SUPPLEMENTARY MATERIALS Comparative efficacy of ...
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15 April 2021
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SUPPLEMENTARY MATERIALS Comparative efficacy of lemborexant and other insomnia treatments: a network meta-analysis
Heather McElroy, MMedStat; Beth O’Leary, MPH, MSc; Michael Adena, PhD; Renee Campbell MD, MBA, MPH; Amir Abbas Tahami Monfared, MD, PHD; and Genevieve Meier, PhD
Supplementary Table 1. Embase search strategy (2019 update) ........................ 6
Supplementary Table 2. Summary of included studies ........................................ 9
Supplementary Table 3. Summary of quality assessment .................................. 18
Supplementary Table 4. Results of individual studies, TST (PSG) data (minutes)
............................................................................................................................ 23
Supplementary Table 5. Results of individual studies, sTST data (minutes) ...... 25
Supplementary Table 6. Results of individual studies, WASO (PSG) data
(minutes) ............................................................................................................. 30
Supplementary Table 7. Results of individual studies, sWASO data (minutes) .. 32
Supplementary Table 8. Results of individual studies, LPS (PSG) data (minutes)
............................................................................................................................ 36
Supplementary Table 9. Results of individual studies, sSOL data (minutes) ...... 39
Supplementary Table 10. Results of individual studies, SE (PSG) data (%) ....... 44
Supplementary Table 11. Results of individual studies, sSE data (%) ................ 46
Supplementary Table 12. Results of individual studies, ISI total score data (scale:
0 to 28 where lower score reflects lower severity) .............................................. 47
Supplementary Table 13. Results of individual studies, quality of sleep
transformed into 1 (poor) to 10 (excellent) scale ................................................. 49
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Supplementary Table 14. Differences in TST (PSG) across the network (minutes)
at 4 weeks: random effects ................................................................................. 53
Supplementary Table 15. Differences in WASO (PSG) across the network
(minutes) at 4 weeks: random effects ................................................................. 54
Supplementary Table 16. Differences in LPS (PSG) across the network (minutes)
at 4 weeks: random effects ................................................................................. 55
Supplementary Table 17. Differences in SE (PSG) across the network (%) at 4
weeks: random effects ........................................................................................ 56
Supplementary Table 18. Comparison of lemborexant with other treatments:
efficacy results at 3 and 6 months....................................................................... 57
Supplementary Table 19. Differences in sTST across the network (minutes) at 4
weeks: random effects ........................................................................................ 59
Supplementary Table 20. Differences in sTST across the network (minutes) at 3
months: fixed effects ........................................................................................... 61
Supplementary Table 21. Differences in sTST across the network (minutes) at 6
months: fixed effects ........................................................................................... 62
Supplementary Table 22. Differences in sWASO across the network (minutes) at
4 weeks: random effects ..................................................................................... 63
Supplementary Table 23. Differences in sWASO across the network (minutes) at
3 months: fixed effects ........................................................................................ 65
Supplementary Table 24. Differences in sWASO across the network (minutes) at
6 months: fixed effects ........................................................................................ 66
Supplementary Table 25. Differences in sSOL across the network (minutes) at 4
weeks: random effects ........................................................................................ 67
Supplementary Table 26. Differences in sSOL across the network (minutes) at 3
months: fixed effects ........................................................................................... 69
Supplementary Table 27. Differences in sSOL across the network (minutes) at 6
months: fixed effects ........................................................................................... 70
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Supplementary Table 28. Differences in ISI total score across the network at 4
weeks: random effects ........................................................................................ 71
Supplementary Table 29. Differences in ISI total score across the network at 3
months: fixed effects ........................................................................................... 72
Supplementary Table 30. Differences in ISI total score across the network at 6
months: fixed effects ........................................................................................... 73
Supplementary Table 31. Differences in sQUAL across the network (scale: 1 to
10 where higher score indicates better quality of sleep) at 4 weeks: random
effects ................................................................................................................. 74
Supplementary Table 32. Differences in sQUAL across the network (scale: 1 to
10 where higher score indicates better quality of sleep) at 3 months: fixed effects
............................................................................................................................ 76
Supplementary Table 33. Differences in sQUAL across the network (scale: 1 to
10 where higher score indicates better quality of sleep) at 6 months: fixed effects
............................................................................................................................ 77
Supplementary Table 34. Results of individual studies, percentage ................... 78
Supplementary Table 35. Results of individual studies, withdrawal due to adverse
event data ........................................................................................................... 80
Supplementary Table 36. Results of individual studies, percentage experiencing
at least one somnolence event data ................................................................... 82
Supplementary Table 37. Results of individual studies, percentage experiencing
at least one dizziness event data ........................................................................ 84
Supplementary Table 38. Results of individual studies, percentage experiencing
at least one fall or accidental injury event data ................................................... 86
Supplementary Table 39. Odds ratios for SAE across the network: fixed effects87
Supplementary Table 40. Odds ratios for withdrawal due to AE across the
network: fixed effects .......................................................................................... 88
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Supplementary Table 41. Odds ratios for somnolence across the network: fixed
effects ................................................................................................................. 90
Supplementary Table 42. Odds ratios for dizziness across the network: fixed
effects ................................................................................................................. 91
Supplementary Table 43. Odds ratios for falls and/or accidental injury across the
network: fixed effects .......................................................................................... 92
Supplementary Table 44. Comparison of each treatment with placebo: NMA
safety results ....................................................................................................... 93
Supplementary Table 45. β for interaction in older subgroup analysis ................ 95
Supplementary Figure 1. Network diagrams for included studies reporting WASO
(PSG), LPS (PSG) and SE (PSG) at 4 weeks .................................................... 96
Supplementary Figure 2. Network diagrams for included studies reporting sTST
and sWASO at 4 weeks, 3 months and 6 months ............................................... 97
Supplementary Figure 3. Network diagram for included studies reporting sSOL
and ISI total score at 4 weeks, 3 months and 6 months ...................................... 98
Supplementary Figure 4. Network diagram for included studies reporting sQUAL
at 4 weeks, 3 months and 6 months ................................................................... 99
Supplementary Figure 5. Ranking of suvorexant, zolpidem-IR, zolpidem-ER,
zopiclone, eszopiclone and zaleplon on objective efficacy outcome measures at
4 weeks ............................................................................................................. 100
Supplementary Figure 6. Ranking of triazolam, ramelteon and placebo on
objective efficacy outcome measures at 4 weeks ............................................. 101
Supplementary Figure 7. Ranking of lemborexant, suvorexant, zolpidem-IR,
zolpidem-ER, zopiclone and eszopiclone on subjective efficacy outcome
measures at 4 weeks ........................................................................................ 102
Supplementary Figure 8. Ranking of zaleplon, trazodone, estazolam, triazolam,
temazepam and brotizolam on subjective efficacy outcome measures at 4 weeks
.......................................................................................................................... 103
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Supplementary Figure 9. Ranking of ramelteon and placebo on subjective
efficacy outcome measures at 4 weeks ............................................................ 104
Supplementary Figure 10. Network diagrams for included studies reporting SAE,
withdrawals due to AE, somnolence, dizziness and falls/accidental injury ........ 105
Supplementary Figure 11. Comparison-adjusted funnel plots for WASO, LPS and
SE (all PSG) at 4 weeks ................................................................................... 106
Supplementary Figure 12. Comparison-adjusted funnel plots for sTST, sWASO,
sSOL and sQUAL at 4 weeks ........................................................................... 107
Supplementary Figure 13. Comparison-adjusted funnel plot for SAE, withdrawals
due to AE, somnolence and dizziness .............................................................. 108
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Supplementary Table 1. Embase search strategy (2019 update)
No. Query
#50 #49 AND [1-6-2017]/sd
#49 #3 AND #48
#48
#4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26 OR #27 OR #28 OR #29 OR #30 OR #31 OR #32 OR #33 OR #34 OR #35 OR #36 OR #37 OR #38 OR #39 OR #40 OR #41 OR #42 OR #43 OR #44 OR #45 OR #46 OR #47
#47 trazodone:ti OR oleptro:ti OR desyrel:ti OR act541468:ti OR 'act 541468':ti
#46 'trazodone'/mj
#45 lemborexant:ti OR 'e 2006':ti OR e2006:ti OR 'lem 10':ti OR 'lem 5':ti
#44 'lemborexant'/mj
#43 suvorexant:ti OR 'mk 4305':ti OR mk4305:ti
#42 'suvorexant'/mj
#41 seltorexant:ti OR 'jnj 42847922':ti OR jnj42847922:ti OR 'min 202':ti OR min202:ti OR 'jnj 922':ti OR jnj922:ti
#40 'seltorexant'/mj
#39 'orexin receptor antagonist':ti OR dora:ti
#38 'orexin receptor antagonist'/exp/mj
#37 alprazolam:ti OR xanax:ti OR alprax:ti OR kalma:ti
#36 'alprazolam'/mj
#35 etizolam:ti OR depas:ti OR etilaam:ti OR etizest:ti OR etizola:ti OR pasaden:ti OR sedekopan:ti
#34 'etizolam'/mj
#33 estazolam:ti OR prosom:ti OR eurodin:ti
#32 'estazolam'/mj
#31 brotizolam:ti OR bondormin:ti OR lendormin:ti OR we941:ti OR 'we 941':ti
#30 'brotizolam'/mj
#29 flunitrazepam:ti OR rohypnol:ti OR hypnodorm:ti
#28 'flunitrazepam'/mj
#27 lorazepam:ti OR ativan:ti OR temesta:ti OR subveta:ti OR truveta:ti OR 'edg 004':ti
#26 'lorazepam'/mj
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No. Query
#25 temazepam:ti OR temaze:ti OR temtabs:ti OR normison:ti OR restoril:ti
#24 'temazepam'/mj
#23 triazolam:ti OR halcion:ti OR hypnostat:ti OR tgar01h:ti
#22 'triazolam'/mj
#21 benzodiazepine*:ti
#20 'benzodiazepine derivative'/mj
#19 ramelteon:ti OR rozerem:ti OR 'tak 375':ti OR tak375:ti
#18 'ramelteon'/mj
#17 eszopiclone:ti OR lunesta:ti OR 's zopiclone':ti OR esopiclone:ti OR estorra:ti OR lunivia:ti
#16 'eszopiclone'/mj
#15 zileze:ti OR zimoclone:ti OR zimovane:ti OR 'zopi puren':ti OR zopicalm:ti OR zopicalma:ti OR zopiclodura:ti OR zopiclon:ti OR zopitan:ti OR zoplicon:ti OR zorclone:ti
#14 zopiclone:ti OR amoban:ti OR imovance:ti OR imovane:ti OR limovan:ti OR optidorm:ti OR rhovane:ti OR 'rp 27267':ti OR siaten:ti OR somnosan:ti OR ximovan:ti
#13 'zopiclone'/mj
#12 ziohex:ti OR zodorm:ti OR zodormdura:ti OR zoldem:ti OR zolirin:ti OR 'zolpi lich':ti OR zolpimist:ti OR zolpinox:ti OR zopidem:ti OR zopim:ti
#11 'sl 800750 23n':ti OR somit:ti OR somnil:ti OR somno:ti OR stilnix:ti OR stilnoct:ti OR stilnox:ti OR stilpidem:ti OR supedal:ti OR 'tovalt odt':ti
#10 'zolpidem tartrate':ti OR ambien:ti OR adormix:ti OR amsic:ti OR bikalm:ti OR dalparan:ti OR durnit:ti OR edluar:ti OR myslee:ti OR niotal:ti OR nitrest:ti
#9 'zolpidem tartrate'/mj
#8 zolpidem:ti OR 'sl 800750':ti OR sl800750:ti
#7 'zolpidem'/mj
#6 'cl 284846':ti OR cl284846:ti OR 'l 846':ti OR l846:ti OR 'ljc 10846':ti OR ljc10846:ti OR 'skp 1041':ti
#5 zaleplon:ti OR sonata:ti OR hegon:ti OR hipnodem:ti OR noctiplon:ti OR plenidon:ti OR starnoc:ti OR zaplon:ti OR zelepion:ti OR zerene:ti
#4 'zaleplon'/mj
#3 #1 OR #2
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No. Query
#2 insomnia:ti OR agrypnia:ti OR hyposomnia:ti OR sleeplessness:ti
#1 'insomnia'/exp/mj
* The search was conducted using Elsevier’s Embase Web site on 6 February 2019.
DE = descriptor; i.e., indexed keywords (subject headings) such as Emtree terms
TI = title; i.e., free text terms appearing in titles of articles
AB = abstract; i.e., free text terms appearing in abstracts of articles
KW = author keywords; i.e., free text terms provided by authors
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Supplementary Table 2. Summary of included studies
Study Study type
Country Duration of treatment
Mean age (years)
% male Patient characteristics Patient Numbers a
Ancoli-Israel 1999 36
MC, DB, PC, AC
USA 2 weeks 71.7 42% Older (≥65years)
≥3month history DSM-IV primary insomnia
placebo = 107
zaleplon, 5mg =166
zaleplon, 10mg =165
zolpidem-IR, 5mg =111
Ancoli-Israel 2010 37
MC, DB, PC
USA 12 weeks 72.0 37% Older (65-85 years)
DSM-IV primary insomnia
sTST ≤6 hr per night for ≥3 nights per week
WASO ≥45min per night for ≥3 nights per week
placebo = 194
eszopiclone, 2mg = 194
Black 2017 38
MC, DB, PC, AC
Australia
Europe
Israel
South Africa
~2 weeks 45.7 37% 18-64 years
Chronic insomnia (DSM-IV-TR)
sSOL≥30min, sWASO≥30min, sTST<6.5hrs for ≥3 nights of 7 consecutive nights
Objective LPS≥20min (with no night <15min) and mean TST<420min over two screening PSG nights
placebo = 177
zolpidem-IR, 10mg =168
Dehlin 1995 39
MC, DB, AC
Sweden 2 weeks 79.0 29% Older (>=60 years)
Insomnia >1 month, MMSE score >=24 points
At least 2 of sSOL>30min, NAW>2, sWASO >45min, sTST<6hrs, awake >2h before expected
zopiclone, 5mg = 50
flunitrazepam, 1mg = 52
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Study Study type
Country Duration of treatment
Mean age (years)
% male Patient characteristics Patient Numbers a
Dorsey 2004 40
MC, DB, PC
USA 4 weeks 50.8 0% Women (39-60 years)
Pre- or postmenopausal insomnia
>=2 nocturnal hot flashes, hot flushes or night sweats.
sTST<=6hrs OR sWASO >=1hr and difficulty functioning in the day
placebo = 73
zolpidem-IR, 10mg = 68
Elie 1999 41 MC, DB, PC, AC
Canada Europe
4 weeks 42.9 37% 18-65 years
Primary insomnia (DSM-III-R) or insomnia with mild nonpsychotic psychiatric disorders.
SOL ≥30 minutes
Daytime impairment due to sleep disturbance
sTST ≤ 6.5 hours OR ≥ NAW ≥ 30 minutes
placebo = 126
zaleplon, 5 mg = 122
zaleplon, 10 mg = 121
zaleplon, 20 mgb = 124
zolpidem-IR, 10 mg = 122
Fry 2000 42 MC, DB, PC
USA 4 weeks 42.0 43% 18- 65 years
Primary insomnia or insomnia with mild non-psychotic psychiatric disorders (DSM-111-R)
placebo = 118
zaleplon, 5mg = 118
zaleplon, 10mg =119
zaleplon, 20mgb = 116
zolpidem-IR, I0mg = 115
Hajak 1994 43
MC, DB, PC, AC
NR 4 weeks 51.0 38% 18-71 years
Insomnia (not further defined)
placebo = 298
zopiclone, 7.5mg = 612
flunitrazepam, 1mg = 290
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Study Study type
Country Duration of treatment
Mean age (years)
% male Patient characteristics Patient Numbers a
triazolam, 0.25mg = 307
Hajak 2009 44
MC, DB, PC, AC
Europe 2 weeks 47.7 35% 18-64 years
Primary insomnia by DSM-IV
sTST<6h and sSOL >=45min
placebo = 142
zolpidem-IR, 10mg = 150
Hedner 2000 45
MC, DB, PC
Europe 2 weeks 72.5 32% Older (≥54 years)
insomnia of ≥2 months (DSM-IV)
placebo = 138
zaleplon, 5mg = 139
zaleplon, 10mg =145
Herring 2016 trial 1 11
MC, DB, PC
Americas, Europe, Asia, South Africa
3 months 55.6 36% Adult (18–65 years) and older ≥65 years
Primary insomnia (DSM-IV-TR)
placebo = 384
suvorexant, 20/15 mg = 254
suvorexant, 40/30 mgb
= 383
Herring 2016 trial 2 11
MC, DB, PC
Americas, Australia, Europe, Asia, South Africa
3 months 56.6 35% Adult (18–65 years) and older ≥65 years
Primary insomnia (DSM-IV-TR)
placebo = 383
suvorexant, 20/15 mg = 239
suvorexant, 40/30 mgb = 387
Krystal 2003 46
MC, DB, PC
USA 6 months 44.0 37% 21-65 years
Primary insomnia (DSM-IV)
placebo =196
eszopiclone, 3mg =595
Lahmeyer 1997 47
MC, DB, PC
USA ~4 weeks 45.2 44% 19-61 years
Chronic insomnia
sTST 4-6 hrs
placebo = 54
zolpidem-IR, 10 mg = 45
zolpidem-IR, 15 mgb = 46
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Study Study type
Country Duration of treatment
Mean age (years)
% male Patient characteristics Patient Numbers a
sSOL≥30 minutes for a minimum of 3 months
Leppik 1997 48
MC, DB, PC, AC
USA 4 weeks 69.0 36% Older (59-85 years)
Chronic insomnia of at least 3 months
placebo = 84
zolpidem-IR, 5mg = 82
triazolam, 0.125mg = 85
temazepam, 15mg = 84
Mayer 2009 49
MC, DB, PC
USA,
Europe, Russia, Australia
6 months 46.2 37% >18 years of age
BMI = 18-34
Chronic insomnia ≥3 months
sTST<= 6.5 hours
sSOL ≥45 minutes per night
Habitual bedtime between 22:00 and 01:00.
