30	2.45 Severity score Standard Deviation 0.32	2.46 Severity score Standard Deviation 0.30	2.40 Severity score Standard Deviation 0.27
Change From Baseline in Average Daily Severity of Moderate/Severe Vasomotor Symptoms (Severity Score A) at Week 12 Week 12	-0.08 Severity score Standard Deviation 0.26	-0.15 Severity score Standard Deviation 0.27	-0.13 Severity score Standard Deviation 0.27	-0.13 Severity score Standard Deviation 0.26	-0.15 Severity score Standard Deviation .026

SECONDARY outcome

Timeframe: Baseline and Up to Week 12

Population: The ITT population, defined as all randomized participants who had at least one pre-baseline and at least one post-baseline average of the number of hot flushes in a week.

Participants recorded the frequency (number) of vasomotor symptoms (hot flushes) on a LogPad on a daily basis during screening and treatment. Frequency Score A was based on the number of moderate hot flushes + the number of severe hot flushes in one day. Baseline average was derived from, at most, 7 completely observed pre-treatment days. Weekly averages during treatment were calculated if at least 4 days with non-missing data were completely observed; if less than 4 days were completely observed, the averages of the previous week were carried forward (LOCF). If the number of days observed in Week 1 were not sufficient, baseline values were carried forward.

Outcome measures

Measure	Placebo n=283 Participants Participants receive encapsulated tablets, orally, once daily (QD) for up to 12 weeks.	Esmirtazapine 2.25 mg n=146 Participants Participants receive esmirtazapine, 2.25 mg, encapsulated tablets, orally QD for up to 12 weeks.	Esmirtazapine 4.5 mg n=144 Participants Participants receive esmirtazapine, 4.5 mg, encapsulated tablets, orally QD for up to 12 weeks.	Esmirtazapine 9 mg n=134 Participants Participants receive esmirtazapine, 9 mg, encapsulated tablets, orally QD for up to 12 weeks.	Esmirtazapine 18 mg n=138 Participants Participants receive esmirtazapine, 18 mg, encapsulated tablets, orally, QD for up to 12 weeks
Change From Baseline in Average Daily Frequency of Moderate/Severe Vasomotor Symptoms (Frequency Score A) by Week Excluding Weeks 4 and 12 Week 11	-4.20 Events per day Standard Deviation 5.38	-5.30 Events per day Standard Deviation 4.65	-6.03 Events per day Standard Deviation 4.86	-5.86 Events per day Standard Deviation 4.34	-5.91 Events per day Standard Deviation 4.57
Change From Baseline in Average Daily Frequency of Moderate/Severe Vasomotor Symptoms (Frequency Score A) by Week Excluding Weeks 4 and 12 Week 2	-3.25 Events per day Standard Deviation 4.08	-4.72 Events per day Standard Deviation 3.85	-5.19 Events per day Standard Deviation 4.59	-4.88 Events per day Standard Deviation 3.24	-5.39 Events per day Standard Deviation 3.96
Change From Baseline in Average Daily Frequency of Moderate/Severe Vasomotor Symptoms (Frequency Score A) by Week Excluding Weeks 4 and 12 Baseline	12.10 Events per day Standard Deviation 5.10	12.19 Events per day Standard Deviation 5.07	12.56 Events per day Standard Deviation 4.66	12.30 Events per day Standard Deviation 4.39	11.52 Events per day Standard Deviation 4.67
Change From Baseline in Average Daily Frequency of Moderate/Severe Vasomotor Symptoms (Frequency Score A) by Week Excluding Weeks 4 and 12 Week 1	-2.21 Events per day Standard Deviation 3.37	-3.20 Events per day Standard Deviation 3.35	-4.08 Events per day Standard Deviation 3.79	-3.63 Events per day Standard Deviation 2.89	-4.18 Events per day Standard Deviation 3.83
Change From Baseline in Average Daily Frequency of Moderate/Severe Vasomotor Symptoms (Frequency Score A) by Week Excluding Weeks 4 and 12 Week 3	-3.71 Events per day Standard Deviation 4.39	-4.82 Events per day Standard Deviation 4.08	-5.68 Events per day Standard Deviation 4.74	-5.13 Events per day Standard Deviation 3.68	-5.59 Events per day Standard Deviation 4.05
Change From Baseline in Average Daily Frequency of Moderate/Severe Vasomotor Symptoms (Frequency Score A) by Week Excluding Weeks 4 and 12 Week 5	-3.90 Events per day Standard Deviation 4.82	-5.29 Events per day Standard Deviation 4.28	-5.83 Events per day Standard Deviation 4.72	-5.50 Events per day Standard Deviation 3.79	-5.54 Events per day Standard Deviation 4.48
Change From Baseline in Average Daily Frequency of Moderate/Severe Vasomotor Symptoms (Frequency Score A) by Week Excluding Weeks 4 and 12 Week 6	-4.02 Events per day Standard Deviation 4.90	-5.41 Events per day Standard Deviation 4.43	-5.96 Events per day Standard Deviation 4.79	-5.58 Events per day Standard Deviation 3.89	-5.62 Events per day Standard Deviation 4.71
Change From Baseline in Average Daily Frequency of Moderate/Severe Vasomotor Symptoms (Frequency Score A) by Week Excluding Weeks 4 and 12 Week 7	-4.11 Events per day Standard Deviation 4.96	-5.33 Events per day Standard Deviation 4.30	-6.10 Events per day Standard Deviation 4.87	-5.69 Events per day Standard Deviation 4.28	-5.93 Events per day Standard Deviation 4.63
Change From Baseline in Average Daily Frequency of Moderate/Severe Vasomotor Symptoms (Frequency Score A) by Week Excluding Weeks 4 and 12 Week 8	-4.04 Events per day Standard Deviation 5.05	-5.19 Events per day Standard Deviation 4.49	-6.14 Events per day Standard Deviation 4.72	-5.86 Events per day Standard Deviation 4.52	-5.72 Events per day Standard Deviation 4.36
Change From Baseline in Average Daily Frequency of Moderate/Severe Vasomotor Symptoms (Frequency Score A) by Week Excluding Weeks 4 and 12 Week 9	-4.11 Events per day Standard Deviation 5.18	-5.15 Events per day Standard Deviation 4.65	-6.23 Events per day Standard Deviation 4.90	-5.96 Events per day Standard Deviation 4.39	-5.95 Events per day Standard Deviation 4.77
Change From Baseline in Average Daily Frequency of Moderate/Severe Vasomotor Symptoms (Frequency Score A) by Week Excluding Weeks 4 and 12 Week 10	-4.11 Events per day Standard Deviation 5.42	-5.18 Events per day Standard Deviation 4.54	-5.97 Events per day Standard Deviation 4.79	-6.00 Events per day Standard Deviation 4.36	-6.11 Events per day Standard Deviation 4.66

SECONDARY outcome

Timeframe: Baseline and up to Week 12

Population: The ITT population, defined as all randomized participants who had at least one pre-baseline and at least one post-baseline average of the number of hot flushes in a week.

Participants recorded the severity of hot flushes on a LogPad on a daily basis during screening and treatment. The severity of hot flushes was defined as: mild (sensation of heat without sweating); moderate (sensation of heat with sweating, able to continue activity); and severe (sensation of heat with sweating, causing cessation of activity). Severity Score A was calculated as the number of moderate hot flushes x 2 + the number of severe hot flushes x 3, divided by the total number of moderate and severe hot flushes per week. If no hot flushes were experienced, this was to be recorded as 'no sensation of heat'. Baseline values were based on, at most, 7 completely observed pre-treatment days. If less than 4 days were completely observed during treatment, the averages of the previous week were carried forward (LOCF). If the number of days observed in Week 1 were not sufficient, baseline values were carried forward.

Outcome measures

Measure	Placebo n=283 Participants Participants receive encapsulated tablets, orally, once daily (QD) for up to 12 weeks.	Esmirtazapine 2.25 mg n=146 Participants Participants receive esmirtazapine, 2.25 mg, encapsulated tablets, orally QD for up to 12 weeks.	Esmirtazapine 4.5 mg n=144 Participants Participants receive esmirtazapine, 4.5 mg, encapsulated tablets, orally QD for up to 12 weeks.	Esmirtazapine 9 mg n=134 Participants Participants receive esmirtazapine, 9 mg, encapsulated tablets, orally QD for up to 12 weeks.	Esmirtazapine 18 mg n=138 Participants Participants receive esmirtazapine, 18 mg, encapsulated tablets, orally, QD for up to 12 weeks
Change From Baseline in Average Daily Severity of Moderate/Severe Vasomotor Symptoms (Severity Score A) by Week Excluding Weeks 4 and 12 Baseline	2.447 Severity score Standard Deviation 0.301	2.451 Severity score Standard Deviation 0.297	2.449 Severity score Standard Deviation 0.315	2.460 Severity score Standard Deviation 0.296	2.400 Severity score Standard Deviation 0.274
Change From Baseline in Average Daily Severity of Moderate/Severe Vasomotor Symptoms (Severity Score A) by Week Excluding Weeks 4 and 12 Week 1	-0.045 Severity score Standard Deviation 0.124	-0.081 Severity score Standard Deviation 0.153	-0.085 Severity score Standard Deviation 0.151	-0.085 Severity score Standard Deviation 0.159	-0.108 Severity score Standard Deviation 0.150
Change From Baseline in Average Daily Severity of Moderate/Severe Vasomotor Symptoms (Severity Score A) by Week Excluding Weeks 4 and 12 Week 2	-0.063 Severity score Standard Deviation 0.172	-0.117 Severity score Standard Deviation 0.199	-0.111 Severity score Standard Deviation 0.212	-0.140 Severity score Standard Deviation 0.200	-0.136 Severity score Standard Deviation 0.178
Change From Baseline in Average Daily Severity of Moderate/Severe Vasomotor Symptoms (Severity Score A) by Week Excluding Weeks 4 and 12 Week 3	-0.071 Severity score Standard Deviation 0.195	-0.133 Severity score Standard Deviation 0.214	-0.119 Severity score Standard Deviation 0.214	-0.150 Severity score Standard Deviation 0.200	-0.137 Severity score Standard Deviation 0.240
Change From Baseline in Average Daily Severity of Moderate/Severe Vasomotor Symptoms (Severity Score A) by Week Excluding Weeks 4 and 12 Week 5	-0.080 Severity score Standard Deviation 0.215	-0.141 Severity score Standard Deviation 0.233	-0.123 Severity score Standard Deviation 0.227	-0.154 Severity score Standard Deviation 0.225	-0.151 Severity score Standard Deviation 0.232
Change From Baseline in Average Daily Severity of Moderate/Severe Vasomotor Symptoms (Severity Score A) by Week Excluding Weeks 4 and 12 Week 6	-0.075 Severity score Standard Deviation 0.215	-0.136 Severity score Standard Deviation 0.246	-0.127 Severity score Standard Deviation 0.234	-0.140 Severity score Standard Deviation 0.236	-0.152 Severity score Standard Deviation 0.245
Change From Baseline in Average Daily Severity of Moderate/Severe Vasomotor Symptoms (Severity Score A) by Week Excluding Weeks 4 and 12 Week 7	-0.088 Severity score Standard Deviation 0.233	-0.144 Severity score Standard Deviation 0.236	-0.131 Severity score Standard Deviation 0.260	-0.140 Severity score Standard Deviation 0.253	-0.144 Severity score Standard Deviation 0.257
Change From Baseline in Average Daily Severity of Moderate/Severe Vasomotor Symptoms (Severity Score A) by Week Excluding Weeks 4 and 12 Week 8	-0.082 Severity score Standard Deviation 0.239	-0.142 Severity score Standard Deviation 0.242	-0.124 Severity score Standard Deviation 0.270	-0.139 Severity score Standard Deviation 0.254	-0.133 Severity score Standard Deviation 0.247
Change From Baseline in Average Daily Severity of Moderate/Severe Vasomotor Symptoms (Severity Score A) by Week Excluding Weeks 4 and 12 Week 9	-0.083 Severity score Standard Deviation 0.242	-0.142 Severity score Standard Deviation 0.257	-0.137 Severity score Standard Deviation 0.260	-0.130 Severity score Standard Deviation 0.265	-0.144 Severity score Standard Deviation 0.246
Change From Baseline in Average Daily Severity of Moderate/Severe Vasomotor Symptoms (Severity Score A) by Week Excluding Weeks 4 and 12 Week 10	-0.084 Severity score Standard Deviation 0.255	-0.147 Severity score Standard Deviation 0.261	-0.125 Severity score Standard Deviation 0.263	-0.141 Severity score Standard Deviation 0.258	-0.162 Severity score Standard Deviation 0.252
Change From Baseline in Average Daily Severity of Moderate/Severe Vasomotor Symptoms (Severity Score A) by Week Excluding Weeks 4 and 12 Week 11	-0.078 Severity score Standard Deviation 0.261	-0.159 Severity score Standard Deviation 0.273	-0.130 Severity score Standard Deviation 0.273	-0.124 Severity score Standard Deviation 0.257	-0.156 Severity score Standard Deviation 0.257

SECONDARY outcome

Timeframe: Baseline and up to Week 12

Population: The ITT population, defined as all randomized participants who had at least one pre-baseline and at least one post-baseline average of the number of hot flushes in a week.

Composite Score A was calculated as Severity Score A x Frequency Score A.