placebo = 224
ramelteon, 8mg = 227
McCall 2006 50
MC, DB, PC
USA 2 weeks 71.1 33% Older (64-86 years)
Primary insomnia (DSM-IV)
sTST ≤6.5hrs per night
sSOL >30 minutes for at least 1 month
placebo = 128
eszopiclone, 2mg = 136
Pinto 2016 51
SC, DB, AC
Brazil 4 weeks 47.4 25% 20-64 years
Symptomatic insomnia ≥3 months
zopiclone, 7.5mg = 102
eszopiclone, 3mg = 97
Randall 2012 52
DB, PC
USA 8 months 50.4 41% 23-70 years
Primary insomnia (DSM-IV-TR)
placebo = 47
zolpidem-IR, 5/10 mg = 44
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Study Study type
Country Duration of treatment
Mean age (years)
% male Patient characteristics Patient Numbers a
Rickels 1986 53
DB, PC
USA 1 week 46.0 37% 20 to 65 years
Chronic insomnia ≥6 months
placebo = 34
brotizolam, 0.25mg/0.5mgb = 29
Rosenberg 1994 54
MC, DB, AC
Denmark 2 weeks NR 31% 18-80 years
At least 2 of: NAW>3, sTST<6hrs, sSOL>30min; sWASO>20min
zolpidem-IR, 10mg = 71
triazolam, 0.25mg = 68
Roth 2006a 55
MC, DB, PC
USA 5 weeks 72.4 31% Older (≥65 years)
Primary insomnia (DSM-IV-Tre) ≥ 3 months
placebo = 274
ramelteon, 4mg = 281
ramelteon, 8mg = 274
Roth 2006b 56
MC, DB, PC
USA, Canada, Australia
3 weeks 44.3 42% 18-64 years
Primary insomnia (DSM-IV)
placebo = 110
zolpidem-ER, 12.5mg = 102
Scharf 1990 57
MC, DB, PC
USA 1 week NR NR 21-65 years
sSOL ≥ 60min OR
NAW ≥ 3
placebo = 80
estazolam, 2mg = 81
Scharf 1994 58
MC, DB, PC
USA 5 weeks 38.0 36% 21-60 years
Chronic insomnia (outpatient)
placebo = 24
zolpidem-IR, 10mg = 26
zolpidem-IR, 15mgb = 25
Scharf 2005 59
MC, DB, PC
USA 2 weeks 72.3 42% Older (65-85 years)
Primary insomnia (DSM-IV)
sTST ≤6.5 hours
sSOL>30mins for at least 1 month
placebo = 80
eszopiclone, 1mg = 72
eszopiclone, 2mg = 79
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Study Study type
Country Duration of treatment
Mean age (years)
% male Patient characteristics Patient Numbers a
Soares 2006 62
MC, DB, PC
NR 4 weeks 49.1 0% Female 40-60 years
Primary insomnia (DSM-IV)
sTST ≤6 hours
sSOL >45mins ≥3 times per week, ≥1 month
placebo = 209
eszopiclone, 3mg = 201
Study 201 60
MC, DB, PC
USA 2 weeks 48.3 37% 18-80 years
Insomnia (DSM)
sSOL ≥ 30 OR sWASO ≥60
6.5 ≥ TIB ≥9.0 hrs
ISI ≥ 15
LPS ≥ 30 and oWASO ≥ 30 and oSE ≤ 85%
placebo = 56
lemborexant, 1mgb = 32
lemborexant, 2.5mgb = 27
lemborexant, 5mg = 38
lemborexant, 10mg = 32
lemborexant, 15mgb = 56
lemborexant, 25mgb = 50
Study 303 14
MC, DB, PC
North America,
Europe,
Asia,
New Zealand
6 months 54.5 32% ≥18 years
Insomnia (DSM 5)
sSOL ≥ 30min and/or sWASO ≥ 60min for at least 3 nights out of 7
ISI ≥ 15
placebo = 321
lemborexant, 5mg = 319
lemborexant, 10mg = 319
Study 304 16
MC, DB, PC, AC
USA ~4 weeks 63.9 14% Male >=65, female >=55 years
Insomnia (DSM-V)
sWASO>=60min
placebo = 208
lemborexant, 5mg = 266
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Study Study type
Country Duration of treatment
Mean age (years)
% male Patient characteristics Patient Numbers a
ISI>=13 lemborexant, 10mg = 269
zolpidem-ER, 6.25mg = 263
Tsutsui 2001 63
MC, DB, AC
Japan 2 weeks 42.2 35% Primary insomnia experiencing difficulties sleeping more than 3 times per week
zolpidem-IR, 10mg =231
zopiclone, 7.5mg = 248
Uchimura 2011 64
MC, DB, PC
Japan 2 weeks 48.8 37% Japanese >18 years
Chronic insomnia (DSM-IV)
sSOL ≥60 min
sTST ≤6.5 h
Bedtime between 9 pm and 1 am.
placebo to ramelteon, 4mgb = 383
ramelteon, 4b to 8mg = 375
ramelteon, 8 to 16mgb = 385
Uchiyama 2011 65
MC, DB, PC
Japan 2 weeks 38.8 37% Japanese 20–85 years
Primary insomnia
placebo = 492
ramelteon, 8mg = 495
Voshaar 2004 66
MC, DB, AC
Netherlands
4 weeks 46.1 33% 18-64 years
Primary insomnia (DSM-III-R)
zolpidem-IR, 10mg = 74
temazepam, 20mg = 85
Walsh 1984 67
MC, DB, PC
NR 1 week 41.4 48% 21-65 years
sTST<6hrs AND
sSOL >60 minutes OR
sNAW ≥2
sWASO >60mins for 3 months
placebo = 124
estazolam, 1 mg = 123
estazolam, 2 mg = 120
Walsh 1998a 68
MC, DB,
USA 2 weeks NR 37% 21-65 years
sSOL ≥30 mins
placebo = 103
trazodone, 50mg = 98
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Study Study type
Country Duration of treatment
Mean age (years)
% male Patient characteristics Patient Numbers a
PC, AC
sTST = 4-6 hours at least 3 nights per week
zolpidem-IR, 10mg = 100
Walsh 1998b 69
MC, DB, PC, AC
USA 2 weeks 40.3 42% 18-60 years
Primary insomnia (DSM-IIIR)
placebo = 34
zaleplon, 5mg = 34
zaleplon, 10mg = 33
triazolam, 0.25mg = 31
Walsh 2000 70
MC, DB, PC
USA 5 weeks 42.1 26% 18–65 years
Primary insomnia (DSM-IV)
placebo = 57
zaleplon, 10mg = 56
Walsh 2007 71
MC, DB, PC
USA 6 months 45.6 39% 21-64 years
Primary insomnia (DSM-IV)
sTST ≤6.5 hours and
sSOL>30 mins ≥ 1 month
placebo = 280
eszopiclone, 3mg = 550
Walsh 2008 72
MC, DB, PC
Argentina Canada, USA, Mexico, Europe
3 weeks 70.2 43% Older (65-87 years)
Primary insomnia (DSM-IV-TR)
sWASO ≥1, ≥ 3 nights per week and
Time spent in bed = 6.5-9 hours
placebo = 106
zolpidem-ER, 6.25mg = 99
Wang-Weigand 2011 73
PC NR 3 weeks 43.2 35% 18-64 years
Bedtime between 22:00-01:00
sSOL ≥60mins
sTST≤6.5hrs
placebo = 278
ramelteon, 8 mg = 274
Ware 1997 74
DB, PC, AC
USA 4 weeks NR 41% 21-55 years
Chronic insomnia and PSG disturbed sleep
placebo = 37
zolpidem-IR, 10mg = 37
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Study Study type
Country Duration of treatment
Mean age (years)
% male Patient characteristics Patient Numbers a
sTST = 4-6 hours
sSOL ≥30 minutes for ≥3-months
triazolam, 0.5mg = 36
Yan 2013 75
MC, DB, AC
China 2 weeks 38.7 31% 18-65 years
Insomnia (Chinese Classification and Diagnostic Criteria of Mental Disorders Version 3)
brotizolam, 0.25mg = 126
estazolam, 1-2mg = 127
Zammit 2004 76
MC, DB, PC
USA ~6 weeks 39.8 35% 21-64 years
Primary insomnia (DSM-IV)
sTST ≤6.5hrs
sSOL≥30min for ≥ 1 month
placebo = 99
eszopiclone, 3 mg = 105
eszopiclone, 2 mg = 104
Zammit 2007 77
MC, DB, PC
USA 5 weeks 38.8 32% 18-64 years
Primary insomnia (DSM-IV-TR)
sSOL ≥30 mins
sTST <6.5 hours for ≥3 months
placebo = 131
ramelteon, 8 mg = 139
ramelteon, 16 mgb = 135
a treatments not included in the analysis are not shown
b dose is not registered and was excluded
Note, for Studies 201, 303 and 304, the NMA was based on information in the clinical study reports. The studies are published now and the publications are cited here.
AC, active control; CBT, cognitive behavioral therapy; ER, extended release; DB, double blind; DSM, Diagnostic and Statistical Manual of Mental Disorders; IR, immediate release; IxRS, interactive voice and/or web response system; MC, multi-center; NMA, network meta-analysis; NR, not reported; PC, placebo control; PSG, polysomnographic; SC, single center; sSOL; subjective sleep onset; sTST, subjective total sleep time
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Supplementary Table 3. Summary of quality assessment
Was randomization carried out appropriately?
Was the concealment of treatment allocation adequate?
Were the groups similar at the outset of the study in terms of prognostic factors?
Were the care providers, participants and outcome assessors blind to treatment allocation?
Were there any unexpected imbalances in drop-outs between groups?
Is there any evidence to suggest that the authors measured more outcomes than they reported?
Did the analysis include an intention-to-treat analysis? If so, was this appropriate and were appropriate methods used to account for missing data?
Did the authors of the study publication declare any conflicts of interest?
Ancoli-Israel 1999 36
Unclear Unclear Yes Yesa Unclear Yesf Yes, Yes, NR Yesg
Ancoli-Israel 2010 37
Unclear Yes Yes Yesa No No Yes, Yes, Yes Yesg
Black 2017 38 Unclear Yes Yes Yes No No Yes, Yes, NR Yesg
Dehlin 1995 39 Unclear Unclear Unclear Yesa Unclear No No Yesg
Dorsey 2004 40
Unclear Unclear Yes Yesa No Yesf Yes, Yes, NR Yesg
Elie 1999 41 Unclear Unclear Yes Yesa Unclear Yesf No Yesg
Fry 2000 42 Unclear Unclear Yes Yesa No Yesf Yes, Yes, NR Yesg
Hajak 1994 43 Yes Unclear Unclear Yes No Yesf Yes, Yes, NR Yesg
Hajak 2009 44 Yes Unclear Yes Yes No No Yes, Yes, Yes Yesg
Hedner 2000 45
Unclear Unclear Yes Yesa Unclear Yesf Yes, Yes, NR Yesg
Herring 2016 trial 1 11
Yes Yes Yes Yes No No Yes, Yes, Yes Yesg
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Page 19
Was randomization carried out appropriately?
Was the concealment of treatment allocation adequate?
Were the groups similar at the outset of the study in terms of prognostic factors?
Were the care providers, participants and outcome assessors blind to treatment allocation?
Were there any unexpected imbalances in drop-outs between groups?
Is there any evidence to suggest that the authors measured more outcomes than they reported?
Did the analysis include an intention-to-treat analysis? If so, was this appropriate and were appropriate methods used to account for missing data?
Did the authors of the study publication declare any conflicts of interest?
Herring 2016 trial 2 11
Yes Yes Yes Yes No No Yes, Yes, Yes Yesg
Krystal 2003 46 Unclear Yes Yes Yesa No No Yes, Yes, Yes No
Lahmeyer 1997 47
Unclear Unclear Yes Yes No Yesf Yes, Yes, NR Yesg
Leppik 1997 48 Unclear Unclear Nob Yesa No Yesf Unclear Yesg
Mayer 2009 49 Unclear Unclear Yes Yesa No No Yes, Yes, Yes Yesg
McCall 2006 50 Unclear Unclear Yes Yes No No Unclear Yesg
Pinto 2016 51 Unclear Unclear Yes Yesa No Yesf Yes, Yes, NR Yesg
Randall 2012 52
Unclear Unclear Yes Yes No Yesf Yes, Yes, Yes Yesh
Rickels 1986 53
Unclear Unclear Unclear Yesa No Yesf Unclear Yesg
Rosenberg 1994 54
Yes Unclear Unclear Yes No Yesf No Yesg
Roth 2006a 55 Unclear Unclear Yes Yesa No No Unclear Yesg
Roth 2006b 56 Unclear Unclear Noc Yesa No Yesf Yes, Yes, NR NRi
15 April 2021
Page 20
Was randomization carried out appropriately?
Was the concealment of treatment allocation adequate?
Were the groups similar at the outset of the study in terms of prognostic factors?
Were the care providers, participants and outcome assessors blind to treatment allocation?
Were there any unexpected imbalances in drop-outs between groups?
Is there any evidence to suggest that the authors measured more outcomes than they reported?
Did the analysis include an intention-to-treat analysis? If so, was this appropriate and were appropriate methods used to account for missing data?
Did the authors of the study publication declare any conflicts of interest?
Scharf 1990 57 Unclear Unclear Unclear Yes No Yesf No No
Scharf 1994 58 Unclear Unclear Yes Yesa No Yesf Unclear No
Scharf 2005 59 Unclear Unclear Yes Yesa Unclear No Yes, Yes, Yes Yesg
Soares 2006 62
Yes Unclear Yes Yesa No No Yes, Yes, NR Yesg
Study 201 60 Yes Yes Yes Yes No No Yes, Yes, Yes Yesg
Study 303 14 Yes Yes Yes Yes No No Yes, Yes, Yes Yesg
Study 304 16 Yes Yes Yes Yes No No Yes, Yes, Yes Yesg
Tsutsui 2001 63
Unclear Unclear Yes Yes No No Yes,j Yes, NR No
Uchimura 2011 64
Yes Yes Yes Yesa No Yesf Yes, Yes, NR Yesg
Uchiyama 2011 65
Yes Yes Yes Yes No No Yes, Yes, NR Yesg
Voshaar 2004 66
Unclear Unclear Yes Yesa Yese Yesf Nok Yesg
Walsh 1984 67 Unclear Unclear Yes Yesa No Yesf No Yesg
15 April 2021
Page 21
Was randomization carried out appropriately?
Was the concealment of treatment allocation adequate?
Were the groups similar at the outset of the study in terms of prognostic factors?
Were the care providers, participants and outcome assessors blind to treatment allocation?
Were there any unexpected imbalances in drop-outs between groups?
Is there any evidence to suggest that the authors measured more outcomes than they reported?
Did the analysis include an intention-to-treat analysis? If so, was this appropriate and were appropriate methods used to account for missing data?
Did the authors of the study publication declare any conflicts of interest?
Walsh 1998a 68
Unclear Unclear Yes Yesa No Yesf Unclear Yesg
Walsh 1998b 69
Yes Unclear Yes Yesa No Yes Yes, Yes, NR Yesg
Walsh 2000 70 Yes Yes Yes Yes No Yesf Yes, Yes, NR Yesg
Walsh 2007 71 Unclear Unclear Yes Yes No No Yes, Yes, Yes Yesg
Walsh 2008 72 Unclear Yes Yes Yesa No No Yes, Yes, No Yesg
Wang-Weigand 2011 73
Unclear Unclear Unclear Yesa No Yesf Yes, Yes, Yes Yesg
Ware 1997 74 Unclear Unclear Nod Yesa No Yes Unclear Yesg
Yan 2013 75 Yes Yes Yes Yes No No Yes, Yes, Yes Yesg
Zammit 2004 76
Unclear Unclear Yes Yesa No No Yes, Yes, NR Yesg
Zammit 2007 77
Unclear Yes Yes Yes Unclear No Yes, Yes, Yes Yesg
a Double-blind study, but no further details of blinding were provided. b Subjective sleep latency and total sleep time at baseline was worse for triazolam vs temazepam (by 10 and 20 minutes respectively) which was not adjusted for in their analyses
15 April 2021
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Was randomization carried out appropriately?
Was the concealment of treatment allocation adequate?
Were the groups similar at the outset of the study in terms of prognostic factors?
Were the care providers, participants and outcome assessors blind to treatment allocation?
Were there any unexpected imbalances in drop-outs between groups?
Is there any evidence to suggest that the authors measured more outcomes than they reported?
Did the analysis include an intention-to-treat analysis? If so, was this appropriate and were appropriate methods used to account for missing data?
Did the authors of the study publication declare any conflicts of interest?
c Misbalance for PSG baseline which was adjusted for in their analyses; balanced for subjective baseline and demographic characteristics d Some misbalance, with placebo arm more severe. e Reason for discontinuation was not reported by treatment group and was higher with zolpidem-IR. Furthermore, number randomized to each group was not reported f Serious adverse events and/or withdrawal due to adverse events were not reported g Study supported by pharmaceutical industry h Study not sponsored by pharmaceutical industry i Authors had pharmaceutical industry affiliation j The primary analysis was per protocol which was appropriate for non-inferiority, and intention to treat was also conducted k The per protocol approach was appropriate, but intention to treat was not reported at all
Note, for Studies 201, 303 and 304, the NMA was based on information in the clinical study reports. The studies are all published now and the publications are cited here.