Outcome measures

Measure	Placebo n=283 Participants Participants receive encapsulated tablets, orally, once daily (QD) for up to 12 weeks.	Esmirtazapine 2.25 mg n=146 Participants Participants receive esmirtazapine, 2.25 mg, encapsulated tablets, orally QD for up to 12 weeks.	Esmirtazapine 4.5 mg n=144 Participants Participants receive esmirtazapine, 4.5 mg, encapsulated tablets, orally QD for up to 12 weeks.	Esmirtazapine 9 mg n=134 Participants Participants receive esmirtazapine, 9 mg, encapsulated tablets, orally QD for up to 12 weeks.	Esmirtazapine 18 mg n=138 Participants Participants receive esmirtazapine, 18 mg, encapsulated tablets, orally, QD for up to 12 weeks
Change From Baseline in Average Daily Moderate/Severe Composite Score (Composite Score A) by Week Week 9	-10.30 Composite score Standard Deviation 14.06	-13.20 Composite score Standard Deviation 12.54	-15.40 Composite score Standard Deviation 12.18	-14.93 Composite score Standard Deviation 11.20	-14.67 Composite score Standard Deviation 12.30
Change From Baseline in Average Daily Moderate/Severe Composite Score (Composite Score A) by Week Baseline	30.19 Composite score Standard Deviation 15.42	30.41 Composite score Standard Deviation 14.56	31.03 Composite score Standard Deviation 12.98	30.40 Composite score Standard Deviation 11.81	27.87 Composite score Standard Deviation 12.56
Change From Baseline in Average Daily Moderate/Severe Composite Score (Composite Score A) by Week Week 1	-5.65 Composite score Standard Deviation 8.99	-8.48 Composite score Standard Deviation 9.10	-10.28 Composite score Standard Deviation 9.19	-9.43 Composite score Standard Deviation 7.84	-10.63 Composite score Standard Deviation 9.63
Change From Baseline in Average Daily Moderate/Severe Composite Score (Composite Score A) by Week Week 2	-8.28 Composite score Standard Deviation 10.93	-12.32 Composite score Standard Deviation 10.18	-12.98 Composite score Standard Deviation 11.36	-12.70 Composite score Standard Deviation 8.75	-13.54 Composite score Standard Deviation 9.89
Change From Baseline in Average Daily Moderate/Severe Composite Score (Composite Score A) by Week Week 3	-9.46 Composite score Standard Deviation 11.92	-12.63 Composite score Standard Deviation 11.09	-14.22 Composite score Standard Deviation 11.88	-13.39 Composite score Standard Deviation 9.82	-13.89 Composite score Standard Deviation 10.28
Change From Baseline in Average Daily Moderate/Severe Composite Score (Composite Score A) by Week Week 4	-9.79 Composite score Standard Deviation 12.39	-13.18 Composite score Standard Deviation 11.29	-14.42 Composite score Standard Deviation 11.88	-13.70 Composite score Standard Deviation 10.28	-13.72 Composite score Standard Deviation 11.38
Change From Baseline in Average Daily Moderate/Severe Composite Score (Composite Score A) by Week Week 5	-9.96 Composite score Standard Deviation 13.19	-13.65 Composite score Standard Deviation 11.77	-14.47 Composite score Standard Deviation 11.65	-14.16 Composite score Standard Deviation 10.09	-13.72 Composite score Standard Deviation 11.33
Change From Baseline in Average Daily Moderate/Severe Composite Score (Composite Score A) by Week Week 6	-10.22 Composite score Standard Deviation 13.40	-13.89 Composite score Standard Deviation 11.88	-14.84 Composite score Standard Deviation 11.92	-14.24 Composite score Standard Deviation 10.26	-13.95 Composite score Standard Deviation 12.05
Change From Baseline in Average Daily Moderate/Severe Composite Score (Composite Score A) by Week Week 7	-10.42 Composite score Standard Deviation 13.49	-13.73 Composite score Standard Deviation 11.66	-15.11 Composite score Standard Deviation 12.32	-14.42 Composite score Standard Deviation 11.23	-14.72 Composite score Standard Deviation 11.87
Change From Baseline in Average Daily Moderate/Severe Composite Score (Composite Score A) by Week Week 8	-10.20 Composite score Standard Deviation 13.71	-13.31 Composite score Standard Deviation 11.98	-15.19 Composite score Standard Deviation 11.93	-14.73 Composite score Standard Deviation 11.56	-14.08 Composite score Standard Deviation 11.21
Change From Baseline in Average Daily Moderate/Severe Composite Score (Composite Score A) by Week Week 10	-10.26 Composite score Standard Deviation 14.77	-13.30 Composite score Standard Deviation 12.34	-14.76 Composite score Standard Deviation 12.07	-15.03 Composite score Standard Deviation 11.24	-15.08 Composite score Standard Deviation 12.09
Change From Baseline in Average Daily Moderate/Severe Composite Score (Composite Score A) by Week Week 11	-10.53 Composite score Standard Deviation 14.73	-13.58 Composite score Standard Deviation 12.61	-14.92 Composite score Standard Deviation 12.41	-14.58 Composite score Standard Deviation 11.28	14.57 Composite score Standard Deviation 11.85
Change From Baseline in Average Daily Moderate/Severe Composite Score (Composite Score A) by Week Week 12	-10.42 Composite score Standard Deviation 14.56	-13.25 Composite score Standard Deviation 12.52	-14.88 Composite score Standard Deviation 12.49	-14.36 Composite score Standard Deviation 11.17	-14.71 Composite score Standard Deviation 12.17

SECONDARY outcome

Timeframe: Baseline and up to Week 12

Population: The ITT population, defined as all randomized participants who had at least one pre-baseline and at least one post-baseline average of the number of hot flushes in a week.

Participants recorded the frequency (number) of vasomotor symptoms (hot flushes) on a LogPad on a daily basis during screening and treatment. Frequency Score B was based on the number of mild hot flushes + the number of moderate hot flushes + the number of severe hot flushes in one day. Baseline average was derived from, at most, 7 completely observed pre-treatment days. Weekly averages during treatment were calculated if at least 4 days with non-missing data were completely observed; if less than 4 days were completely observed, the averages of the previous week were carried forward (LOCF). If the number of days observed in Week 1 were not sufficient, baseline values were carried forward.

Outcome measures

Measure	Placebo n=283 Participants Participants receive encapsulated tablets, orally, once daily (QD) for up to 12 weeks.	Esmirtazapine 2.25 mg n=146 Participants Participants receive esmirtazapine, 2.25 mg, encapsulated tablets, orally QD for up to 12 weeks.	Esmirtazapine 4.5 mg n=144 Participants Participants receive esmirtazapine, 4.5 mg, encapsulated tablets, orally QD for up to 12 weeks.	Esmirtazapine 9 mg n=134 Participants Participants receive esmirtazapine, 9 mg, encapsulated tablets, orally QD for up to 12 weeks.	Esmirtazapine 18 mg n=138 Participants Participants receive esmirtazapine, 18 mg, encapsulated tablets, orally, QD for up to 12 weeks
Change From Baseline in Average Daily Frequency of Mild to Severe Vasomotor Symptoms (Frequency Score B) by Week Baseline	13.29 Events per day Standard Deviation 5.35	13.48 Events per day Standard Deviation 5.35	13.66 Events per day Standard Deviation 4.96	13.41 Events per day Standard Deviation 4.61	13.00 Events per day Standard Deviation 6.09
Change From Baseline in Average Daily Frequency of Mild to Severe Vasomotor Symptoms (Frequency Score B) by Week Week 1	-2.22 Events per day Standard Deviation 3.41	-3.24 Events per day Standard Deviation 3.23	-3.81 Events per day Standard Deviation 3.33	-3.57 Events per day Standard Deviation 2.96	-4.16 Events per day Standard Deviation 4.69
Change From Baseline in Average Daily Frequency of Mild to Severe Vasomotor Symptoms (Frequency Score B) by Week Week 2	-3.35 Events per day Standard Deviation 4.17	-4.81 Events per day Standard Deviation 4.03	-5.19 Events per day Standard Deviation 4.46	-4.79 Events per day Standard Deviation 3.28	-5.50 Events per day Standard Deviation 4.75
Change From Baseline in Average Daily Frequency of Mild to Severe Vasomotor Symptoms (Frequency Score B) by Week Week 3	-3.83 Events per day Standard Deviation 4.46	-5.05 Events per day Standard Deviation 4.15	-5.66 Events per day Standard Deviation 4.74	-5.08 Events per day Standard Deviation 3.72	-5.79 Events per day Standard Deviation 4.88
Change From Baseline in Average Daily Frequency of Mild to Severe Vasomotor Symptoms (Frequency Score B) by Week Week 4	-3.97 Events per day Standard Deviation 4.63	-5.37 Events per day Standard Deviation 4.14	-6.01 Events per day Standard Deviation 4.80	-5.38 Events per day Standard Deviation 3.98	-5.85 Events per day Standard Deviation 5.30
Change From Baseline in Average Daily Frequency of Mild to Severe Vasomotor Symptoms (Frequency Score B) by Week Week 5	-4.06 Events per day Standard Deviation 4.91	-5.61 Events per day Standard Deviation 4.46	-6.13 Events per day Standard Deviation 4.81	-5.57 Events per day Standard Deviation 4.03	-5.90 Events per day Standard Deviation 5.31
Change From Baseline in Average Daily Frequency of Mild to Severe Vasomotor Symptoms (Frequency Score B) by Week Week 6	-4.25 Events per day Standard Deviation 4.86	-5.82 Events per day Standard Deviation 4.51	-6.32 Events per day Standard Deviation 4.89	-5.75 Events per day Standard Deviation 4.11	-5.89 Events per day Standard Deviation 5.24
Change From Baseline in Average Daily Frequency of Mild to Severe Vasomotor Symptoms (Frequency Score B) by Week Week 7	-4.27 Events per day Standard Deviation 4.85	-5.69 Events per day Standard Deviation 4.36	-6.47 Events per day Standard Deviation 4.89	-5.90 Events per day Standard Deviation 4.45	-6.15 Events per day Standard Deviation 5.18
Change From Baseline in Average Daily Frequency of Mild to Severe Vasomotor Symptoms (Frequency Score B) by Week Week 8	-4.19 Events per day Standard Deviation 4.94	-5.54 Events per day Standard Deviation 4.50	-6.51 Events per day Standard Deviation 4.72	-6.06 Events per day Standard Deviation 4.55	-6.03 Events per day Standard Deviation 4.73
Change From Baseline in Average Daily Frequency of Mild to Severe Vasomotor Symptoms (Frequency Score B) by Week Week 9	-4.30 Events per day Standard Deviation 5.06	-5.47 Events per day Standard Deviation 4.71	-6.59 Events per day Standard Deviation 4.79	-6.08 Events per day Standard Deviation 4.51	-6.26 Events per day Standard Deviation 5.26
Change From Baseline in Average Daily Frequency of Mild to Severe Vasomotor Symptoms (Frequency Score B) by Week Week 10	-4.29 Events per day Standard Deviation 5.39	-5.59 Events per day Standard Deviation 4.73	-6.36 Events per day Standard Deviation 4.81	-6.18 Events per day Standard Deviation 4.46	-6.35 Events per day Standard Deviation 5.05
Change From Baseline in Average Daily Frequency of Mild to Severe Vasomotor Symptoms (Frequency Score B) by Week Week 11	-4.43 Events per day Standard Deviation 5.42	-5.68 Events per day Standard Deviation 4.83	-6.45 Events per day Standard Deviation 4.91	-6.08 Events per day Standard Deviation 4.48	-6.28 Events per day Standard Deviation 4.98
Change From Baseline in Average Daily Frequency of Mild to Severe Vasomotor Symptoms (Frequency Score B) by Week Week 12	-4.40 Events per day Standard Deviation 5.44	-5.63 Events per day Standard Deviation 4.71	-6.45 Events per day Standard Deviation 4.96	-6.10 Events per day Standard Deviation 4.48	-6.32 Events per day Standard Deviation 4.99

SECONDARY outcome

Timeframe: Baseline and up to Week 12

Population: The ITT population, defined as all randomized participants who had at least one pre-baseline and at least one post-baseline average of the number of hot flushes in a week.

Participants recorded the severity of hot flushes on a LogPad on a daily basis during screening and treatment. The severity of hot flushes was defined as: mild (sensation of heat without sweating); moderate (sensation of heat with sweating, able to continue activity); and severe (sensation of heat with sweating, causing cessation of activity). Severity Score B was calculated as the number of mild hot flushes + the number of moderate hot flushes x 2 + the number of severe hot flushes x 3, divided by the total number of all hot flushes per week. If no hot flushes were experienced, this was to be recorded as 'no sensation of heat'. Baseline values were based on, at most, 7 completely observed pre-treatment days. If less than 4 days were completely observed during treatment, the averages of the previous week were carried forward (LOCF). If the number of days observed in Week 1 were not sufficient, baseline values were carried forward.