NR, not reported
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Supplementary Table 4. Results of individual studies, TST (PSG) data (minutes)
4 weeks
Arm-level Timepoint Statistic Group 1 N Mean se Group 2 N Mean se
Study 201 Average of days 14-15
Change placebo 52 59.2 7.01 lemborexant 68 102.4 8.40
Study 304 Average of days 29-30
Change placebo 208 30.2 2.95 lemborexant 535 66.7 1.86
zolpidem-ER 263 44.9 2.67
McCall 2006
2 weeks Change placebo 128a 27.6 3.84 eszopiclone 136a 56.2 3.71
Mayer 2009
Average of last 2 nights of month
Actual placebo 224a 373.8 3.05 ramelteon 227a 380.0 3.03
Pinto 2016
Day 28 Actual zopiclone 97 364.8b 3.78b eszopiclone 102 378.2b 5.23b
Randall 2012
Average of 2 nights in month
Actual placebo 47 382.7 8.20 zolpidem-IR 44 418.2 5.71
Walsh 1998b
Average of nights 16-17
Actual placebo 34a 411.3c 7.87c zaleplon 67a 407.6c 5.61c
triazolam 31a 420.5c 8.25c
Walsh 2000
Average of first 2 nights of week 4
Actual placebo 47 390.1 6.01 zaleplon 49 403.4 6.03
Zammit 2007
Average of nights 29-30
Actual placebo 131a 385.9 4.12 ramelteon 139a 391.5 4.04
Trial-level
Timepoint Statistic Group 2 – Group 1 N Mean difference se difference
Black 2017
Average of nights 15-16
Change zolpidem-IR - placebo 345 6.0d 5.10d
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3 months
Arm-level Timepoint Statistic Group 1 N Mean se Group 2 N Mean se
Mayer 2009
Average of last 2 nights of month 3
Actual placebo 224a 379.3 3.13 ramelteon 227a 382.5 3.11
6 months
Arm-level Timepoint Statistic Group 1 N Mean se Group 2 N Mean se
Mayer 2009
Average of last 2 nights of month 6
Actual placebo 224a 380.1 3.26 ramelteon 227a 381.4 3.23
Randall 2012
Average of 2 nights in month 8
Actual placebo 47 371.4 9.50 zolpidem-IR 44 411.0 4.93
The number of patients was not used directly in the NMA, but may have been used to estimate se. Where the number of patients for this outcome was not reported, the following imputation was done: a Baseline N was used. Medians were reported instead of mean for Black 2017, Pinto 2016 and Walsh 1998b, and the following imputation was done: b Method of Wan et al 2014 was used to impute mean and sd from median and IQR. c Mean was set to the median and the sd was calculated as the weighted average of sd from Mayer 2009, Randall 2012, Walsh 2000 and Zammit 2007. d Mean was set to the median and the asymptotic se was calculated from the 95% confidence interval. ER, extended release; IQR, interquartile range; IR, immediate release; N, number of patients; PSG, polysomnographic; sd, standard deviation; se, standard error; TST, total sleep time.
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Supplementary Table 5. Results of individual studies, sTST data (minutes)
4 weeks
Arm-level Timepoint Statistic Group 1 N Mean se Group 2 N Mean se
Study 303 Last 7 nights of month
Change placebo 291 27.5 3.90 lemborexant 566 44.4 2.80
Study 304 Last 7 nights of month
Change placebo 208 40.7 5.29 lemborexant 535 71.4 3.37
zolpidem-ER 263 71.0 4.84
Dorsey 2004
Week 4 Change placebo 73a 23.0 5.00 zolpidem-IR 68a 51.0 5.00
Hajak 2009 Week 2 (average of week)
Change placebo 130 33.3 5.00 zolpidem-IR 141 67.5 4.80
Herring 2016 - Trial 1
Average over last week of month 1
Change placebo 365 23.1 2.73 suvorexant 244 39.4 3.34
Herring 2016 - Trial 2
Average over last week of month 1
Change placebo 350 22.4 2.91 suvorexant 219 43.4 3.70
Leppik 1997
Week 4 (average)
Change placebo 75 51.8 8.00 zolpidem-IR 77 70.0 7.40
triazolam 75 72.7 6.70 temazepam 76 61.8 6.40
McCall 2006
2 weeks Change placebo 128a
32.4 5.21 eszopiclone 136a 48.6 4.72
Roth 2006b Nights 17-21 Change placebo 110a
66.8 7.75 zolpidem-ER 102a 90.5 8.00
Scharf 2005
Week 2 Change placebo 80 51.5 14.87 eszopiclone 151 77.7 10.27
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Soares 2006
Average of 4 weeks
Change placebo 209a
33.6 4.86e eszopiclone 201a 56.6 4.95e
Walsh 2008
Average of week 3
Change placebo 102b
47.2 6.01e zolpidem-ER 95b 71.2 6.23e
Ancoli-Israel 1999
2 weeks actual placebo 107 326.0d 6.14f zaleplon 331 336.0d 3.49f
zolpidem-IR 111 360.0d 6.03f
Ancoli-Israel 2010
Week 3 actual placebo 194 313.0 5.00 eszopiclone 194 349.0 4.00
Elie 1999 Average of week 4
actual placebo 107 377.0d 6.14f zaleplon 201 377.9d 4.48f
zolpidem-IR 100 400.0d 6.35f
Fry 2000 Week 4 actual placebo 107 364.3d 6.14f zaleplon 203 368.2d 4.46f
zolpidem-IR 98 392.9d 6.41f
Hedner 2000
2 weeks actual placebo 136 311.2c 6.87c zaleplon 265 333.2c 4.60c
Krystal 2003
Average of weeks 1-4
actual placebo 195 333.1 5.00 eszopiclone 593 373.9 2.77
Lahmeyer 1997
Week 4 (average)
actual placebo 54 360.0 8.64 zolpidem-IR 45 390.0 9.47
Mayer 2009
Average of last 2 nights of month
actual placebo 224a
340.3 4.04 ramelteon 227a 342.2 4.04
Randall 2012
average of 2 nights in month 1
actual placebo 47 385.2 10.50 zolpidem-IR 44 408.0 9.95
Rickels 1986
1 week actual placebo 34 348.0 13.78e brotizolam 29 402.0 14.92e
Rosenberg 1994
14 days actual zolpidem-IR
71 415.5c 6.45c triazolam 68 414.0c 5.24c
Roth 2006a Week 3 actual placebo 274a
324.3 3.00 ramelteon 274a 332.1 3.00
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Scharf 1994
4 weeks actual placebo 23 325.0 20.43 zolpidem-IR 22 358.0 14.71
Uchimura 2011
Days 1-7 actual placebo 380 334.2 3.00 ramelteon 378 342.6 3.00
Uchiyama 2011
Days 8-14 actual placebo 478 342.0 2.40 ramelteon 478 345.0 2.40
Voshaar 2004
4 weeks actual zolpidem-IR
74 413.0 9.07 temazepam 85 386.0 8.89
Walsh 2007
Average of 4 weeks
actual placebo 280 336.3 4.20 eszopiclone 548 384.6 2.89
Walsh 1998a
Week 2 actual placebo 103a
357.0 6.00 zolpidem-IR 100a 371.0 7.00
trazodone 98a 370.0 6.00
Walsh 2000
Week 4 actual placebo 47 356.9 11.48 zaleplon 50 382.4 9.12
Zammit 2004
Average of Nights 1,15,29,43 and 44
actual placebo 99 363.8 6.38 eszopiclone 209 396.9 6.89
Zammit 2007
Week 5 actual placebo 131a
347.1 5.70 ramelteon 139a 365.4 5.60
Trial-level Timepoint Statistic Group 2 – Group 1 N Mean difference se difference
Black 2017 Average of Weeks 1 and 2
Change zolpidem-IR - placebo 343 21.8d 4.54d
3 months
Arm-level Timepoint Statistic Group 1 N Mean se Group 2 N Mean se
Study 303 last 7 nights of month
Change placebo 269 46.4 4.31 lemborexant 507 66.0 3.12
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Herring 2016 - Trial 1
average over last 2 weeks of month 3
Change placebo 339 40.6 2.83 suvorexant 228 51.2 3.49
Herring 2016 - Trial 2
average over last 2 weeks of month 3
Change placebo 325 37.7 3.32 suvorexant 197 59.8 4.23
Ancoli-Israel 2010
Week 12 actual placebo 194 335.0 5.00 eszopiclone 194 367.0 5.00
Krystal 2003
Average of weeks 8-12
actual placebo 195 341.7 4.98 eszopiclone 593 378.2 2.90
Mayer 2009
average of last 2 nights of month
actual placebo 224a
344.9 4.16 ramelteon 227a 352.3 4.16
Walsh 2007
Average of 4 weeks in Month 3
actual placebo 280 347.6 4.47 eszopiclone 548 390.9 2.87
6 months
Arm-level Timepoint Statistic Group 1 N Mean se Group 2 N Mean se
Study 303 last 7 nights of month
Change placebo 242 51.4 4.60 lemborexant 455 71.9 3.33
Krystal 2003
Average of weeks 20-24
actual placebo 195 339.3 5.52 eszopiclone 593 378.3 2.97
Mayer 2009
average of last 2 nights of month
actual placebo 224a
349.5 4.35 ramelteon 227a 345.4 4.34
Randall 2012
average of 2 nights in month 8
actual placebo 47 390.0 9.63 zolpidem-IR 44 402.0 11.76
Walsh 2007
Average of 4 weeks in Month 6
actual placebo 280 346.8 4.63 eszopiclone 548 391.9 2.93
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The number of patients was not used directly in the NMA, but may have been used to estimate se. Where the number of patients for this outcome was not reported, the following imputation was done: a Baseline N was used. b N based on degrees of freedom using proportional split between groups. Medians were reported instead of mean for Ancoli-Israel 1999, Black 2017, Elie 1999, Fry 2000, Hedner 2000 and Rosenberg 1994, and the following imputation was done: c Method of Wan et al 2014 was used to impute mean and sd from median and range. d Mean was set to the median (asymptotic se was calculated from the confidence interval for Black 2017). If the se was not reported and was not able to be calculated from the standard deviation or confidence interval, the following imputation was done: e Calculated from p-value f Based on weighted average of standard deviation from Ancoli-Israel 2010, Krystal 2003, Mayer 2009, Randall 2012, Rickels 1986, Roth 2006a, Scharf 1994, Uchimura 2011, Uchiyama 2011, Voshaar 2004, Walsh 2007, Walsh 1998a, Walsh 2000, Zammit 2004, Zammit 2007. ER, extended release; N, number of patients; sd, standard deviation; se, standard error; TST, total sleep time.
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Supplementary Table 6. Results of individual studies, WASO (PSG) data (minutes)
4 weeks
Arm-level Timepoint Statistic Group 1 N Mean se Group 2 N Mean se
Study 201 Average of days 14-15
Change placebo 52 -38.2 4.70 lemborexant 68 -50.7 4.10
Study 304 Average of days 29-30
Change placebo 208 -21.4 2.46 lemborexant 535 -46.1 1.55
zolpidem-ER 263 -37.7 2.22
Herring 2016 - Trial 1
Month 1 Change placebo 272b -18.7 2.58 suvorexant 185b -45.0 3.14
Herring 2016 - Trial 2
Month 1 Change placebo 271b -22.5 2.58 suvorexant 133b -46.6 3.70
McCall 2006
2 weeks Change placebo 128a -12.5 3.17 eszopiclone 136a -25.3 3.46
Randall 2012
Average of 2 nights in month 1
Actual placebo 47c 78.1 6.70 zolpidem-IR 44c 58.2 6.20
Zammit 2004
Night 29 Actual placebo 99 54.5 4.77 eszopiclone 209 42.2 2.38
Zammit 2007
Average of nights 29-30
Actual placebo 131 56.4 3.11 ramelteon 139 59.9 3.04
Trial-level Timepoint Statistic Group 2 – Group 1 N Mean difference se difference
Black 2017 Average of nights 15-16
Change zolpidem-IR - placebo 345 3.5d 3.78d
Roth 2006b
Average of nights 15-16
Change zolpidem-ER – placebo 199 -16.0 3.72
Walsh 2008
Average of nights 15-16
Change zolpidem-ER – placebo 199 -11.5 3.98
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3 months
Arm-level Timepoint Statistic Group 1 N Mean se Group 2 N Mean se
Herring 2016 – Trial 1
Month 3 Change placebo 251b -25.0 2.68 suvorexant 172b -41.6 3.27
Herring 2016 – Trial 2
Month 3 Change placebo 255b -24.8 2.65 suvorexant 127b -56.0 3.75
6 months
Arm-level Timepoint Statistic Group 1 N Mean se Group 2 N Mean se
Randall 2012
Average of 2 nights in month 8
Actual placebo 47c 84.3 6.59 zolpidem-IR 44c 58.3 4.93
Notes: Roth 2006b and Walsh 2008 report 6 hour WASO. The number of patients was not used directly in the NMA, but may have been used to estimate se. Where the number of patients for this outcome was not reported, the following imputation was done: a Baseline N was used. b N for LPS was used as the authors reported N for all PSG outcomes were similar to LPS. c Completers N was used. Medians were reported instead of mean for Black 2017, and the following imputation was done: d Mean was set to the median and the asymptotic se was calculated from the 95% confidence interval. ER, extended release; IR, immediate release; N, number of patients; LPS, latency to persistent sleep; PSG, polysomnographic; se, standard error; WASO, wake time after sleep onset
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Supplementary Table 7. Results of individual studies, sWASO data (minutes)
4 weeks
Arm-level Timepoint Statistic Group 1 N Mean se Group 2 N Mean se
Study 201 Days 8-15 change placebo 56 -31.6 5.17 lemborexant 68 -49.7 4.73
Study 303 Last 7 nights of month
change placebo 297 -17.2 3.10 lemborexant 590 -23.4 2.17
Study 304 Last 7 nights of month
change placebo 208 -36.1 4.49 lemborexant 535 -52.1 2.84
zolpidem-ER 263 -62.0 4.06
Hajak 2009 Average of week 2
change placebo 85 -21.7 5.80 zolpidem-IR 93 -46.9 5.6
Herring 2016 - Trial 1
Average over last week of month 1
change placebo 365b -17.9 1.84 suvorexant 244b -23.3 2.24
Herring 2016 - Trial 2
Average over last week of month 1
change placebo 350b -20.8 1.89 suvorexant 219b -29.2 2.40
McCall 2006
2 weeks change placebo 128a -24.5 4.27 eszopiclone 136a -31.3 3.92
Roth 2006b
Nights 17-21 change placebo 110a -32.3 6.25 zolpidem-ER 102a -48.3 5.5
Scharf 2005
Second week change placebo 80 2.0 7.71 eszopiclone 151 -43.4 7.46
Soares 2006
Average of 4 weeks
change placebo 209a -16.0 2.96f eszopiclone 201a -30.9 3.02f
Walsh 2008
Average of week 3
change placebo 100 -14.3 4.42d zolpidem-ER 94 -29.1 4.56d
Ancoli-Israel 2010
Week 3 actual placebo 194 83.0 3.00 eszopiclone 194 65.0 3.00
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Dorsey 2004
Week 4 actual placebo 73 47.0 4.72 zolpidem-IR 68 29.0 5.30
Krystal 2003
Average of weeks 1-4
actual placebo 195 62.8 5.53 eszopiclone 593 47.4 3.19
Mayer 2009
Average of last 2 nights of month
actual placebo 224a 84.9 3.72 ramelteon 227a 90.8 3.71
Randall 2012
Average of 2 nights in month
actual placebo 47c 53.2 7.73 zolpidem-IR 44c 46.4 7.55
Rickels 1986g
1 week actual placebo 34 48.0 6.11e brotizolam 29 30.0 6.61e
Voshaar 2004
4 weeks actual zolpidem-IR
74 40.0 4.18 temazepam 85 39.0 4.12
Walsh 1998a
2 weeks actual placebo 103a 49.8 4.00 zolpidem-IR 100a 39.5 3.60
trazodone 98a 42.1 4.30
Walsh 2007
Average of 4 weeks
actual placebo 280 46.5 2.84 eszopiclone 548 29.4 1.48
Zammit 2004
Average of Nights 1,15,29,43 and 44
actual placebo 99 49.1 3.63 eszopiclone 209 47.3 3.05
Trial-level Timepoint Statistic Group 2 – Group 1 N Mean difference se difference
Black 2017 Average of Weeks 1 and 2
change zolpidem-IR - placebo 345 -12.7h 3.11h
3 months
Arm-level Timepoint Statistic Group 1 N Mean se Group 2 N Mean se
Study 303 Last 7 nights of month
change placebo 278 -26.8 3.32 lemborexant 529 -38.6 2.40
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Herring 2016 - Trial 1
Average over last 2 weeks of month 3
change placebo 339b -29.6 1.79 suvorexant 228b -32.0 2.19
Herring 2016 - Trial 2
Average over last 2 weeks of month 3
change placebo 325b -29.8 2.02 suvorexant 197b -37.5 2.58
Ancoli-Israel 2010
Week 12 actual placebo 194 73.0 4.00 eszopiclone 194 55 4
Krystal 2003
Average of weeks 8-12
actual placebo 195 56.1 4.81 eszopiclone 593 42.2 2.88
Mayer 2009
Average of last 2 nights of month 3
actual placebo 224a 80.7 3.54 ramelteon 227a 83.5 3.54
Walsh 2007
Average of 4 weeks in Month 3
actual placebo 280 43.3 2.58 eszopiclone 548 25.7 1.42
6 months
Arm-level Timepoint Statistic Group 1 N Mean se Group 2 N Mean se
Study 303 Last 7 nights of month
change placebo 248 -29.3 3.61 lemborexant 471 -44.4 2.60
Krystal 2003
Average of weeks 20-24
actual placebo 195 48.2 4.25 eszopiclone 593 44.2 3.05
Mayer 2009
Average of last 2 nights of month 6
actual placebo 224a 79.5 3.82 ramelteon 227a 90.9 3.80
Randall 2012
average of 2 nights in month 8
actual placebo 47c 59.6 7.64 zolpidem-IR 44c 52.3 8.79
Walsh 2007
Average of 4 weeks in month 6
actual placebo 280 38.6 2.49 eszopiclone 548 22.2 1.40
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The number of patients was not used directly in the NMA, but may have been used to estimate se. Where the number of patients for this outcome was not reported, the following imputation was done: a Baseline N was used. b N for sTST was used as the authors reported N for all diary outcomes were similar to N for sTST. c Completers N was used. If the se was not reported and was not able to be calculated from the standard deviation or confidence interval, the following imputation was done: d Calculated from F-statistic e Calculated from p-value f Based on weighted average of standard deviation from Hajak 2009, Herring 2016 (both trials), McCall 2006, Roth 2006b, Scharf 2005, Study 201, Study 304, Walsh 2008. Note, Study 303 was not used for imputation as the results of this trial were not available at the time. g Rickels 1986 reported sWASO based on physician survey rather than from patient sleep diary. However, the authors note results were similar as the physician based their responses on the diary. h Mean was set to the median and the asymptotic se derived from the confidence interval. ER, extended release; IR, immediate release; N, number of patients; se, standard error; sTST, subjective total sleep time; WASO, wake time after sleep onset
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Supplementary Table 8. Results of individual studies, LPS (PSG) data (minutes)
4 weeks
Arm-level Timepoint Statistic Group 1 N Mean se Group 2 N Mean se
Study 201 Average of days 14-15
Change placebo 52 -22.4 4.02 lemborexant 68 -53.8 5.26
Study 304 Average of days 29-30
Change placebo 200 -7.9 2.26 lemborexant 520 -20.5 1.44
zolpidem-ER 250 -7.5 2.22
Herring 2016 - Trial 1
Month 1 Change placebo 272 -23.3 1.84 suvorexant 185 -33.6 2.22
Herring 2016 - Trial 2
Month 1 Change placebo 271 -24.6 2.07 suvorexant 133 -32.5 2.96
McCall 2006
2 weeks Change placebo 128a -17.0 2.92 eszopiclone 136a -33.5 2.57
Ware 1997 Nights 27-28 Change placebo 35 -15.0 5.00 zolpidem-IR 34 -7.0 6.00
triazolam 30 0.0 5.00
Mayer 2009
average of last 2 nights of month
Actual placebo 224a 39.0 2.00 ramelteon 227a 31.0 2.00
Pinto 2016 Day 28 Actual zopiclone 97 15.7d 1.99d eszopiclone 102 10.6d 1.17d
Randall 2012
Average of 2 nights in month 1
Actual placebo 47c 30.8 3.14 zolpidem-IR 44c 12.7 1.33
Scharf 1994
Average of nights 29-30
Actual placebo 23 48.0 8.03 zolpidem-IR 22 25.8 2.92
Walsh 2000
Average of first 2 nights of week 4
Actual placebo 47 36.1 3.63 zaleplon 50 30.1 4.26
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Walsh 1998b
Average of nights 16-17
Actual placebo 34a 20.5e 4.93e zaleplon 67a 17.4e 3.66e
triazolam 31a 23.8e 5.38e
Wang-Weigand 2011
Night 21 Actual placebo 90b 38.9 4.76g ramelteon 82b 21.6 4.99g
Zammit 2004
Night 29 Actual placebo 99 30.2 2.83 eszopiclone 209 21.0 2.17
Zammit 2007
Average of nights 29-30
Actual placebo 131a 42.5 2.97 ramelteon 139a 31.5 2.91
Trial-level Timepoint Statistic Group 2 – Group 1 N Mean difference se difference
Black 2017 Average of nights 15-16
Change zolpidem-IR - placebo 345 -10.5f 3.4f
Roth 2006b
Average of nights 15-16
Change zolpidem-ER – placebo 199 -7.6 3.6
Walsh 2008
Average of nights 15-16
Change zolpidem-ER – placebo 199 -5.8 2.6
3 months
Arm-level Timepoint Statistic Group 1 N Mean se Group 2 N Mean se
Herring 2016 – Trial 1
Month 3 Change placebo 251 -26.6 1.86 suvorexant 172 -34.7 2.27
Herring 2016 – Trial 2
Month 3 Change placebo 255 -28.6 2.32 suvorexant 127 -28.9 3.32
Mayer 2009
Average of last 2 nights of month
Actual placebo 224a 37.0 2.00 ramelteon 227a 31.0 2.00
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6 months
Arm-level Timepoint Statistic Group 1 N Mean se Group 2 N Mean se
Mayer 2009
Average of last 2 nights of month
Actual placebo 224a 40.0 2.00 ramelteon 227a 31.0 2.00
Randall 2012
Average of 2 nights in month 8
Actual placebo 47c 29.8 3.92 zolpidem-IR 44c 14.2 1.84
The number of patients was not used directly in the NMA, but may have been used to estimate se. Where the number of patients for this outcome was not reported, the following imputation was done: a Baseline N was used. b N for sSL in the PSG subgroup was used. c Completers N was used. Medians were reported instead of mean for Black 2017, Pinto 2016 and Walsh 1998b, and the following imputation was done: d Method of Wan et al 2014 was used to impute mean and sd from median and interquartile range. e Mean was set to the median, and standard deviation was based on weighted average of standard deviation from Mayer 2009, Randall 2012, Scharf 1994, Walsh 2000, Wang-Weigand 2011, Ware 1997, Zammit 2004, Zammit 2007. f Mean was set to the median and the asymptotic se was calculated from the 95% confidence interval. If the se was not reported and was not able to be calculated from the standard deviation or confidence interval, the following imputation was done: g Calculated from p-value. ER, extended release; IR, immediate release; N, number of patients; LPS, latency to persistent sleep; PSG, polysomnographic; se, standard error
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Supplementary Table 9. Results of individual studies, sSOL data (minutes)
4 weeks
Arm-level Timepoint Statistic Group 1 N Mean se Group 2 N Mean se
Study 201 Days 8-15 Change placebo 56 -13.5 3.77 lemborexant 68 -26.8 3.70
Study 303 Last 7 nights of month
Change placebo 299 -10.5 1.67 lemborexant 595 -21.2 1.18
Study 304 Last 7 nights of month
Change placebo 196 -8.1 1.96 lemborexant 510 -25.0 1.52
zolpidem-ER 246 -17.0 1.96
Hajak 2009 Week 2 (average)
Change placebo 130 -22.3 3.30 zolpidem-IR 141 -53.1 3.20
Herring 2016 – Trial 1
Average over last week of month 1
Change placebo 365b -11.7 1.79 suvorexant 244b -17.1 2.17
Herring 2016 – Trial 2
Average over last week of month 1
Change placebo 350b -14.1 2.17 suvorexant 219b -21.0 2.76
Lahmeyer 1997
Week 4 (average)
Change placebo 54a -15.0 6.03f zolpidem-IR 45a -31.0 6.61f
Leppik 1997
Week 4 (average)
Change placebo 75 -21.4 4.60 zolpidem-IR 77 -39.7 4.70
triazolam 75 -39.4 5.00 temazepam 76 -39.4 4.70
McCall 2006
2 weeks Change placebo 128a -29.6 4.92 eszopiclone 136a -40.8 5.09
Roth 2006b
Nights 17-21 Change placebo 110a -27.8 4.50 zolpidem-ER 102a -28.8 4.00
Scharf 2005
2 weeks Change placebo 80 -52.6 16.77 eszopiclone 151 -60.6 11.92
Soares 2006
Average of 4 weeks
Change placebo 209a -10.1 3.07f eszopiclone 201a -25.8 3.13f
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Walsh 2008
Week 3 (average)
Change placebo 101 -21.6 3.04e zolpidem-ER 95 -26.3 3.13e
Ancoli-Israel 1999
2 weeks Actual placebo 107 56.0d 3.54g zaleplon 331 34.5d 2.01g
zolpidem-IR 111 41.0d 3.47g
Ancoli-Israel 2010
Week 3 Actual placebo 194 69.0 5.00 eszopiclone 194 55.0 4.00
Dorsey 2004
Week 4 Actual placebo 73 31.0 2.90 zolpidem-IR 68 29.0 2.64
Elie 1999 Week 4 (average)
Actual placebo 107b 36.5d 3.54g zaleplon 201b 30.7d 2.58g
zolpidem-IR 100b 36.5d 3.66g
Fry 2000 Week 4 Actual placebo 107 48.0d 3.54g zaleplon 203 40.5d 2.57g
zolpidem-IR 98 35.0d 3.70g
Hedner 2000
2 weeks Actual placebo 138a 50.0d 3.12 zaleplon 284a 38.5d 2.17
Krystal 2003
Average of weeks 1-4
Actual placebo 195 71.3 4.28 eszopiclone 593 44.3 1.50
Mayer 2009
Week 4 Actual placebo 224a 59.0 2.00 ramelteon 227a 49.0 2.00
Randall 2012
Average of 2 nights in month 1
Actual placebo 47c 43.2 6.55 zolpidem-IR 44c 21.5 2.32
Roth 2006a
Week 3 Actual placebo 274a 69.3 2.50 ramelteon 274a 60.3 2.50
Scharf 1994
4 weeks Actual placebo 23 69.2 11.51 zolpidem-IR 22 37.5 4.05
Uchimura 2011
Days 8-14 Actual placebo 380 57.9 1.30 ramelteon 378 57.5 1.30
Uchiyama 2011
Days 8-14 Actual placebo 478 59.5 1.04 ramelteon 478 57.1 1.04
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Voshaar 2004
4 weeks Actual zolpidem-IR
74a 46.0 3.84 temazepam 85a 46.0 3.69
Walsh 2007
Month 1 (average of 4 weeks)
Actual placebo 280 60.3 2.93 eszopiclone 548 39.9 1.58
Walsh 1998a
Week 2 Actual placebo 103 64.7 4.60 zolpidem-IR 100 48.1 3.10
trazodone 98 54.5 4.10
Walsh 2000
Week 4 Actual placebo 47 59.3 6.43 zaleplon 47 41.2 5.62
Wang-Weigand 2011
Night 21 Actual placebo 271 72.0 1.82e ramelteon 262 67.0 1.85e
Zammit 2004
Average of Nights 1,15,29,43 and 44
Actual placebo 99 58.4 4.31 eszopiclone 209 46.2 4.78
Zammit 2007
Week 5 Actual placebo 131a 61.5 3.70 ramelteon 139a 44.8 3.60
Trial-level Timepoint Statistic Group 2 – Group 1 N Mean difference se difference
Black 2017 Average of Weeks 1 and 2
change zolpidem-IR - placebo 345 -6.1d 2.40d
3 months
Arm-level Timepoint Statistic Group 1 N Mean se Group 2 N Mean se
Study 303 Last 7 nights of month
Change placebo 279 -13.3 1.94 lemborexant 532 -26.3 1.39
Herring 2016 – Trial 1
Average over last 2 weeks of month 3
Change placebo 339b -17.3 1.58 suvorexant 228b -22.5 1.94
Herring 2016 – Trial 2
Average over last 2 weeks of month 3
Change placebo 325b -20.5 2.24 suvorexant 197b -28.1 2.88
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Ancoli-Israel 2010
Week 12 Actual placebo 194 59.0 4.00 eszopiclone 194 47.0 4.00
Krystal 2003
Average of weeks 8-12
Actual placebo 195 63.2 4.09 eszopiclone 593 46.3 2.21
Mayer 2009
Week 12 Actual placebo 224a 57.0 2.00 ramelteon 227a 49.0 3.00
Walsh 2007
Month 3 (average of 4 weeks)
Actual placebo 280 59.9 3.19 eszopiclone 548 38.5 1.61
6 months
Arm-level Timepoint Statistic Group 1 N Mean se Group 2 N Mean se
Study 303 Last 7 nights of month
Change placebo 249 -16.3 1.91 lemborexant 474 -29.5 1.37
Krystal 2003
Average of weeks 20-24
Actual placebo 195 63.1 4.15 eszopiclone 593 47.0 2.08
Mayer 2009
Week 24 Actual placebo 224a 55.0 2.50 ramelteon 227a 49.0 2.00
Randall 2012
Average of 2 nights in month 8
Actual placebo 47c 36.5 5.11 zolpidem-IR 44c 27.3 4.73
Walsh 2007
Month 6 (average of 4 weeks)
Actual placebo 280 59.6 2.98 eszopiclone 548 38.1 1.49
The number of patients was not used directly in the NMA, but may have been used to estimate se. Where the number of patients for this outcome was not reported, the following imputation was done: a Baseline N was used. b N for sTST was used. c Completers N was used. Medians were reported instead of mean for Ancoli-Israel 1999, Black 2017, Elie 1999, Fry 2000, Hedner 2000, and the following imputation was done: d Mean was set to median and se imputed as below (for Black 2017 asymptotic se was calculated from confidence interval). If the se was not reported and was not able to be calculated from the standard deviation or confidence interval, the following imputation was done:
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e Calculated from p-value. f Based on weighted average of standard deviation of change from baseline, that is from Study 201, Study 304, Hajak 2009, Herring 2016 (both trials), Leppik 1997McCall 2006, Roth 2006b, Scharf 2005, Walsh 2008. g Based on weighted average of standard deviation of 4-week endpoint , that is from Ancoli-Israel 2010, Dorsey 2004, Krystal 2003, Mayer 2009, Randall 2012, Roth 2006a, Scharf 1994, Uchimura 2011, Uchiyama 2011, Voshaar 2004, Walsh 2007, Walsh 1998a, Walsh 2000, Wang-Weigand 2011, Zammit 2004, Zammit 2007 ER, extended release; IR, immediate release; N, number of patients; se, standard error; sSOL, subjective sleep onset latency; sTST, subjective total sleep time.
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Supplementary Table 10. Results of individual studies, SE (PSG) data (%)
4 weeks
Arm-level Timepoint Statistic Group 1 N Mean se Group 2 N Mean se
Study 201 Average of days 14-15
Change placebo 52 14.1 1.00 lemborexant 68 20.8 1.0
Study 304 Average of days 29-30
Change placebo 208 6.3 0.60 lemborexant 535 13.9 0.38
zolpidem-ER 263 9.5 0.55
McCall 2006
2 weeks Change placebo 128a 5.8 0.80 eszopiclone 136a 11.7 0.8
Ware 1997 Nights 27-28 Change placebo 35 5.0 2.00 zolpidem-IR 34 1.0 2.00
triazolam 30 3.0 1.00
Pinto 2016 Day 28 Actual zopiclone 97 86.3c 0.79c eszopiclone 102 89.1c 0.66c
Randall 2012
Average of 2 nights in month 1
Actual placebo 47b 79.8 1.43 zolpidem-IR 44b 86.3 1.25
Scharf 1994
Average of nights 29-30
Actual placebo 23 80.7 2.79 zolpidem-IR 22 87.9 1.36
Zammit 2004
Night 29 Actual placebo 99 82.9 1.18 eszopiclone 209 87.3 0.6
Zammit 2007
Average of nights 29-30
Actual placebo 131a 80.4 0.86 ramelteon 139a 81.8 0.84
Trial-level Timepoint Statistic Group 2 – Group 1 N Mean difference se difference
Roth 2006b
Average of nights 15-16
Change zolpidem-ER – placebo 199 3.0 1.3
Walsh 2008
Average of nights 15-16
Change zolpidem-ER – placebo 199 2.3 1.2
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6 months
Arm-level Timepoint Statistic Group 1 N Mean se Group 2 N Mean se
Randall 2012
Average of 2 nights in month 8
Actual placebo 47b 78.9 1.52 zolpidem-IR 44b 85.7 0.98
The number of patients was not used directly in the NMA, but may have been used to estimate se. Where the number of patients for this outcome was not reported, the following imputation was done: a Baseline N was used. b Completers N was used. c Medians and interquartile range were reported (but not mean or standard deviation) and Wan method was used for imputation. ER, extended release; IR, immediate release; N, number of patients; PSG, polysomnographic; se, standard error; SE, sleep efficiency
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Supplementary Table 11. Results of individual studies, sSE data (%)
Arm-level Timepoint Statistic Group 1 N Mean se Group 2 N Mean se
4 weeks
Study 201 Average of days 8-15
Change placebo 56 9.2 1.41 lemborexant 68 16.6 1.29
Study 303 Average of last 7 nights of month
Change placebo 291 5.5 0.73 lemborexant 566 8.5 0.53
Study 304 Average of last 7 nights of month
Change placebo 208 8.7 1.06 lemborexant 535 14.6 0.68
zolpidem-ER 263 14.8 0.97
3 months
Study 303 Average of last 7 nights of month
Change placebo 269 8.6 0.80 lemborexant 507 12.9 0.56
6 months
Study 303 Average of last 7 nights of month
Change placebo 242 9.6 0.84 lemborexant 455 14.2 0.61
ER, extended release; N, number of patients; se, standard error; sSE, subjective sleep efficiency
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Supplementary Table 12. Results of individual studies, ISI total score data (scale: 0 to 28 where lower score reflects lower severity)
Arm-level Timepoint Statistic Group 1 N Mean se Group 2 N Mean se
4 weeks
Study 201 Day 15 change placebo 52 -3.4 0.68 lemborexant 67 -5.1 0.59
Study 303 Month 1 change placebo 296 -5.2 0.30 lemborexant 586 -7.1 0.25
Study 304 Day 31 change placebo 208 -5.6 0.42 lemborexant 535 -7.6 0.27
zolpidem-ER 263 -7.9 0.38
Herring 2016 – Trial 1
month 1 change placebo 360b -2.9 0.23 suvorexant 241b -4.0 0.26
Herring 2016 – Trial 2
month 1 change placebo 347b -3.2 0.23 suvorexant 213b -4.8 0.31
McCall 2006
Night 14 (Day 15)
change placebo 128a -3.8 0.47 eszopiclone 136a -5.8 0.43
Ancoli-Israel 2010
3 weeks actual placebo 194 13.5 0.50 eszopiclone 194 11.0 0.50
Pinto 2016 ~ Day 28 actual zopiclone 97 7.8 0.54 eszopiclone 102 7.4 0.49
Soares 2006
4 weeks actual placebo 209 11.0 0.63c eszopiclone 201 8.0 0.65c
Walsh 2007
1 month clinic visit
actual placebo 280 13.8 0.32 eszopiclone 548 9.2 0.24
3 months
Study 303 Month 3 change placebo 283 -6.1 0.33 lemborexant 533 -8.7 0.27
Herring 2016 – Trial 1
Month 3 change placebo 339 -4.6 0.26 suvorexant 228 -5.7 0.31
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Arm-level Timepoint Statistic Group 1 N Mean se Group 2 N Mean se
Herring 2016 – Trial 2
Month 3 change placebo 320b -5.3 0.28 suvorexant 197b -6.6 0.36
Ancoli-Israel 2010
12 weeks actual placebo 194b 12.0 0.60 eszopiclone 194b 10.0 0.70
Walsh 2007
3 month clinic visit
actual placebo 280 13.1 0.32 eszopiclone 548 8.6 0.25
6 months
Study 303 Month 6 change placebo 257 -7.2 0.36 lemborexant 492 -9.9 0.29
Walsh 2007
6 month clinic visit
actual placebo 280 12.9 0.34 eszopiclone 548 8.3 0.26
ER, extended release; ISI, Insomnia Severity Index; N, number of patients; NMA, network meta-analysis; PGI-S, patient global impression – severity; se, standard error
The number of patients was not used directly in the NMA, but may have been used to estimate se. Where the number of patients for this outcome was not reported, the following imputation was done: a Baseline N was used. b N for PGI-S was used as the authors reported N for all rating scales were similar. c se was estimated from the p-value.