Outcome measures

Measure	Placebo n=283 Participants Participants receive encapsulated tablets, orally, once daily (QD) for up to 12 weeks.	Esmirtazapine 2.25 mg n=146 Participants Participants receive esmirtazapine, 2.25 mg, encapsulated tablets, orally QD for up to 12 weeks.	Esmirtazapine 4.5 mg n=144 Participants Participants receive esmirtazapine, 4.5 mg, encapsulated tablets, orally QD for up to 12 weeks.	Esmirtazapine 9 mg n=134 Participants Participants receive esmirtazapine, 9 mg, encapsulated tablets, orally QD for up to 12 weeks.	Esmirtazapine 18 mg n=138 Participants Participants receive esmirtazapine, 18 mg, encapsulated tablets, orally, QD for up to 12 weeks
Change From Baseline in Average Daily Severity of Mild to Severe Vasomotor Symptoms (Severity Score B) by Week Baseline	2.332 Severity score Standard Deviation 0.369	2.331 Severity score Standard Deviation 0.375	2.349 Severity score Standard Deviation 0.373	2.350 Severity score Standard Deviation 0.347	2.270 Severity score Standard Deviation 0.332
Change From Baseline in Average Daily Severity of Mild to Severe Vasomotor Symptoms (Severity Score B) by Week Week 1	-0.080 Severity score Standard Deviation 0.220	-0.132 Severity score Standard Deviation 0.246	-0.167 Severity score Standard Deviation 0.245	-0.140 Severity score Standard Deviation 0.245	-0.192 Severity score Standard Deviation 0.273
Change From Baseline in Average Daily Severity of Mild to Severe Vasomotor Symptoms (Severity Score B) by Week Week 2	-0.111 Severity score Standard Deviation 0.291	-0.210 Severity score Standard Deviation 0.342	-0.223 Severity score Standard Deviation 0.341	-0.225 Severity score Standard Deviation 0.341	-0.250 Severity score Standard Deviation 0.312
Change From Baseline in Average Daily Severity of Mild to Severe Vasomotor Symptoms (Severity Score B) by Week Week 3	-0.121 Severity score Standard Deviation 0.307	-0.217 Severity score Standard Deviation 0.373	-0.246 Severity score Standard Deviation 0.400	-0.240 Severity score Standard Deviation 0.337	-0.272 Severity score Standard Deviation 0.389
Change From Baseline in Average Daily Severity of Mild to Severe Vasomotor Symptoms (Severity Score B) by Week Week 4	-0.113 Severity score Standard Deviation 0.312	-0.224 Severity score Standard Deviation 0.409	-0.240 Severity score Standard Deviation 0.388	-0.249 Severity score Standard Deviation 0.387	-0.273 Severity score Standard Deviation 0.411
Change From Baseline in Average Daily Severity of Mild to Severe Vasomotor Symptoms (Severity Score B) by Week Week 5	-0.124 Severity score Standard Deviation 0.354	-0.234 Severity score Standard Deviation 0.411	-0.228 Severity score Standard Deviation 0.403	-0.254 Severity score Standard Deviation 0.368	-0.266 Severity score Standard Deviation 0.409
Change From Baseline in Average Daily Severity of Mild to Severe Vasomotor Symptoms (Severity Score B) by Week Week 6	-0.121 Severity score Standard Deviation 0.360	-0.222 Severity score Standard Deviation 0.429	-0.214 Severity score Standard Deviation 0.386	-0.245 Severity score Standard Deviation 0.396	-0.275 Severity score Standard Deviation 0.436
Change From Baseline in Average Daily Severity of Mild to Severe Vasomotor Symptoms (Severity Score B) by Week Week 7	-0.142 Severity score Standard Deviation 0.389	-0.234 Severity score Standard Deviation 0.433	-0.232 Severity score Standard Deviation 0.444	-0.242 Severity score Standard Deviation 0.424	-0.287 Severity score Standard Deviation 0.460
Change From Baseline in Average Daily Severity of Mild to Severe Vasomotor Symptoms (Severity Score B) by Week Week 8	-0.139 Severity score Standard Deviation 0.408	-0.251 Severity score Standard Deviation 0.440	-0.234 Severity score Standard Deviation 0.467	-0.251 Severity score Standard Deviation 0.447	-0.273 Severity score Standard Deviation 0.463
Change From Baseline in Average Daily Severity of Mild to Severe Vasomotor Symptoms (Severity Score B) by Week Week 9	-0.136 Severity score Standard Deviation 0.408	-0.245 Severity score Standard Deviation 0.438	-0.256 Severity score Standard Deviation 0.454	-0.256 Severity score Standard Deviation 0.462	-0.292 Severity score Standard Deviation 0.474
Change From Baseline in Average Daily Severity of Mild to Severe Vasomotor Symptoms (Severity Score B) by Week Week 10	-0.143 Severity score Standard Deviation 0.431	-0.244 Severity score Standard Deviation 0.452	-0.257 Severity score Standard Deviation 0.465	-0.257 Severity score Standard Deviation 0.467	-0.307 Severity score Standard Deviation 0.460
Change From Baseline in Average Daily Severity of Mild to Severe Vasomotor Symptoms (Severity Score B) by Week Week 11	-0.149 Severity score Standard Deviation 0.439	-0.260 Severity score Standard Deviation 0.467	-0.245 Severity score Standard Deviation 0.463	-0.224 Severity score Standard Deviation 0.459	-0.308 Severity score Standard Deviation 0.477
Change From Baseline in Average Daily Severity of Mild to Severe Vasomotor Symptoms (Severity Score B) by Week Week 12	-0.152 Severity score Standard Deviation 0.457	-0.255 Severity score Standard Deviation 0.471	-0.240 Severity score Standard Deviation 0.465	-0.210 Severity score Standard Deviation 0.450	-0.280 Severity score Standard Deviation 0.472

SECONDARY outcome

Timeframe: Baseline and up to Week 12

Population: The ITT population, defined as all randomized participants who had at least one pre-baseline and at least one post-baseline average of the number of hot flushes in a week.

Composite Score B was calculated as Severity Score B x Frequency Score B.