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Supplementary Table 13. Results of individual studies, quality of sleep transformed into 1 (poor) to 10 (excellent) scale
4 weeks
Arm-level Timepoint Statistic Group 1 N Mean se Group 2 N Mean se
Study 303 Last 7 nights of month
Change placebo 300 0.6 0.08 lemborexant 595 0.8 0.06
Study 304 Last 7 nights of month
Change placebo 208 1.0 0.13 lemborexant 535 1.6 0.08
zolpidem-ER 263 1.7 0.11
Hajak 2009 Week 2 (average) Change placebo 128 0.8 0.11 zolpidem-IR 140 1.6 0.11
Herring 2016 - Trial 1
Average over last week of month 1
Change placebo 110 0.6 0.08 suvorexant 102 0.9 0.15
Herring 2016 - Trial 2
Average over last week of month 1
Change placebo 209 0.6 0.08 suvorexant 201 1.2 0.08
Roth 2006b Nights 17-21 Change placebo 110 1.8 0.30 zolpidem-ER 102 2.7 0.30
Scharf 2005 Week 2 Change placebo 80 1.1 0.27 eszopiclone 151 1.9 0.19
Walsh 2008 Week 3 (average) Change placebo 103 1.3 0.15 zolpidem-ER 96 1.6 0.15
Ancoli-Israel 1999
Week 2 Actual placebo 101 5.5 0.16 zaleplon 325 6.0 0.09
zolpidem-IR 110 6.3 0.15
Dehlin 1995b
Week 2 Actual zopiclone 50 6.8 0.27 flunitrazepam 52 7.2 0.25
Elie 1999 Week 4 (average) Actual placebo 107 5.8 0.16 zaleplon 202 5.9 0.12
zolpidem-IR 100 6.4 0.17
Fry 2000 Week 4 Actual placebo 107 6.4 0.15 zaleplon 203 6.3 0.11
zolpidem-IR 98 6.8 0.16
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Hedner 2000
Week 2 Actual placebo 136 5.8 0.10 zaleplon 268 6.0 0.06
Krystal 2003 Average of weeks 1-4
Actual placebo 195 5.5 0.11 eszopiclone 593 6.6 0.07
Lahmeyer 1997
Week 4 (average) Actual placebo 54 5.2 0.33 zolpidem-IR 45 5.8 0.30
Mayer 2009 Average of last 2 nights of month
Actual placebo 224 5.2 0.10 ramelteon 227 5.2 0.10
McCall 2006 2 weeks Actual placebo 128 6.7 0.14 eszopiclone 136 7.3 0.14
Randall 2012
average of 2 nights in month 1
Actual placebo 47 4.8 0.26 zolpidem-IR 44 5.9 0.32
Rosenberg 1994
14 days Actual zolpidem-IR
71 6.6 0.19 triazolam 68 6.7 0.19
Scharf 1990 Days 1-2,3-5,7 Actual placebo 76 5.6 0.20 estazolam 72 6.6 0.25
Scharf 1994 Week 4 Actual placebo 23 4.9 0.31 zolpidem-IR 22 5.2 0.38
Walsh 1984 Average of 7 days Actual placebo 124 5.7 0.16 estazolam 243 6.5 0.11
Walsh 2007 Average of 4 weeks
Actual placebo 280 6.0 0.09 eszopiclone 548 7.1 0.07
Walsh 1998a
Week 2 Actual placebo 103 5.3 0.18 zolpidem-IR 100 5.7 0.15
trazodone 98 5.7 0.21
Zammit 2004
Average of nights 1,15,29,43 and 44
Actual placebo 99 5.4 0.16 eszopiclone 209 5.9 0.11
Zammit 2007
Week 5 Actual placebo 131 6.0 0.09 ramelteon 139 6.1 0.09
Trial-level Timepoint Statistic Group 2 – Group 1 N Mean difference se difference
Black 2017 Average of Days 15-16
Change zolpidem-IR - placebo 343 1.0 0.34
Uchiyama 2011
Days 8-14 Actual ramelteon – placebo 971 0.1 0.07
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3 months
Arm-level Timepoint Statistic Group 1 N Mean se Group 2 N Mean se
Study 303 Last 7 nights of month
Change placebo 280 0.9 0.09 lemborexant 532 1.1 0.07
Herring 2016 - Trial 1
Average over last 2 weeks of month 3
Change placebo 80 0.9 0.08 suvorexant 151 1.2 0.08
Herring 2016 - Trial 2
Average over last 2 weeks of month 3
Change placebo 208 1.2 0.08 suvorexant 535 1.5 0.15
Krystal 2003 Average of weeks 8-12
Actual placebo 195 5.8 0.11 eszopiclone 593 6.8 0.06
Mayer 2009 Average of last 2 nights of month
Actual placebo 224 5.4 0.10 ramelteon 227 5.4 0.10
Walsh 2007 Month 3 (average of 4 weeks)
Actual placebo 280 6.2 0.09 eszopiclone 548 7.2 0.07
6 months
Arm-level Timepoint Statistic Group 1 N Mean se Group 2 N Mean se
Study 303 Last 7 nights of month
Change placebo 249 1.1 0.11 lemborexant 474 1.5 0.08
Krystal 2003 Average of weeks 20-24
Actual placebo 195 6.0 0.12 eszopiclone 593 6.8 0.07
Mayer 2009 Average of last 2 nights of month
Actual placebo 224 5.5 0.10 ramelteon 227 5.5 0.10
Randall 2012
Average of 2 nights in month 8
Actual placebo 47 5.1 0.26 zolpidem-IR 44 5.2 0.32
Walsh 2007 Month 6 (average of 4 weeks)
Actual placebo 280 6.2 0.10 eszopiclone 548 7.3 0.07
If the se was not reported and was not able to be calculated from the standard deviation or confidence interval, the following imputation was done:
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a Based on weighted average of standard deviation the transformed 4-week endpoint, that is from Dehlin 1995, Elie 1999, Hedner 2000, Krystal 2003, Lahmeyer 1997, Mayer 2009, Rosenberg 1994, Scharf 1990, Scharf 1994, Uchiyama 2011, Walsh 1984, Walsh 2007, Walsh 1998a, Zammit 2004, Zammit 2007. b Dehlin 1995 was subsequently excluded from the network as zopiclone and flunitrazepam were not included in any other studies, so were disconnected from the network. ER, extended release; IR, immediate release; N, number of patients; se, standard error
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Supplementary Table 14. Differences in TST (PSG) across the network (minutes) at 4 weeks: random effects
placebo lemborexant zolpidem-IR zolpidem-ER zopiclone eszopiclone zaleplon triazolam ramelteon
placebo 38.1
(16.3, 60.7) 17.2
(-2.8, 42.1) 15.5
(-12.3, 42.9) 14.0
(-29.3, 54.4) 28.1
(-2.3, 56.7) 7.0
(-16.5, 30.0) 16.1
(-16.9, 48.1) 6.4
(-14.9, 27.6)
lemborexant -38.1
(-60.7, -16.3) -21.1
(-50.2, 13.0) -22.6
(-51.0, 4.6) -24.2
(-73.1, 21.7) -10.0
(-48.2, 25.6) -31.1
(-63.9, 0.5) -22.1
(-62.1, 16.4) -31.7
(-62.8, -1.3)
zolpidem-IR -17.2
(-42.1, 2.8) 21.1
(-13.0, 50.2) -1.6
(-40.0, 31.0) -3.2
(-54.6, 40.6) 11.1
(-29.6, 44.5) -10.2
(-45.3, 19.5) -1.3
(-43.4, 35.6) -10.7
(-44.3, 17.5)
zolpidem-ER -15.5
(-42.9, 12.3) 22.6
(-4.6, 51.0) 1.6
(-31.0, 40.0) -1.5
(-52.7, 47.3) 12.7
(-28.6, 52.3) -8.4
(-44.7, 27.5) 0.6
(-42.3, 42.7) -9.1
(-43.7, 25.8)
zopiclone -14.0
(-54.4, 29.3) 24.2
(-21.7, 73.1) 3.2
(-40.6, 54.6) 1.5
(-47.3, 52.7) 14.2
(-16.3, 45.1) -6.9
(-53.6, 42.0) 2.2
(-50.0, 55.6) -7.6
(-52.9, 40.6)
eszopiclone -28.1
(-56.7, 2.3) 10.0
(-25.6, 48.2) -11.1
(-44.5, 29.6) -12.7
(-52.3, 28.6) -14.2
(-45.1, 16.3) -21.1
(-57.7, 17.2) -12.0
(-55.4, 32.1) -21.7
(-57.2, 15.4)
zaleplon -7.0
(-30.0, 16.5) 31.1
(-0.5, 63.9) 10.2
(-19.5, 45.3) 8.4
(-27.5, 44.7) 6.9
(-42.0, 53.6) 21.1
(-17.2, 57.7) 9.1
(-23.3, 40.7) -0.7
(-31.7, 31.0)
triazolam -16.1
(-48.1, 16.9) 22.1
(-16.4, 62.1) 1.3
(-35.6, 43.4) -0.6
(-42.7, 42.3) -2.2
(-55.6, 50.0) 12.0
(-32.1, 55.4) -9.1
(-40.7, 23.3) -9.7
(-47.9, 29.6)
ramelteon -6.4
(-27.6, 14.9) 31.7
(1.3, 62.8) 10.7
(-17.5, 44.3) 9.1
(-25.8, 43.7) 7.6
(-40.6, 52.9) 21.7
(-15.4, 57.2) 0.7
(-31.0, 31.7) 9.7
(-29.6, 47.9)
Notes: data are posterior median difference (95% credible interval) and are presented as column treatment versus row treatment. Thus, a positive mean difference indicates longer sleep time with column treatment compared with row treatment
ER, extended release; IR, immediate release; PSG, polysomnographic; TST, total sleep time
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Supplementary Table 15. Differences in WASO (PSG) across the network (minutes) at 4 weeks: random effects
placebo lemborexant suvorexant zolpidem-IR zolpidem-ER eszopiclone ramelteon
placebo -21.3
(-29.6, -10.1) -25.3
(-35.2, -15.0) -1.6
(-15.8, 8.0) -14.0
(-21.6, -5.9) -12.5
(-23.2, -1.8) 3.5
(-10.8, 18.0)
lemborexant 21.3 (10.1, 29.6)
-4.1 (-19.4, 8.7)
19.6 (0.3, 31.9)
7.2 (-4.6, 16.8)
8.7 (-7.1, 21.8)
24.8 (6.0, 40.8)
suvorexant 25.3 (15.0, 35.2)
4.1 (-8.7, 19.4)
23.8 (5.5, 36.8)
11.3 (-1.4, 24.2)
12.8 (-2.0, 27.4)
28.8 (11.2, 46.3)
zolpidem-IR 1.6 (-8.0, 15.8)
-19.6 (-31.9, -0.3)
-23.8 (-36.8, -5.5)
-12.4 (-24.1, 4.5)
-10.9 (-24.7, 7.4)
5.1 (-11.2, 26.2)
zolpidem-ER 14.0 (5.9, 21.6)
-7.2 (-16.8, 4.6)
-11.3 (-24.2, 1.4)
12.4 (-4.5, 24.1)
1.5 (-12.0, 14.5)
17.6 (1.0, 33.7)
eszopiclone 12.5 (1.8, 23.2)
-8.7 (-21.8, 7.1)
-12.8 (-27.4, 2.0)
10.9 (-7.4, 24.7)
-1.5 (-14.5, 12.0)
16.1 (-1.8, 34.0)
ramelteon -3.5 (-18.0, 10.8)
-24.8 (-40.8, -6.0)
-28.8 (-46.3, -11.2)
-5.1 (-26.2, 11.2)
-17.6 (-33.7, -1.0)
-16.1 (-34.0, 1.8)
Notes: data are posterior median difference (95% credible interval) and are presented as column treatment versus row treatment. Thus, a negative mean difference indicates shorter wake time with column treatment compared with row treatment
ER, extended release; IR, immediate release; PSG, polysomnographic; WASO, wake time after sleep onset
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Supplementary Table 16. Differences in LPS (PSG) across the network (minutes) at 4 weeks: random effects
placebo lemborex
ant suvorexa
nt zolpidem-
IR zolpidem-
ER zopiclone eszopiclo
ne zaleplon triazolam ramelteon
placebo -18.6
(-29.0,-10.9) -9.2
(-17.8, -0.5) -12.4
(-19.1, -4.7) -5.2
(-12.3, 1.5) -7.5
(-22.2, 7.1) -12.6
(-21.7, -3.7) -4.2
(-14.7, 6.6) 4.5
(-7.0, 15.9) -10.6
(-18.9, -3.2)
lemborexant
18.6 (10.9, 29.0)
9.4 (-1.8, 23.4)
6.3 (-3.8, 19.7)
13.4 (4.9, 24.4)
11.1 (-4.8, 29.6)
6.0 (-5.6, 20.1)
14.5 (1.6, 29.7)
23.2 (9.6, 38.8)
8.0 (-3.0, 20.7)
suvorexant
9.2 (0.5, 17.8)
-9.4 (-23.4, 1.8)
-3.1 (-14.0, 8.6)
4.1 (-7.4, 14.8)
1.7 (-15.5,18.6)
-3.4 (-16.1, 8.9)
5.1 (-8.6, 18.8)
13.7 (-0.8, 27.9)
-1.4 (-13.7, 9.7)
zolpidem-IR
12.4 (4.7, 19.1)
-6.3 (-19.7, 3.8)
3.1 (-8.6, 14.0)
7.2 (-3.5, 16.5)
4.9 (-12.1,20.6)
-0.2 (-12.4,10.7)
8.1 (-4.6, 20.5)
16.8 (3.9, 29.1)
1.8 (-9.9, 11.5)
zolpidem-ER
5.2 (-1.5, 12.3)
-13.4 (-24.4, -4.9)
-4.1 (-14.8, 7.4)
-7.2 (-16.5, 3.5)
-2.3 (-18.3,14.1)
-7.4 (-18.6, 4.0)
1.0 (-11.3,14.0)
9.7 (-3.5, 23.1)
-5.4 (-16.1, 4.7)
zopiclone
7.5 (-7.1, 22.2)
-11.1 (-29.6, 4.8)
-1.7 (-18.6,15.5)
-4.9 (-20.6,12.1)
2.3 (-14.1,18.3)
-5.1 (-16.7, 6.4)
3.3 (-14.4,21.6)
12.0 (-6.4, 30.4)
-3.0 (-20.2,13.1)
eszopiclone
12.6 (3.7, 21.7)
-6.0 (-20.1, 5.6)
3.4 (-8.9, 16.1)
0.2 (-10.7, 12.4)
7.4 (-4.0, 18.6)
5.1 (-6.4, 16.7)
8.4 (-5.3, 22.5)
17.1 (2.7, 31.7)
2.1 (-10.3, 13.5)
zaleplon 4.2
(-6.6, 14.7) -14.5
(-29.7, -1.6) -5.1
(-18.8, 8.6) -8.1
(-20.5, 4.6) -1.0
(-14.0,11.3) -3.3
(-21.6,14.4) -8.4
(-22.5, 5.3) 8.6
(-4.7, 21.8) -6.4
(-20.1, 6.2)
triazolam
-4.5 (-15.9, 7.0)
-23.2 (-38.8, -9.6)
-13.7 (-27.9, 0.8)
-16.8 (-29.1, -3.9)
-9.7 (-23.1, 3.5)
-12.0 (-30.4, 6.4)
-17.1 (-31.7, -2.7)
-8.6 (-21.8, 4.7)
-15.1 (-29.3, -1.7)
ramelteon
10.6 (3.2, 18.9)
-8.0 (-20.7, 3.0)
1.4 (-9.7, 13.7)
-1.8 (-11.5, 9.9)
5.4 (-4.7, 16.1)
3.0 (-13.1,20.2)
-2.1 (-13.5,10.3)
6.4 (-6.2, 20.1)
15.1 (1.7, 29.3)
Notes: data are posterior median difference (95% credible interval) and are presented as column treatment versus row treatment. Thus, a negative mean difference indicates shorter sleep onset with column treatment than row treatment
ER, extended release; IR, immediate release; LPS, latency to persistent sleep; PSG, polysomnographic
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Supplementary Table 17. Differences in SE (PSG) across the network (%) at 4 weeks: random effects
placebo lemborexant zolpidem-IR zolpidem-ER zopiclone eszopiclone triazolam ramelteon
placebo
7.2 (3.4, 10.8)
3.8 (-0.4, 7.5)
2.6 (-1.2, 6.5)
2.8 (-1.2, 6.7)
5.4 (1.8, 8.7)
1.9 (-3.9, 7.6)
1.4 (-4.1, 6.9)
lemborexant -7.2
(-10.8, -3.4)
-3.3 (-9.0, 1.8)
-4.6 (-9.8, 0.9)
-4.4 (-8.8, 0.1)
-1.8 (-6.5, 2.9)
-5.3 (-12.1, 1.4)
-5.8 (-12.3, 0.9)
zolpidem-IR -3.8
(-7.5, 0.4) 3.3
(-1.8, 9.0)
-1.2 (-6.4, 4.7)
-1.1 (-6.3, 4.8)
1.5 (-3.4, 7.0)
-1.9 (-7.5, 3.9)
-2.4 (-8.9, 4.6)
zolpidem-ER -2.6
(-6.5, 1.2) 4.6
(-0.9, 9.8) 1.2
(-4.7, 6.4)
0.2 (-5.5, 5.7)
2.7 (-2.6, 7.9)
-0.7 (-7.8, 6.0)
-1.2 (-8.0, 5.4)
zopiclone -2.8
(-6.7, 1.2) 4.4
(-0.1, 8.8) 1.1
(-4.8, 6.3) -0.2
(-5.7, 5.5)
2.6 (-1.6, 6.7)
-0.9 (-8.0, 5.9)
-1.4 (-8.1, 5.4)
eszopiclone -5.4
(-8.7, -1.8) 1.8
(-2.9, 6.5) -1.5
(-7.0, 3.4) -2.7
(-7.9, 2.6) -2.6
(-6.7, 1.6)
-3.4 (-10.2, 3.1)
-4.0 (-10.4, 2.6)
triazolam -1.9
(-7.6, 3.9) 5.3
(-1.4, 12.1) 1.9
(-3.9, 7.5) 0.7
(-6.0, 7.8) 0.9
(-5.9, 8.0) 3.4
(-3.1, 10.2)
-0.5 (-8.3, 7.5)
ramelteon -1.4
(-6.9, 4.1) 5.8
(-0.9, 12.3) 2.4
(-4.6, 8.9) 1.2
(-5.4, 8.0) 1.4
(-5.4, 8.1) 4.0
(-2.6, 10.4) 0.5
(-7.5, 8.3)
Notes: data are posterior median difference (95% credible interval) and are presented as column treatment versus row treatment. Thus, a positive mean difference indicates better sleep efficiency with column treatment compared with row treatment
ER, extended release; IR, immediate release; PSG, polysomnographic; SE, sleep efficiency
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Supplementary Table 18. Comparison of lemborexant with other treatments: efficacy results at 3 and 6 months
Lemborexant 3 months 6 months
vs
Comparator sTST, min sWASO,
min sSOL, min ISI (scale 0-28)
sQUAL (scale 1-10) sTST, min sWASO,
min sSOL, min ISI (scale 0-28)
sQUAL (scale 1-10)
placebo 19.6 (9.2, 30.0)
-11.9 (-19.9, -3.8)
-13.0 (-17.7, -8.3)
-2.6 (-3.4, -1.8)
0.2 (0.0, 0.4)
20.5 (9.4, 31.6)
-15.1 (-23.8, -6.4)
-13.2 (-17.8, -8.6)
-2.7 (-3.6, -1.8)
0.4 (0.1, 0.7)
suvorexant 4.2 (-8.2, 16.6)
-7.2 (-16.2, 1.9)
-7.1 (-13.2, -0.9)
-1.4 (-2.4, -0.4)
-0.1 (-0.4, 0.2) NA NA NA NA NA
zolpidem-IR NA NA NA NA NA 5.3 (-26.2,36.7)
-8.3 (-32.5,16.0)
-4.2 (-18.5,10.2) NA 0.3
(-0.6, 1.2)
zolpidem-ER NA NA NA NA NA NA NA NA NA NA
zopiclone NA NA NA NA NA NA NA NA NA NA
eszopiclone -19.4 (-31.7, -7.1)
5.1 (-4.1, 14.3)
5.1 (-1.7, 11.9)
1.5 (0.4, 2.6)
-0.8 (-1.1, -0.5)
-22.7 (-36.6, -9.0)
-1.6 (-11.7, 8.4)
6.4 (-0.7, 13.4)
1.9 (0.7, 3.1)
-0.6 (-0.9, -0.2)
zaleplon NA NA NA NA NA NA NA NA NA NA
trazodone NA NA NA NA NA NA NA NA NA NA
flunitrazepam NA NA NA NA NA NA NA NA NA NA
estazolam NA NA NA NA NA NA NA NA NA NA
triazolam NA NA NA NA NA NA NA NA NA NA
temazepam NA NA NA NA NA NA NA NA NA NA
brotizolam NA NA NA NA NA NA NA NA NA NA
ramelteon 11.6 (-3.9, 27.2)
-14.8 (-27.4, -2.0)
-5.1 (-13.5, 3.4) NA 0.2
(-0.2, 0.6) 24.0
(7.6, 40.3) -26.6
(-40.3,-13.0) -7.3
(-15.0, 0.5) NA 0.4 (0.0, 0.8)
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Lemborexant 3 months 6 months
vs
Comparator sTST, min sWASO,
min sSOL, min ISI (scale 0-28)
sQUAL (scale 1-10) sTST, min sWASO,
min sSOL, min ISI (scale 0-28)
sQUAL (scale 1-10)
Number of studies 7 7 7 5 6 5 5 5 2 5
Number of treatments 5 5 5 4 5 5 5 5 3 5
Number of participants 4,320 4,351 4,355 3,116 3,853 2,885 2,877 2,881 1,577 2,881
Notes: Data is mean difference between lemborexant and each comparator reported as median (95% CrI) from fixed effects NMA. sQUAL is reported on scale from 1 to 10 where higher score indicates better quality of sleep. ISI is measured on scale from 0 to 28 where lower scores indicate lower severity. Thus, for sTST and sQUAL positive differences indicate lemborexant performs better; and for sWASO, sSOL and ISI negative difference indicates lemborexant performs better. Statistically significant differences (95% CrI excluding 0) are highlighted in bold font.
ER, extended release; CrI, credible interval; IR, immediate release; ISI, Insomnia Severity Index; min, minutes; NA, not available; sQUAL, subjective quality of sleep; sSOL, subjective sleep onset latency, sTST, subjective total sleep time; sWASO, subjective wake time after sleep onset
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Supplementary Table 19. Differences in sTST across the network (minutes) at 4 weeks: random effects
placebo lemborex
ant suvorexa
nt zolpidem
-IR zolpidem
-ER eszopiclo
ne zaleplon trazodon
e triazolam temazepa
m brotizola
m ramelteo
n
placebo
22.5 (12.6, 32.7)
18.5 (8.9, 28.2)
27.9 (22.0, 34.0)
24.7 (13.8, 35.6)
34.9 (27.9, 41.3)
9.6 (1.8, 17.8)
19.7 (2.3, 37.3)
26.2 (12.2, 40.5)
12.1 (-3.5, 27.5)
58.3 (18.3, 97.8)
7.1 (1.0, 13.7)
lemborexant
-22.5 (-32.7, -12.6)
-4.0 (-18.1,
9.8)
5.3 (-6.3, 17.2)
2.1 (-10.3, 14.6)
12.3 (-0.2, 24.3)
-13.0 (-25.6,
0.0)
-2.9 (-23.0, 17.4)
3.7 (-13.6, 21.2)
-10.5 (-29.2,
7.9)
35.7 (-5.7, 76.4)
-15.4 (-27.3, -3.6)
suvorexant
-18.5 (-28.2, -8.9)
4.0 (-9.8, 18.1)
9.4 (-1.8, 20.9)
6.2 (-8.3, 20.7)
16.4 (4.2, 27.7)
-8.9 (-21.3,
3.9)
1.3 (-18.8, 21.3)
7.7 (-9.3, 25.0)
-6.4 (-24.7, 11.8)
39.7 (-1.4, 80.5)
-11.4 (-22.8,
0.3)
zolpidem-IR
-27.9 (-34.0, -22.0)
-5.3 (-17.2,
6.3)
-9.4 (-20.9,
1.8)
-3.2 (-15.7,
9.1)
7.0 (-2.4, 15.7)
-18.3 (-26.6, -9.8)
-8.2 (-25.8,
9.4)
-1.7 (-15.0, 11.7)
-15.8 (-30.9, -0.9)
30.4 (-10.1, 70.4)
-20.8 (-29.4, -12.1)
zolpidem-ER
-24.7 (-35.6, -13.8)
-2.1 (-14.6, 10.3)
-6.2 (-20.7,
8.3)
3.2 (-9.1, 15.7)
10.2 (-2.9, 22.8)
-15.1 (-28.3, -1.5)
-5.0 (-25.5, 15.7)
1.6 (-16.2, 19.5)
-12.6 (-31.6,
6.3)
33.6 (-7.9, 74.6)
-17.5 (-30.0, -4.9)
eszopiclone
-34.9 (-41.3, -27.9)
-12.3 (-24.3,
0.2)
-16.4 (-27.7, -4.2)
-7.0 (-15.7,
2.4)
-10.2 (-22.8,
2.9)
-25.3 (-35.3, -14.3)
-15.1 (-33.6,
3.8)
-8.6 (-24.0,
7.4)
-22.8 (-39.6, -5.8)
23.4 (-17.0, 63.6)
-27.8 (-36.5, -17.9)
zaleplon
-9.6 (-17.8, -1.8)
13.0 (0.0, 25.6)
8.9 (-3.9, 21.3)
18.3 (9.8, 26.6)
15.1 (1.5, 28.3)
25.3 (14.3, 35.3)
10.2 (-8.9, 28.9)
16.7 (1.1, 32.1)
2.5 (-14.5, 19.1)
48.6 (7.7, 88.9)
-2.5 (-12.7,
7.6)
trazodone
-19.7 (-37.3, -2.3)
2.9 (-17.4, 23.0)
-1.3 (-21.3, 18.8)
8.2 (-9.4, 25.8)
5.0 (-15.7, 25.5)
15.1 (-3.8, 33.6)
-10.2 (-28.9,
8.9)
6.5 (-15.3, 28.5)
-7.7 (-30.7, 15.3)
38.4 (-5.2, 81.8)
-12.6 (-31.1,
6.1)
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placebo lemborex
ant suvorexa
nt zolpidem
-IR zolpidem
-ER eszopiclo
ne zaleplon trazodon
e triazolam temazepa
m brotizola
m ramelteo
n
triazolam
-26.2 (-40.5, -12.2)
-3.7 (-21.2, 13.6)
-7.7 (-25.0,
9.3)
1.7 (-11.7, 15.0)
-1.6 (-19.5, 16.2)
8.6 (-7.4, 24.0)
-16.7 (-32.1, -1.1)
-6.5 (-28.5, 15.3)
-14.2 (-31.7,
3.2)
32.0 (-10.5, 74.1)
-19.1 (-34.6, -3.7)
temazepam
-12.1 (-27.5,
3.5)
10.5 (-7.9, 29.2)
6.4 (-11.8, 24.7)
15.8 (0.9, 30.9)
12.6 (-6.3, 31.6)
22.8 (5.8, 39.6)
-2.5 (-19.1, 14.5)
7.7 (-15.3, 30.7)
14.2 (-3.2, 31.7)
46.2 (3.0, 89.1)
-5.0 (-21.6, 12.0)
brotizolam
-58.3 (-97.8, -18.3)
-35.7 (-76.4,
5.7)
-39.7 (-80.5,
1.4)
-30.4 (-70.4, 10.1)
-33.6 (-74.6,
7.9)
-23.4 (-63.6, 17.0)
-48.6 (-88.9, -7.7)
-38.4 (-81.8,
5.2)
-32.0 (-74.1, 10.5)
-46.2 (-89.1, -3.0)
-51.1 (-91.3, -10.6)
ramelteon
-7.1 (-13.7, -1.0)
15.4 (3.6, 27.3)
11.4 (-0.3, 22.8)
20.8 (12.1, 29.4)
17.5 (4.9, 30.0)
27.8 (17.9, 36.5)
2.5 (-7.6, 12.7)
12.6 (-6.1, 31.1)
19.1 (3.7, 34.6)
5.0 (-12.0, 21.6)
51.1 (10.6, 91.3)
Notes: data are posterior median difference (95% credible interval) and are presented as column treatment versus row treatment. Thus, a positive mean difference indicates longer sleep time with column treatment compared with row treatment
ER, extended release; IR, immediate release; sTST, subjective total sleep time
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Supplementary Table 20. Differences in sTST across the network (minutes) at 3 months: fixed effects
placebo lemborexant suvorexant eszopiclone ramelteon
placebo 19.6 (9.2, 30.0) 15.4 (8.6, 22.1) 39.0 (32.3, 45.7) 8.0 (-3.5, 19.5)
lemborexant -19.6 (-30.0, -9.2) -4.2 (-16.6, 8.2) 19.4 (7.1, 31.7) -11.6 (-27.2, 3.9)
suvorexant -15.4 (-22.1, -8.6) 4.2 (-8.2, 16.6) 23.6 (14.2, 33.2) -7.4 (-20.7, 5.9)
eszopiclone -39.0 (-45.7, -32.3) -19.4 (-31.7, -7.1) -23.6 (-33.2, -14.2) -31.0 (-44.4, -17.7)
ramelteon -8.0 (-19.5, 3.5) 11.6 (-3.9, 27.2) 7.4 (-5.9, 20.7) 31.0 (17.7, 44.4)
Notes: data are posterior median difference (95% credible interval) and are presented as column treatment versus row treatment. Thus, a positive mean difference indicates longer sleep time with column treatment compared with row treatment
sTST, subjective total sleep time
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Supplementary Table 21. Differences in sTST across the network (minutes) at 6 months: fixed effects
placebo lemborexant zolpidem-IR eszopiclone ramelteon
placebo 20.5 (9.4, 31.6) 15.3 (-14.1, 44.7) 43.2 (35.1, 51.3) -3.4 (-15.4, 8.6)
lemborexant -20.5 (-31.6, -9.4) -5.3 (-36.7, 26.2) 22.7 (9.0, 36.6) -24.0 (-40.3, -7.6)
zolpidem-IR -15.3 (-44.7, 14.1) 5.3 (-26.2, 36.7) 28.0 (-2.5, 58.4) -18.7 (-50.4, 13.1)
eszopiclone -43.2 (-51.3, -35.1) -22.7 (-36.6, -9.0) -28.0 (-58.4, 2.5) -46.6 (-61.2, -32.1)
ramelteon 3.4 (-8.6, 15.4) 24.0 (7.6, 40.3) 18.7 (-13.1, 50.4) 46.6 (32.1, 61.2)
Notes: data are posterior median difference (95% credible interval) and are presented as column treatment versus row treatment. Thus, a positive mean difference indicates longer sleep time with column treatment compared with row treatment
IR, immediate release; sTST, subjective total sleep time
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Supplementary Table 22. Differences in sWASO across the network (minutes) at 4 weeks: random effects
placebo lemborex
ant suvorexa
nt zolpidem
-IR zolpidem
-ER eszopicl
one trazodon
e temazep
am brotizola
m ramelteo
n
placebo
-10.9 (-19.0, -3.4)
-6.9 (-15.1,
1.3)
-14.0 (-21.0, -7.3)
-19.0 (-28.0, -10.0)
-14.4 (-19.9, -9.3)
-9.6 (-23.2,
3.9)
-14.8 (-31.3,
1.6)
-17.7 (-37.8,
1.9)
6.0 (-8.2, 20.1)
lemborexant 10.9 (3.4, 19.0)
4.0 (-6.9, 15.7)
-3.1 (-13.3,
7.4)
-8.1 (-18.1,
2.6)
-3.6 (-12.7,
6.0)
1.2 (-14.0, 17.1)
-3.8 (-21.9, 14.5)
-6.8 (-28.2, 14.6)
16.9 (1.1, 33.3)
suvorexant 6.9
(-1.3, 15.1)
-4.0 (-15.7,
6.9)
-7.1 (-18.0,
3.4)
-12.1 (-24.2,
0.1)
-7.5 (-17.5,
1.9)
-2.8 (-18.5, 13.0)
-7.9 (-26.3, 10.4)
-10.9 (-32.3, 10.4)
12.9 (-3.4, 29.1)
zolpidem-IR 14.0 (7.3, 21.0)
3.1 (-7.4, 13.3)
7.1 (-3.4, 18.0)
-5.0 (-16.1,
6.4)
-0.5 (-9.2, 8.2)
4.3 (-9.0, 17.8)
-0.8 (-15.7, 14.2)
-3.7 (-24.9, 17.1)
20.0 (4.3, 35.9)
zolpidem-ER 19.0
(10.0, 28.0)
8.1 (-2.6, 18.1)
12.1 (-0.1, 24.2)
5.0 (-6.4, 16.1)
4.6 (-6.0, 14.8)
9.4 (-6.9, 25.4)
4.2 (-14.6, 22.8)
1.2 (-20.8, 22.8)
25.0 (8.2, 41.7)
eszopiclone 14.4 (9.3, 19.9)
3.6 (-6.0, 12.7)
7.5 (-1.9, 17.5)
0.5 (-8.2, 9.2)
-4.6 (-14.8,
6.0)
4.8 (-9.6, 19.4)
-0.3 (-17.6, 16.9)
-3.3 (-23.9, 17.2)
20.4 (5.5, 35.7)
trazodone 9.6
(-3.9, 23.2)
-1.2 (-17.1, 14.0)
2.8 (-13.0, 18.5)
-4.3 (-17.8,
9.0)
-9.4 (-25.4,
6.9)
-4.8 (-19.4,
9.6)
-5.1 (-25.3, 14.7)
-8.1 (-32.4, 15.9)
15.7 (-4.0, 35.1)
temazepam 14.8 (-1.6, 31.3)
3.8 (-14.5, 21.9)
7.9 (-10.4, 26.3)
0.8 (-14.2, 15.7)
-4.2 (-22.8, 14.6)
0.3 (-16.9, 17.6)
5.1 (-14.7, 25.3)
-3.0 (-28.6, 22.8)
20.8 (-0.9, 42.5)
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placebo lemborex
ant suvorexa
nt zolpidem
-IR zolpidem
-ER eszopicl
one trazodon
e temazep
am brotizola
m ramelteo
n
brotizolam 17.7 (-1.9, 37.8)
6.8 (-14.6, 28.2)
10.9 (-10.4, 32.3)
3.7 (-17.1, 24.9)