Outcome measures

Measure	Placebo n=283 Participants Participants receive encapsulated tablets, orally, once daily (QD) for up to 12 weeks.	Esmirtazapine 2.25 mg n=146 Participants Participants receive esmirtazapine, 2.25 mg, encapsulated tablets, orally QD for up to 12 weeks.	Esmirtazapine 4.5 mg n=144 Participants Participants receive esmirtazapine, 4.5 mg, encapsulated tablets, orally QD for up to 12 weeks.	Esmirtazapine 9 mg n=134 Participants Participants receive esmirtazapine, 9 mg, encapsulated tablets, orally QD for up to 12 weeks.	Esmirtazapine 18 mg n=138 Participants Participants receive esmirtazapine, 18 mg, encapsulated tablets, orally, QD for up to 12 weeks
Change From Baseline in Average Daily Mild to Severe Composite Symptoms Score (Composite Score B) by Week Week 7	-10.58 Composite score Standard Deviation 13.23	-14.09 Composite score Standard Deviation 11.45	-15.48 Composite score Standard Deviation 12.16	-14.63 Composite score Standard Deviation 11.18	-14.93 Composite score Standard Deviation 12.04
Change From Baseline in Average Daily Mild to Severe Composite Symptoms Score (Composite Score B) by Week Week 8	-10.34 Composite score Standard Deviation 13.43	-13.66 Composite score Standard Deviation 11.73	-15.56 Composite score Standard Deviation 11.76	-14.92 Composite score Standard Deviation 11.38	-14.40 Composite score Standard Deviation 11.18
Change From Baseline in Average Daily Mild to Severe Composite Symptoms Score (Composite Score B) by Week Week 9	-10.49 Composite score Standard Deviation 13.78	-13.53 Composite score Standard Deviation 12.33	-15.77 Composite score Standard Deviation 11.91	-15.05 Composite score Standard Deviation 11.09	-14.98 Composite score Standard Deviation 12.44
Change From Baseline in Average Daily Mild to Severe Composite Symptoms Score (Composite Score B) by Week Week 10	-10.44 Composite score Standard Deviation 14.56	-13.71 Composite score Standard Deviation 12.27	-15.15 Composite score Standard Deviation 11.92	-15.21 Composite score Standard Deviation 11.11	-15.32 Composite score Standard Deviation 12.09
Change From Baseline in Average Daily Mild to Severe Composite Symptoms Score (Composite Score B) by Week Week 11	-10.76 Composite score Standard Deviation 14.57	-13.96 Composite score Standard Deviation 12.53	-15.34 Composite score Standard Deviation 12.27	-14.79 Composite score Standard Deviation 11.16	-14.95 Composite score Standard Deviation 11.95
Change From Baseline in Average Daily Mild to Severe Composite Symptoms Score (Composite Score B) by Week Week 12	-10.66 Composite score Standard Deviation 14.44	-13.66 Composite score Standard Deviation 12.32	-15.32 Composite score Standard Deviation 12.38	-14.71 Composite score Standard Deviation 11.11	-15.04 Composite score Standard Deviation 12.17
Change From Baseline in Average Daily Mild to Severe Composite Symptoms Score (Composite Score B) by Week Baseline	31.39 Composite score Standard Deviation 15.37	31.70 Composite score Standard Deviation 14.47	32.13 Composite score Standard Deviation 12.91	31.51 Composite score Standard Deviation 11.80	29.35 Composite score Standard Deviation 13.55
Change From Baseline in Average Daily Mild to Severe Composite Symptoms Score (Composite Score B) by Week Week 1	-5.66 Composite score Standard Deviation 8.94	-8.53 Composite score Standard Deviation 8.85	-10.01 Composite score Standard Deviation 8.60	-9.37 Composite score Standard Deviation 7.74	-10.61 Composite score Standard Deviation 10.31
Change From Baseline in Average Daily Mild to Severe Composite Symptoms Score (Composite Score B) by Week Week 2	-8.38 Composite score Standard Deviation 10.91	-12.40 Composite score Standard Deviation 10.12	-12.98 Composite score Standard Deviation 11.05	-12.60 Composite score Standard Deviation 8.58	-13.64 Composite score Standard Deviation 10.46
Change From Baseline in Average Daily Mild to Severe Composite Symptoms Score (Composite Score B) by Week Week 3	-9.57 Composite score Standard Deviation 11.88	-12.86 Composite score Standard Deviation 10.89	-14.40 Composite score Standard Deviation 11.69	-13.34 Composite score Standard Deviation 9.69	-14.09 Composite score Standard Deviation 10.80
Change From Baseline in Average Daily Mild to Severe Composite Symptoms Score (Composite Score B) by Week Week 4	-9.93 Composite score Standard Deviation 12.36	-13.48 Composite score Standard Deviation 11.06	-14.69 Composite score Standard Deviation 11.89	-13.75 Composite score Standard Deviation 10.24	-14.01 Composite score Standard Deviation 11.91
Change From Baseline in Average Daily Mild to Severe Composite Symptoms Score (Composite Score B) by Week Week 5	-10.12 Composite score Standard Deviation 13.13	-13.96 Composite score Standard Deviation 11.65	014.78 Composite score Standard Deviation 11.54	-14.22 Composite score Standard Deviation 10.12	-14.08 Composite score Standard Deviation 11.82
Change From Baseline in Average Daily Mild to Severe Composite Symptoms Score (Composite Score B) by Week Week 6	-10.45 Composite score Standard Deviation 13.24	-14.29 Composite score Standard Deviation 11.65	-15.19 Composite score Standard Deviation 11.83	-14.40 Composite score Standard Deviation 10.30	-14.21 Composite score Standard Deviation 12.22

SECONDARY outcome

Timeframe: Up to 12 weeks

Population: The ITT population, defined as all randomized participants who had at least one pre-baseline and at least one post-baseline average of the number of hot flushes in a week.

A participant was defined as a (hot flush) responder for a study week if a reduction of at least 50% for average daily frequency of moderate/severe vasomotor symptoms (hot flushes) (Frequency Score A) compared to Baseline was recorded. A study week was taken into account if at least 4 days were completely observed. The last observation was carried forward if there were less than 4 complete days observed. In cases where Week 1 did not have 4 days that were completely observed, the participant was considered a non-responder. An LOCF approach was used.

Outcome measures

Measure	Placebo n=283 Participants Participants receive encapsulated tablets, orally, once daily (QD) for up to 12 weeks.	Esmirtazapine 2.25 mg n=146 Participants Participants receive esmirtazapine, 2.25 mg, encapsulated tablets, orally QD for up to 12 weeks.	Esmirtazapine 4.5 mg n=144 Participants Participants receive esmirtazapine, 4.5 mg, encapsulated tablets, orally QD for up to 12 weeks.	Esmirtazapine 9 mg n=134 Participants Participants receive esmirtazapine, 9 mg, encapsulated tablets, orally QD for up to 12 weeks.	Esmirtazapine 18 mg n=138 Participants Participants receive esmirtazapine, 18 mg, encapsulated tablets, orally, QD for up to 12 weeks
Total Number of Responders by Week Week 1	37 Participants	29 Participants	35 Participants	32 Participants	42 Participants
Total Number of Responders by Week Week 2	56 Participants	49 Participants	60 Participants	48 Participants	65 Participants
Total Number of Responders by Week Week 3	85 Participants	53 Participants	63 Participants	47 Participants	72 Participants
Total Number of Responders by Week Week 4	76 Participants	58 Participants	70 Participants	52 Participants	71 Participants
Total Number of Responders by Week Week 5	76 Participants	63 Participants	65 Participants	56 Participants	71 Participants
Total Number of Responders by Week Week 6	84 Participants	67 Participants	70 Participants	55 Participants	69 Participants
Total Number of Responders by Week Week 7	89 Participants	59 Participants	72 Participants	60 Participants	75 Participants
Total Number of Responders by Week Week 8	93 Participants	65 Participants	73 Participants	66 Participants	72 Participants
Total Number of Responders by Week Week 9	96 Participants	67 Participants	74 Participants	68 Participants	75 Participants
Total Number of Responders by Week Week 10	97 Participants	65 Participants	73 Participants	67 Participants	77 Participants
Total Number of Responders by Week Week 11	95 Participants	70 Participants	78 Participants	65 Participants	72 Participants
Total Number of Responders by Week Week 12	99 Participants	70 Participants	75 Participants	65 Participants	77 Participants

SECONDARY outcome

Timeframe: Up to 12 weeks

Population: The ITT population, defined as all randomized participants who had at least one pre-baseline and at least one post-baseline average of the number of hot flushes in a week. An LOCF approach was used.

A participant was defined as a (hot flush) remitter for a study week if at most one moderate/severe vasomotor symptom per day on average was recorded. A study week was taken into account if at least 4 days were completely observed. The last observation was carried forward if there were less than 4 complete days observed. In cases where Week 1 did not have 4 days that were completely observed, the participant was considered a non-remitter.