-1.2 (-22.8, 20.8)
3.3 (-17.2, 23.9)
8.1 (-15.9, 32.4)
3.0 (-22.8, 28.6)
23.7 (-0.6, 48.1)
ramelteon -6.0
(-20.1, 8.2)
-16.9 (-33.3, -1.1)
-12.9 (-29.1,
3.4)
-20.0 (-35.9, -4.3)
-25.0 (-41.7, -8.2)
-20.4 (-35.7, -5.5)
-15.7 (-35.1,
4.0)
-20.8 (-42.5,
0.9)
-23.7 (-48.1,
0.6)
Notes: data are posterior median difference (95% credible interval) and are presented as column treatment versus row treatment. Thus, a negative mean difference indicates shorter wake time with column treatment compared with row treatment
ER, extended release; IR, immediate release; sWASO, subjective wake time after sleep onset
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Supplementary Table 23. Differences in sWASO across the network (minutes) at 3 months: fixed effects
placebo lemborexant suvorexant eszopiclone ramelteon
placebo -11.9 (-19.9, -3.8) -4.7 (-8.9, -0.5) -17.0 (-21.6, -12.3) 2.9 (-6.9, 12.7)
lemborexant 11.9 (3.8, 19.9) 7.2 (-1.9, 16.2) -5.1 (-14.3, 4.1) 14.8 (2.0, 27.4)
suvorexant 4.7 (0.5, 8.9) -7.2 (-16.2, 1.9) -12.3 (-18.5, -6.0) 7.6 (-3.1, 18.2)
eszopiclone 17.0 (12.3, 21.6) 5.1 (-4.1, 14.3) 12.3 (6.0, 18.5) 19.9 (9.0, 30.7)
ramelteon -2.9 (-12.7, 6.9) -14.8 (-27.4, -2.0) -7.6 (-18.2, 3.1) -19.9 (-30.7, -9.0)
Notes: data are posterior median difference (95% credible interval) and are presented as column treatment versus row treatment. Thus, a negative mean difference indicates shorter wake time with column treatment compared with row treatment
sWASO, subjective wake time after sleep onset
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Supplementary Table 24. Differences in sWASO across the network (minutes) at 6 months: fixed effects
placebo lemborexant zolpidem-IR eszopiclone ramelteon
placebo -15.1 (-23.8, -6.4) -6.8 (-29.5, 15.8) -13.5 (-18.4, -8.6) 11.5 (1.0, 22.1)
lemborexant 15.1 (6.4, 23.8) 8.3 (-16.0, 32.5) 1.6 (-8.4, 11.7) 26.6 (13.0, 40.3)
zolpidem-IR 6.8 (-15.8, 29.5) -8.3 (-32.5, 16.0) -6.7 (-29.9, 16.5) 18.3 (-6.6, 43.4)
eszopiclone 13.5 (8.6, 18.4) -1.6 (-11.7, 8.4) 6.7 (-16.5, 29.9) 25.0 (13.3, 36.7)
ramelteon -11.5 (-22.1, -1.0) -26.6 (-40.3, -13.0) -18.3 (-43.4, 6.6) -25.0 (-36.7, -13.3)
Notes: data are posterior median difference (95% credible interval) and are presented as column treatment versus row treatment. Thus, a negative mean difference indicates shorter wake time with column treatment compared with row treatment
IR, immediate release; sWASO, subjective wake time after sleep onset
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Supplementary Table 25. Differences in sSOL across the network (minutes) at 4 weeks: random effects
placebo
lemborexant
suvorexant
zolpidem-IR
zolpidem-ER
eszopiclone zaleplon trazodone triazolam
temazepam
ramelteon
placebo
-13.2 (-20.2, -6.0)
-6.1 (-15.0,
2.9)
-13.4 (-18.1, -8.9)
-5.1 (-12.7,
2.6)
-17.5 (-23.5, -11.4)
-13.6 (-19.7, -7.7)
-8.2 (-22.0,
5.4)
-15.1 (-30.0, -0.3)
-14.4 (-25.6, -3.4)
-6.2 (-11.5, -1.3)
lemborexant
13.2 (6.0, 20.2)
7.1 (-4.4, 18.5)
-0.2 (-8.9, 8.0)
8.0 (-1.0, 17.2)
-4.4 (-13.6,
5.1)
-0.5 (-9.9, 8.7)
5.0 (-10.6, 20.3)
-2.0 (-18.5, 14.4)
-1.2 (-14.5, 11.8)
6.9 (-2.0, 15.5)
suvorexant
6.1 (-2.9, 15.0)
-7.1 (-18.5,
4.4)
-7.2 (-17.5,
2.6)
1.0 (-10.7, 12.8)
-11.4 (-22.1, -0.5)
-7.5 (-18.4,
3.1)
-2.1 (-18.5, 14.1)
-9.0 (-26.4,
8.2)
-8.3 (-22.6,
5.8)
-0.1 (-10.6, 10.0)
zolpidem-IR
13.4 (8.9, 18.1)
0.2 (-8.0, 8.9)
7.2 (-2.6, 17.5)
8.3 (-0.4, 17.5)
-4.2 (-11.6,
3.8)
-0.3 (-6.6, 6.3)
5.2 (-8.3, 18.8)
-1.8 (-16.4, 13.1)
-1.0 (-11.6,
9.6)
7.1 (0.4, 14.0)
zolpidem-ER
5.1 (-2.6, 12.7)
-8.0 (-17.2,
1.0)
-1.0 (-12.8, 10.7)
-8.3 (-17.5,
0.4)
-12.4 (-22.1, -2.7)
-8.5 (-18.4,
1.0)
-3.1 (-18.9, 12.4)
-10.1 (-26.9,
6.6)
-9.3 (-22.9,
4.0)
-1.1 (-10.6,
7.8)
eszopiclone
17.5 (11.4, 23.5)
4.4 (-5.1, 13.6)
11.4 (0.5, 22.1)
4.2 (-3.8, 11.6)
12.4 (2.7, 22.1)
3.9 (-4.9, 12.3)
9.4 (-5.8, 24.2)
2.4 (-13.9, 18.3)
3.1 (-9.7, 15.6)
11.3 (3.1, 19.0)
zaleplon
13.6 (7.7, 19.7)
0.5 (-8.7, 9.9)
7.5 (-3.1, 18.4)
0.3 (-6.3, 6.6)
8.5 (-1.0, 18.4)
-3.9 (-12.3,
4.9)
5.5 (-9.2, 20.1)
-1.5 (-17.3, 14.2)
-0.8 (-13.0, 11.3)
7.4 (-0.5, 15.2)
trazodone
8.2 (-5.4, 22.0)
-5.0 (-20.3, 10.6)
2.1 (-14.1, 18.5)
-5.2 (-18.8,
8.3)
3.1 (-12.4, 18.9)
-9.4 (-24.2,
5.8)
-5.5 (-20.1,
9.2)
-7.0 (-26.8, 12.9)
-6.2 (-23.4, 10.7)
1.9 (-12.7, 16.5)
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placebo
lemborexant
suvorexant
zolpidem-IR
zolpidem-ER
eszopiclone zaleplon trazodone triazolam
temazepam
ramelteon
triazolam
15.1 (0.3, 30.0)
2.0 (-14.4, 18.5)
9.0 (-8.2, 26.4)
1.8 (-13.1, 16.4)
10.1 (-6.6, 26.9)
-2.4 (-18.3, 13.9)
1.5 (-14.2, 17.3)
7.0 (-12.9, 26.8)
0.7 (-15.3, 16.6)
8.9 (-6.8, 24.6)
temazepam
14.4 (3.4, 25.6)
1.2 (-11.8, 14.5)
8.3 (-5.8, 22.6)
1.0 (-9.6, 11.6)
9.3 (-4.0, 22.9)
-3.1 (-15.6,
9.7)
0.8 (-11.3, 13.0)
6.2 (-10.7, 23.4)
-0.7 (-16.6, 15.3)
8.2 (-4.0, 20.3)
ramelteon
6.2 (1.3, 11.5)
-6.9 (-15.5,
2.0)
0.1 (-10.0, 10.6)
-7.1 (-14.0, -0.4)
1.1 (-7.8, 10.6)
-11.3 (-19.0, -3.1)
-7.4 (-15.2,
0.5)
-1.9 (-16.5, 12.7)
-8.9 (-24.6,
6.8)
-8.2 (-20.3,
4.0)
Notes: data are posterior median difference (95% credible interval) and are presented as column treatment versus row treatment. Thus, a negative mean difference indicates shorter sleep onset with column treatment than row treatment
ER, extended release; IR, immediate release; sSOL, subjective sleep onset latency
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Supplementary Table 26. Differences in sSOL across the network (minutes) at 3 months: fixed effects
placebo lemborexant suvorexant eszopiclone ramelteon
placebo -13.0 (-17.7, -8.3) -6.0 (-10.0, -1.9) -18.1 (-23.1, -13.1) -8.0 (-15.0, -0.9)
lemborexant 13.0 (8.3, 17.7) 7.1 (0.9, 13.2) -5.1 (-11.9, 1.7) 5.1 (-3.4, 13.5)
suvorexant 6.0 (1.9, 10.0) -7.1 (-13.2, -0.9) -12.1 (-18.5, -5.7) -2.0 (-10.1, 6.1)
eszopiclone 18.1 (13.1, 23.1) 5.1 (-1.7, 11.9) 12.1 (5.7, 18.5) 10.1 (1.4, 18.8)
ramelteon 8.0 (0.9, 15.0) -5.1 (-13.5, 3.4) 2.0 (-6.1, 10.1) -10.1 (-18.8, -1.4)
Notes: data are posterior median difference (95% credible interval) and are presented as column treatment versus row treatment. Thus, a negative mean difference indicates shorter sleep onset with column treatment than row treatment
sSOL, subjective sleep onset latency
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Supplementary Table 27. Differences in sSOL across the network (minutes) at 6 months: fixed effects
placebo lemborexant zolpidem-IR eszopiclone ramelteon
placebo -13.2 (-17.8, -8.6) -9.0 (-22.7, 4.6) -19.6 (-24.9, -14.3) -5.9 (-12.2, 0.3)
lemborexant 13.2 (8.6, 17.8) 4.2 (-10.2, 18.5) -6.4 (-13.4, 0.7) 7.3 (-0.5, 15.0)
zolpidem-IR 9.0 (-4.6, 22.7) -4.2 (-18.5, 10.2) -10.6 (-25.1, 4.0) 3.1 (-11.9, 18.1)
eszopiclone 19.6 (14.3, 24.9) 6.4 (-0.7, 13.4) 10.6 (-4.0, 25.1) 13.7 (5.4, 21.9)
ramelteon 5.9 (-0.3, 12.2) -7.3 (-15.0, 0.5) -3.1 (-18.1, 11.9) -13.7 (-21.9, -5.4)
Notes: data are posterior median difference (95% credible interval) and are presented as column treatment versus row treatment. Thus, a negative mean difference indicates shorter sleep onset with column treatment than row treatment
IR, immediate release; sSOL, subjective sleep onset latency
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Supplementary Table 28. Differences in ISI total score across the network at 4 weeks: random effects
placebo lemborexant suvorexant zolpidem-ER zopiclone eszopiclone
placebo -1.9 (-3.3, -0.5) -1.3 (-2.9, 0.3) -2.2 (-4.4, -0.1) -2.8 (-5.5, 0.2) -3.2 (-4.4, -1.9)
lemborexant 1.9 (0.5, 3.3) 0.6 (-1.6, 2.7) -0.3 (-2.5, 1.8) -0.9 (-4.0, 2.4) -1.3 (-3.1, 0.6)
suvorexant 1.3 (-0.3, 2.9) -0.6 (-2.7, 1.6) -0.9 (-3.6, 1.8) -1.4 (-4.6, 1.9) -1.9 (-3.8, 0.3)
zolpidem-ER 2.2 (0.1, 4.4) 0.3 (-1.8, 2.5) 0.9 (-1.8, 3.6) -0.6 (-4.0, 3.1) -1.0 (-3.4, 1.6)
zopiclone 2.8 (-0.2, 5.5) 0.9 (-2.4, 4.0) 1.4 (-1.9, 4.6) 0.6 (-3.1, 4.0) -0.4 (-3.0, 2.1)
eszopiclone 3.2 (1.9, 4.4) 1.3 (-0.6, 3.1) 1.9 (-0.3, 3.8) 1.0 (-1.6, 3.4) 0.4 (-2.1, 3.0)
Notes: data are posterior median difference (95% credible interval) and are presented as column treatment versus row treatment. ISI is measured on scale from 0 to 28 where lower scores indicate lower severity. Thus, negative difference indicates column treatment is numerically better
ER, extended release; ISI, Insomnia Severity Index
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Supplementary Table 29. Differences in ISI total score across the network at 3 months: fixed effects
placebo lemborexant suvorexant eszopiclone
placebo -2.6 (-3.4, -1.8) -1.2 (-1.8, -0.6) -4.1 (-4.8, -3.4)
lemborexant 2.6 (1.8, 3.4) 1.4 (0.4, 2.4) -1.5 (-2.6, -0.4)
suvorexant 1.2 (0.6, 1.8) -1.4 (-2.4, -0.4) -2.9 (-3.8, -2.0)
eszopiclone 4.1 (3.4, 4.8) 1.5 (0.4, 2.6) 2.9 (2.0, 3.8)
Notes: data are posterior median difference (95% credible interval) and are presented as column treatment versus row treatment. ISI is measured on scale from 0 to 28 where lower scores indicate lower severity. Thus, negative difference indicates column treatment is numerically better
ISI, Insomnia Severity Index
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Supplementary Table 30. Differences in ISI total score across the network at 6 months: fixed effects
placebo lemborexant eszopiclone
placebo
-2.7 (-3.6, -1.8) -4.6 (-5.4, -3.8)
lemborexant 2.7 (1.8, 3.6)
-1.9 (-3.1, -0.7)
eszopiclone 4.6 (3.8, 5.4) 1.9 (0.7, 3.1)
Notes: data are posterior median difference (95% credible interval) and are presented as column treatment versus row treatment. ISI is measured on scale from 0 to 28 where lower scores indicate lower severity. Thus, negative difference indicates column treatment is numerically better
ISI, Insomnia Severity Index
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Supplementary Table 31. Differences in sQUAL across the network (scale: 1 to 10 where higher score indicates better quality of sleep) at 4 weeks: random effects
placeb
o lemborex
ant suvorexa
nt zolpidem-
IR zolpidem-
ER eszopiclo
ne zaleplo
n trazodo
ne estazola
m triazola
m ramelte
on
placebo
0.3 (0.1, 0.6)
0.5 (0.2, 0.8)
0.7 (0.5, 0.9)
0.5 (0.2, 0.8)
0.9 (0.7, 1.1)
0.2 (0.0, 0.4)
0.5 (0.0, 1.1)
0.9 (0.5, 1.3)
0.8 (0.1, 1.4)
0.1 (-0.1, 0.3)
lemborexant
-0.3 (-0.6, -0.1)
0.1 (-0.3, 0.5)
0.3 (0.0, 0.6)
0.2 (-0.2, 0.5)
0.6 (0.2, 0.9)
-0.1 (-0.5, 0.2)
0.2 (-0.4, 0.8)
0.5 (0.0, 1.0)
0.4 (-0.3, 1.1)
-0.3 (-0.6, 0.1)
suvorexant
-0.5 (-0.8, -0.2)
-0.1 (-0.5, 0.3)
0.2 (-0.2, 0.5)
0.0 (-0.4, 0.4)
0.4 (0.1, 0.8)
-0.3 (-0.6, 0.1)
0.1 (-0.5, 0.7)
0.4 (-0.1, 0.9)
0.3 (-0.4, 1.0)
-0.4 (-0.8, 0.0)
zolpidem-IR
-0.7 (-0.9, -0.5)
-0.3 (-0.6, 0.0)
-0.2 (-0.5, 0.2)
-0.2 (-0.5, 0.2)
0.2 (-0.1, 0.5)
-0.5 (-0.7, -0.2)
-0.1 (-0.7, 0.4)
0.2 (-0.2, 0.6)
0.1 (-0.5, 0.7)
-0.6 (-0.9, -0.3)
zolpidem-ER
-0.5 (-0.8, -0.2)
-0.2 (-0.5, 0.2)
0.0 (-0.4, 0.4)
0.2 (-0.2, 0.5)
0.4 (0.0, 0.7)
-0.3 (-0.7, 0.1)
0.0 (-0.6, 0.7)
0.4 (-0.1, 0.9)
0.3 (-0.4, 0.9)
-0.4 (-0.8, -0.1)
eszopiclone
-0.9 (-1.1, -0.7)
-0.6 (-0.9, -0.2)
-0.4 (-0.8, -0.1)
-0.2 (-0.5, 0.1)
-0.4 (-0.7, 0.0)
-0.7 (-1.0, -0.4)
-0.4 (-0.9, 0.2)
0.0 (-0.5, 0.4)
-0.1 (-0.8, 0.5)