Outcome measures

Measure	Placebo n=283 Participants Participants receive encapsulated tablets, orally, once daily (QD) for up to 12 weeks.	Esmirtazapine 2.25 mg n=146 Participants Participants receive esmirtazapine, 2.25 mg, encapsulated tablets, orally QD for up to 12 weeks.	Esmirtazapine 4.5 mg n=144 Participants Participants receive esmirtazapine, 4.5 mg, encapsulated tablets, orally QD for up to 12 weeks.	Esmirtazapine 9 mg n=134 Participants Participants receive esmirtazapine, 9 mg, encapsulated tablets, orally QD for up to 12 weeks.	Esmirtazapine 18 mg n=138 Participants Participants receive esmirtazapine, 18 mg, encapsulated tablets, orally, QD for up to 12 weeks
Total Number of Remitters by Week Week 10	25 Participants	19 Participants	25 Participants	23 Participants	25 Participants
Total Number of Remitters by Week Week 1	3 Participants	2 Participants	7 Participants	2 Participants	2 Participants
Total Number of Remitters by Week Week 2	6 Participants	11 Participants	13 Participants	8 Participants	13 Participants
Total Number of Remitters by Week Week 3	8 Participants	15 Participants	16 Participants	7 Participants	17 Participants
Total Number of Remitters by Week Week 4	10 Participants	15 Participants	18 Participants	15 Participants	17 Participants
Total Number of Remitters by Week Week 5	13 Participants	18 Participants	16 Participants	12 Participants	17 Participants
Total Number of Remitters by Week Week 6	15 Participants	15 Participants	21 Participants	13 Participants	18 Participants
Total Number of Remitters by Week Week 7	19 Participants	19 Participants	22 Participants	16 Participants	21 Participants
Total Number of Remitters by Week Week 8	23 Participants	19 Participants	25 Participants	18 Participants	21 Participants
Total Number of Remitters by Week Week 9	24 Participants	19 Participants	25 Participants	19 Participants	26 Participants
Total Number of Remitters by Week Week 11	25 Participants	22 Participants	23 Participants	21 Participants	28 Participants
Total Number of Remitters by Week Week 12	27 Participants	23 Participants	24 Participants	20 Participants	26 Participants

SECONDARY outcome

Timeframe: Baseline and Week 12

Population: All participants who received study drug and had valid answers recorded for the WHQ domain for sleep problems.

The WHQ is a 36-item, user-friendly, and rapid way of assessing nine domains of physical and emotional health for mid-aged women. Participants self-administered the WHQ questionnaire; scoring is based on a 4-point scale as follows: 'Yes definitely=1', 'Yes sometimes=2', 'No not much=3' and 'No not at all=4'. Each score is transformed to a value '1' for scores '1' and '2' and to a value '0' for scores '3' and '4'. Sleep problems encompass Items 1, 11, and 29 of the 36 total items. The transformed sums of items 1, 11, and 29 were divided by 3 to get the score; therefore, the domain ranges from 0 to 1, where lower values are better.

Outcome measures

Measure	Placebo n=265 Participants Participants receive encapsulated tablets, orally, once daily (QD) for up to 12 weeks.	Esmirtazapine 2.25 mg n=138 Participants Participants receive esmirtazapine, 2.25 mg, encapsulated tablets, orally QD for up to 12 weeks.	Esmirtazapine 4.5 mg n=134 Participants Participants receive esmirtazapine, 4.5 mg, encapsulated tablets, orally QD for up to 12 weeks.	Esmirtazapine 9 mg n=128 Participants Participants receive esmirtazapine, 9 mg, encapsulated tablets, orally QD for up to 12 weeks.	Esmirtazapine 18 mg n=128 Participants Participants receive esmirtazapine, 18 mg, encapsulated tablets, orally, QD for up to 12 weeks
Change From Baseline in Women's Health Questionnaire (WHQ) Sleep Problems Symptoms Domain Score at Week 12 Baseline	0.714 Score on a scale Standard Deviation 0.291 • Interval -0.19 to -0.03	0.659 Score on a scale Standard Deviation 0.321 • Interval -0.18 to 0.01	0.684 Score on a scale Standard Deviation 0.298 • Interval -0.14 to -0.03	0.688 Score on a scale Standard Deviation 0.270	0.693 Score on a scale Standard Deviation 0.260 • Interval -0.2 to -0.03
Change From Baseline in Women's Health Questionnaire (WHQ) Sleep Problems Symptoms Domain Score at Week 12 Week 12	-0.140 Score on a scale Standard Deviation 0.325	-0.232 Score on a scale Standard Deviation 0.338	-0.251 Score on a scale Standard Deviation 0.336	-0.224 Score on a scale Standard Deviation 0.381	-0.195 Score on a scale Standard Deviation 0.328

SECONDARY outcome

Timeframe: Baseline and Week 12

Population: All participants who received study drug and had valid answers recorded for the WHQ domain for vasomotor symptoms.

The WHQ is a 36-item, user-friendly, and rapid way of assessing nine domains of physical and emotional health for mid-aged women. Participants self-administered the WHQ questionnaire; scoring is based on a 4-point scale as follows: 'Yes definitely=1', 'Yes sometimes=2', 'No not much=3' and 'No not at all=4'. Each score is transformed to a value '1' for scores '1' and '2' and to a value '0' for scores '3' and '4'. Vasomotor symptoms encompass Items 19 and 27 of the 36 total items. The transformed sums of items 19+27 are divided by 2 to get the score; therefore, the domain ranges from 0 to 1, where lower values are better.

Outcome measures

Measure	Placebo n=265 Participants Participants receive encapsulated tablets, orally, once daily (QD) for up to 12 weeks.	Esmirtazapine 2.25 mg n=138 Participants Participants receive esmirtazapine, 2.25 mg, encapsulated tablets, orally QD for up to 12 weeks.	Esmirtazapine 4.5 mg n=134 Participants Participants receive esmirtazapine, 4.5 mg, encapsulated tablets, orally QD for up to 12 weeks.	Esmirtazapine 9 mg n=128 Participants Participants receive esmirtazapine, 9 mg, encapsulated tablets, orally QD for up to 12 weeks.	Esmirtazapine 18 mg n=128 Participants Participants receive esmirtazapine, 18 mg, encapsulated tablets, orally, QD for up to 12 weeks
Change From Baseline in WHQ Vasomotor Symptoms Domain Score at Week 12 Baseline	0.983 Score on a scale Standard Deviation 0.091 • Interval -0.19 to -0.03	0.989 Score on a scale Standard Deviation 0.0873 • Interval -0.12 to 0.03	0.993 Score on a scale Standard Deviation 0.061 • Interval -0.16 to -0.02	0.984 Score on a scale Standard Deviation 0.087	0.984 Score on a scale Standard Deviation 0.087 • Interval -0.23 to -0.09
Change From Baseline in WHQ Vasomotor Symptoms Domain Score at Week 12 Week 12	-0.085 Score on a scale Standard Deviation 0.260	-0.196 Score on a scale Standard Deviation 0.349	-0.224 Score on a scale Standard Deviation 0.381	-0.117 Score on a scale Standard Deviation 0.277	-0.164 Score on a scale Standard Deviation 0.314

Adverse Events

Placebo

Serious events: 2 serious events

Other events: 91 other events

Deaths: 0 deaths

Esmirtazapine 2.25 mg

Serious events: 1 serious events

Other events: 71 other events

Deaths: 0 deaths

Esmertazapine 4.5 mg

Serious events: 1 serious events

Other events: 70 other events

Deaths: 0 deaths

Esmirtazapine 9 mg

Serious events: 3 serious events

Other events: 58 other events

Deaths: 0 deaths

Esmirtazapine 18 mg

Serious events: 1 serious events

Other events: 80 other events

Deaths: 0 deaths

Serious adverse events

Measure	Placebo n=314 participants at risk Participants receive encapsulated tablets, orally, once daily (QD) for up to 12 weeks.	Esmirtazapine 2.25 mg n=162 participants at risk Participants receive esmirtazapine, 2.25 mg, encapsulated tablets, orally QD for up to 12 weeks.	Esmertazapine 4.5 mg n=160 participants at risk Participants receive esmirtazapine, 4.5 mg, encapsulated tablets, orally QD for up to 12 weeks.	Esmirtazapine 9 mg n=151 participants at risk Participants receive esmirtazapine, 9 mg, encapsulated tablets, orally QD for up to 12 weeks.	Esmirtazapine 18 mg n=158 participants at risk Participants receive esmirtazapine, 18 mg, encapsulated tablets, orally QD for up to 12 weeks.
Cardiac disorders Wolff-Parkinson-White Syndrome	0.00% 0/314 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	0.00% 0/162 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	0.00% 0/160 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	0.66% 1/151 • Number of events 1 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	0.00% 0/158 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.
Gastrointestinal disorders Diverticular perforation	0.00% 0/314 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	0.62% 1/162 • Number of events 1 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	0.00% 0/160 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	0.00% 0/151 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	0.00% 0/158 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.
General disorders Asthenia	0.00% 0/314 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	0.00% 0/162 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	0.00% 0/160 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	0.66% 1/151 • Number of events 1 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	0.00% 0/158 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.
General disorders Non-cardiac chest pain	0.00% 0/314 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	0.00% 0/162 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	0.00% 0/160 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	0.66% 1/151 • Number of events 1 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	0.00% 0/158 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.
Infections and infestations Diverticulitis	0.00% 0/314 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	0.00% 0/162 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	0.62% 1/160 • Number of events 1 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	0.00% 0/151 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	0.00% 0/158 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Ovarian fibroma	0.00% 0/314 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	0.00% 0/162 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	0.00% 0/160 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	0.66% 1/151 • Number of events 1 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	0.00% 0/158 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.
Nervous system disorders Syncope vasovagal	0.32% 1/314 • Number of events 1 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	0.00% 0/162 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	0.00% 0/160 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	0.00% 0/151 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	0.63% 1/158 • Number of events 1 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.
Psychiatric disorders Nightmare	0.32% 1/314 • Number of events 1 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	0.00% 0/162 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	0.00% 0/160 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	0.00% 0/151 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	0.00% 0/158 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.
Psychiatric disorders Suicidal ideation	0.32% 1/314 • Number of events 1 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	0.00% 0/162 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	0.00% 0/160 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	0.00% 0/151 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	0.00% 0/158 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.

Other adverse events

Measure	Placebo n=314 participants at risk Participants receive encapsulated tablets, orally, once daily (QD) for up to 12 weeks.	Esmirtazapine 2.25 mg n=162 participants at risk Participants receive esmirtazapine, 2.25 mg, encapsulated tablets, orally QD for up to 12 weeks.	Esmertazapine 4.5 mg n=160 participants at risk Participants receive esmirtazapine, 4.5 mg, encapsulated tablets, orally QD for up to 12 weeks.	Esmirtazapine 9 mg n=151 participants at risk Participants receive esmirtazapine, 9 mg, encapsulated tablets, orally QD for up to 12 weeks.	Esmirtazapine 18 mg n=158 participants at risk Participants receive esmirtazapine, 18 mg, encapsulated tablets, orally QD for up to 12 weeks.
Gastrointestinal disorders Abdominal distension	1.6% 5/314 • Number of events 5 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	1.2% 2/162 • Number of events 3 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	1.9% 3/160 • Number of events 3 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	2.6% 4/151 • Number of events 5 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	6.3% 10/158 • Number of events 11 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.
Gastrointestinal disorders Dry mouth	1.9% 6/314 • Number of events 6 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	4.9% 8/162 • Number of events 9 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	4.4% 7/160 • Number of events 7 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	7.9% 12/151 • Number of events 12 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	5.7% 9/158 • Number of events 10 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.
General disorders Fatigue	2.9% 9/314 • Number of events 10 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	9.9% 16/162 • Number of events 18 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	16.2% 26/160 • Number of events 28 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	10.6% 16/151 • Number of events 19 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	14.6% 23/158 • Number of events 25 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.
General disorders Oedema peripheral	0.96% 3/314 • Number of events 4 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	5.6% 9/162 • Number of events 10 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	5.0% 8/160 • Number of events 10 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	2.0% 3/151 • Number of events 6 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	3.8% 6/158 • Number of events 11 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.
Infections and infestations Influenza	4.8% 15/314 • Number of events 15 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	5.6% 9/162 • Number of events 9 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	1.9% 3/160 • Number of events 3 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	4.0% 6/151 • Number of events 6 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	1.3% 2/158 • Number of events 2 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.
Investigations Weight increased	1.9% 6/314 • Number of events 6 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	4.3% 7/162 • Number of events 7 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	8.1% 13/160 • Number of events 13 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	7.3% 11/151 • Number of events 11 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	11.4% 18/158 • Number of events 18 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.
Metabolism and nutrition disorders Increased appetite	1.3% 4/314 • Number of events 4 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	4.9% 8/162 • Number of events 8 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	5.0% 8/160 • Number of events 8 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	6.6% 10/151 • Number of events 11 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	8.9% 14/158 • Number of events 14 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.
Musculoskeletal and connective tissue disorders Arthralgia	5.1% 16/314 • Number of events 20 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	3.7% 6/162 • Number of events 6 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	2.5% 4/160 • Number of events 5 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	2.0% 3/151 • Number of events 3 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	3.8% 6/158 • Number of events 6 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.
Nervous system disorders Dizziness	3.8% 12/314 • Number of events 12 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	4.9% 8/162 • Number of events 8 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	2.5% 4/160 • Number of events 4 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	3.3% 5/151 • Number of events 5 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	8.2% 13/158 • Number of events 14 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.
Nervous system disorders Headache	10.5% 33/314 • Number of events 52 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	8.6% 14/162 • Number of events 18 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	5.6% 9/160 • Number of events 11 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	3.3% 5/151 • Number of events 14 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	8.2% 13/158 • Number of events 17 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.
Nervous system disorders Somnolence	1.9% 6/314 • Number of events 7 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	11.7% 19/162 • Number of events 25 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	13.1% 21/160 • Number of events 23 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	7.3% 11/151 • Number of events 12 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	17.1% 27/158 • Number of events 30 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.
Reproductive system and breast disorders Menopausal symptoms	2.5% 8/314 • Number of events 8 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	3.1% 5/162 • Number of events 5 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	6.2% 10/160 • Number of events 10 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	4.0% 6/151 • Number of events 6 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.	2.5% 4/158 • Number of events 4 • Non-serious adverse events were collected up to 7 days after the last dose of study drug; serious adverse events were collected for up to 30 days after the last dose of study drug.

Additional Information

Senior Vice President, Global Clinical Development

Merck Sharp & Dohme Corp

Phone: 1-800-672-6372

Email: ClinicalTrialsDisclosure@merck.com

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place

Restriction type: LTE60