-0.8 (-1.1, -0.5)
zaleplon
-0.2 (-0.4, 0.0)
0.1 (-0.2, 0.5)
0.3 (-0.1, 0.6)
0.5 (0.2, 0.7)
0.3 (-0.1, 0.7)
0.7 (0.4, 1.0)
0.3 (-0.2, 0.9)
0.7 (0.2, 1.1)
0.5 (-0.1, 1.2)
-0.1 (-0.4, 0.2)
trazodone
-0.5 (-1.1, 0.0)
-0.2 (-0.8, 0.4)
-0.1 (-0.7, 0.5)
0.1 (-0.4, 0.7)
0.0 (-0.7, 0.6)
0.4 (-0.2, 0.9)
-0.3 (-0.9, 0.2)
0.3 (-0.4, 1.0)
0.2 (-0.6, 1.0)
-0.5 (-1.1, 0.1)
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placeb
o lemborex
ant suvorexa
nt zolpidem-
IR zolpidem-
ER eszopiclo
ne zaleplo
n trazodo
ne estazola
m triazola
m ramelte
on
estazolam
-0.9 (-1.3, -0.5)
-0.5 (-1.0, 0.0)
-0.4 (-0.9, 0.1)
-0.2 (-0.6, 0.2)
-0.4 (-0.9, 0.1)
0.0 (-0.4, 0.5)
-0.7 (-1.1, -0.2)
-0.3 (-1.0, 0.4)
-0.1 (-0.8, 0.6)
-0.8 (-1.2, -0.3)
triazolam
-0.8 (-1.4, -0.1)
-0.4 (-1.1, 0.3)
-0.3 (-1.0, 0.4)
-0.1 (-0.7, 0.5)
-0.3 (-0.9, 0.4)
0.1 (-0.5, 0.8)
-0.5 (-1.2, 0.1)
-0.2 (-1.0, 0.6)
0.1 (-0.6, 0.8)
-0.7 (-1.3, 0.0)
ramelteon
-0.1 (-0.3, 0.1)
0.3 (-0.1, 0.6)
0.4 (0.0, 0.8)
0.6 (0.3, 0.9)
0.4 (0.1, 0.8)
0.8 (0.5, 1.1)
0.1 (-0.2, 0.4)
0.5 (-0.1, 1.1)
0.8 (0.3, 1.2)
0.7 (0.0, 1.3)
Notes: data are posterior median difference (95% credible interval) and are presented as column treatment versus row treatment. Thus, a positive mean difference indicates better sleep quality with column treatment compared with row treatment
ER, extended release; IR, immediate release; sQUAL, subjective quality of sleep
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Supplementary Table 32. Differences in sQUAL across the network (scale: 1 to 10 where higher score indicates better quality of sleep) at 3 months: fixed effects
placebo lemborexant suvorexant eszopiclone ramelteon
placebo 0.2 (0.0, 0.4) 0.3 (0.1, 0.5) 1.0 (0.8, 1.2) 0.0 (-0.3, 0.3)
lemborexant -0.2 (-0.4, 0.0) 0.1 (-0.2, 0.4) 0.8 (0.5, 1.1) -0.2 (-0.6, 0.2)
suvorexant -0.3 (-0.5, -0.1) -0.1 (-0.4, 0.2) 0.7 (0.5, 0.9) -0.3 (-0.6, 0.0)
eszopiclone -1.0 (-1.2, -0.8) -0.8 (-1.1, -0.5) -0.7 (-0.9, -0.5) -1.0 (-1.3, -0.7)
ramelteon 0.0 (-0.3, 0.3) 0.2 (-0.2, 0.6) 0.3 (0.0, 0.6) 1.0 (0.7, 1.3)
Notes: data are posterior median difference (95% credible interval) and are presented as column treatment versus row treatment. Thus, a positive mean difference indicates better sleep quality with column treatment compared with row treatment
sQUAL, subjective quality of sleep
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Supplementary Table 33. Differences in sQUAL across the network (scale: 1 to 10 where higher score indicates better quality of sleep) at 6 months: fixed effects
placebo lemborexant zolpidem-IR eszopiclone ramelteon
placebo 0.4 (0.1, 0.7) 0.1 (-0.7, 0.9) 1.0 (0.8, 1.1) 0.0 (-0.3, 0.3)
lemborexant -0.4 (-0.7, -0.1) -0.3 (-1.2, 0.6) 0.6 (0.2, 0.9) -0.4 (-0.8, 0.0)
zolpidem-IR -0.1 (-0.9, 0.7) 0.3 (-0.6, 1.2) 0.9 (0.0, 1.7) -0.1 (-1.0, 0.8)
eszopiclone -1.0 (-1.1, -0.8) -0.6 (-0.9, -0.2) -0.9 (-1.7, 0.0) -1.0 (-1.3, -0.6)
ramelteon 0.0 (-0.3, 0.3) 0.4 (0.0, 0.8) 0.1 (-0.8, 1.0) 1.0 (0.6, 1.3)
Notes: data are posterior median difference (95% credible interval) and are presented as column treatment versus row treatment. Thus, a positive mean difference indicates better sleep quality with column treatment compared with row treatment
IR, immediate release; sQUAL, subjective quality of sleep
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Supplementary Table 34. Results of individual studies, percentage
experiencing at least one serious adverse event (SAE) data
Trial Duration Group 1 n N % Group 2 n N %
Black 2017 ~2 weeksb placebo 0 177 0.0% zolpidem-IR 0 168 0.0%
Dehlin 1995 2 weeks zopiclone
0 NR 0.0% flunitrazepam 0 NR 0.0%
Hajak 2009 2 weeks placebo 0 142 0.0% zolpidem-IR 2 150 1.3%
McCall 2006 2 weeksb placebo 2 128 1.6% eszopiclone 1 136 0.7%
Scharf 2005 2 weeks placebo 0 80 0.0% eszopiclone 1 151 0.7%
Study 201 2 weeks placebo 1 56 1.8% lemborexant 0 70 0.0%
Tsutsui 2001 2 weeks zolpidem-IR
1 211 0.5% zopiclone 0 225 0.0%
Uchimura 2011
2 weeks placebo NR NR <1% ramelteon NR NR <1%
Uchiyama 2011
2 weeks placebo 0 482 0.0% ramelteon 1 489 0.2%
Walsh 1998b 2 weeks placebo 0 34 0.0% zaleplon 0 67 0.0%
triazolam 0 31 0.0%
Yan 2013 2 weeks estazolam
0 125 0.0% brotizolam 0 126 0.0%
Walsh 2008 3 weeks placebo 1 106 0.9% zolpidem-ER 0 99 0.0%
Soares 2006 4 weeks placebo 0 209 0.0% eszopiclone 0 201 0.0%
Study 304 ~4 weeks placebo 0 209 0.0% lemborexant 2 534 0.4%
zolpidem-ER 4 263 1.5%
Voshaar 2004
4 weeks no “major” AEs
Roth 2006a 5 weeksb 8 SAEs reported across 3 treatment groups
Zammit 2007 5 weeks placebo 0 131 0.0% ramelteon 0 139 0.0%
Zammit 2004c
~6 weeks placebo 0 99 0.0% eszopiclone 0 209 0.0%
Ancoli-Israel 2010
3 months placebo 2 194 1.0% eszopiclone 4 194 2.1%
Herring 2016 - trial 1a
3 months placebo 11 384 2.9% suvorexant 1 254 0.4%
Herring 2016 - trial 2
3 months placebo 5 383 1.3% suvorexant 2 239 0.8%
Krystal 2003 6 months placebo 2 195 1.0% eszopiclone 17 593 2.9%
Mayer 2009 6 months placebo 2 224 0.9% ramelteon 5 227 2.2%
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Trial Duration Group 1 n N % Group 2 n N %
Study 303 6 months placebo 5 319 1.6% lemborexant 16 628 2.5%
Walsh 2007c 6 months placebo 3 280 1.1% eszopiclone 2 548 0.4%
AE, adverse event; ER, extended release; IR, immediate release; n, number of patients with at least one event; N, number of patients at risk; NR, not reported; SAE, serious adverse event. a Herring et al (2016) also report that no SAE were reported in the following 4-6 months randomized extension period. b It is not clear whether the AEs were reported for the double-blind treatment period, or also included the follow-up period (Black 2017: 28 days, Dehlin 1995: 1 week placebo run-in and 1 week follow-up, McCall 2006: 5-7 days, Roth 2006a: 1 week). The double-blind treatment duration is reported here. c Only treatment-related SAE were reported.
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Supplementary Table 35. Results of individual studies, withdrawal due to adverse event data
Trial Duration Group 1 n N % Group 2 n N %
Rickels 1986 1 week placebo 0 34 0.0% brotizolam 0 29 0.0%
Scharf 1990 1 week placebo 3 80 3.8% estazolam 1 81 1.2%
Walsh 1984 1 week placebo 2 124 1.6% estazolam 4 243 1.6%
Black 2017 ~2 weeks placebo 2 177 1.1% zolpidem-IR 6 168 3.6%
Dehlin 1995 2 weeks zopiclone 0 NR 0.0% flunitrazepam 0 NR 0.0%
Hajak 2009 2 weeks placebo 4 142 2.8% zolpidem-IR 10 150 6.7%
Hedner 2000a
2 weeks placebo 7 143 4.9% zaleplon 15 294 5.1%
McCall 2006 2 weeks placebo 3 128 2.3% eszopiclone 2 136 1.5%
Rosenberg 1994
2 weeks zolpidem-IR
2 87 2.3% triazolam 3 91 3.3%
Scharf 2005 2 weeks placebo 5 80 6.3% estazolam 3 151 2.0%
Study 201 2 weeks placebo 0 56 0.0% lemborexant 0 70 0.0%
Tsutsui 2001 2 weeks zolpidem-IR
18 211 8.5% zopiclone 23 225 10.2%
Uchiyama 2011b
2 weeks placebo 6 482 1.2% ramelteon 8 489 1.6%
Walsh 1998a 2 weeks placebo 2 104 1.9% zolpidem-IR 5 102 4.9%
trazodone 5 100 5.0%
Walsh 1998b 2 weeks placebo 0 34 0.0% zaleplon 1 67 1.5%
triazolam 0 31 0.0%
Yan 2013 2 weeks estazolam 0 125 0.0% brotizolam 0 126 0.0%
Roth 2006b 3 weeks placebo 2 110 1.8% zolpidem-ER 6 102 5.9%
Walsh 2008 3 weeks placebo 0 106 0.0% zolpidem-ER 1 99 1.0%
Dorsey 2004 4 weeks placebo 2 73 2.7% zolpidem-IR 5 68 7.4%
Elie 1999 4 weeks placebo 2 126 1.6% zolpidem-IR 7 122 5.7%
zaleplon 9 241 3.7%
Fry 2000 4 weeks placebo 4 119 3.4% zolpidem-IR 7 116 6.0%
zaleplon 8 238 3.4%
Hajak 1994 4 weeks placebo 3 298 1.0% zopiclone 15 612 2.5%
flunitrazepam
6 290 2.1% triazolam 2 307 0.7%
Lahmeyer 1997
~4 weeks placebo 0 54 0.0% zolpidem-IR 4 45 8.9%
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Trial Duration Group 1 n N % Group 2 n N %
Leppik 1997 4 weeks placebo 6 84 7.1% zolpidem-IR 2 82 2.4%
triazolam 5 85 5.9% temazepam 5 84 6.0%
Pinto 2016c 4 weeks zopiclone 15 131 11.5% eszopiclone 9 131 6.9%
Soares 2006 4 weeks placebo 3 209 1.4% eszopiclone 11 201 5.5%
Study 304 ~4 weeks placebo 2 209 1.0% lemborexant 5 534 0.9%
zolpidem-ER 6 263 2.3%
Ware 1997 4 weeks placebo 0 37 0.0% zolpidem-IR 3 37 8.1%
triazolam 4 36 11.1%
Roth 2006a 5 weeks placebo 8 274 2.9% ramelteon 7 274 2.6%
Scharf 1994 5 weeks placebo 0 24 0.0% zolpidem-IR 0 26 0.0%
Walsh 2000 5 weeks placebo 1 57 1.8% zaleplon 3 56 5.4%
Zammit 2007 5 weeks placebo 2 131 1.5% ramelteon 3 139 2.2%
Zammit 2004 ~6 weeks placebo 0 99 0.0% eszopiclone 3 209 1.4%
Ancoli-Israel 2010
3 months placebo 9 194 4.6% eszopiclone 14 194 7.2%
Herring 2016 - trial 1
3 months placebo 23 384 6.0% suvorexant 6 254 2.4%
Herring 2016 - trial 2
3 months placebo 17 383 4.4% suvorexant 9 239 3.8%
Krystal 2003 6 months placebo 14 196 7.1% eszopiclone 76 595 12.8%
Mayer 2009d 6 months placebo 10 224 4.5% ramelteon 7 227 3.1%
Study 303 6 months placebo 8 319 2.5% lemborexant 22 628 3.5%
Walsh 2007 6 months placebo 22 280 7.9% eszopiclone 48 548 8.8%
Randall 2012
8 months placebo 0 65 0.0% zolpidem-IR 2 60 3.3%
a For Hedner 2000 it was assumed that the 15 patients not in the efficacy population, but in safety population were equally distributed between the 3 groups. b Uchiyama reported numerator in Figure 1 (6 vs 8) which was inconsistent with the percentage reported in the text (2.3% vs 2.7%). The numerator was used in the NMA. c Pinto reported withdrawal due to intolerance d Mayer 2009 reported inconsistent results for ramelteon: the disposition figure reported 7 withdrew due to AE whereas the text reported 8. Results published on ICTRP reported 7, so that has been used in the NMA. AE, adverse event; ER, extended release; IR, immediate release; n, number of patients with at least one event; N, number of patients at risk; NR, not reported
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Supplementary Table 36. Results of individual studies, percentage experiencing at least one somnolence event data
Trial Duration Group 1 n N % Group 2 n N %
Scharf 1990c 1 week placebo 18 80 22.5% estazolam 38 81 46.9%
Ancoli-Israel 1999
2 weeks placebo 2 107 2% zolpidem-IR 11 111 10%
zaleplon 7 166 4%
Black 2017 ~2 weeksb placebo 4 177 2.3% zolpidem-IR 4 168 2.4%
Hajak 2009 2 weeks placebo 4 142 2.8% zolpidem-IR 3 150 2.0%
McCall 2006 2 weeksb placebo 7 128 5.5% eszopiclone 9 136 6.6%
Rosenberg 1994
2 weeks zolpidem-IR
2 71 2.8% triazolam 5 68 7.4%
Scharf 2005 2 weeks placebo 7 80 8.8% estazolam 8 151 5.3%
Study 201 2 weeks placebo 0 56 0.0% lemborexant 6 70 8.6%
Uchiyama 2011 2 weeks placebo 4 482 0.8% ramelteon 15 489 3.1%
Walsh 1998a 2 weeks placebo 8 104 8% zolpidem-IR 16 102 16%
trazodone 23 100 23%
Walsh 1998b 2 weeks placebo 2 34 5.9% zaleplon 3 67 4.5%
triazolam 1 31 3.2%
Roth 2006b 3 weeks placebo 2 110 1.8% zolpidem-ER 15 102 14.7%
Walsh 2008 3 weeks placebo 5 106 5% zolpidem-ER 6 99 6%
Wang-Weigand 2011
3 weeks placebo 5 278 1.8% ramelteon 12 274 4.4%
Elie 1999 4 weeks placebo 1 126 0.8% zolpidem-IR 6 122 4.9%
zaleplon 9 241 3.7%
Fry 2000 4 weeks placebo 4 119 3.4% zolpidem-IR 13 116 11.2%
zaleplon 15 238 6.3%
Study 304 ~4 weeks placebo 4 209 1.9% lemborexant 30 534 5.6%
zolpidem-ER 4 263 1.5%
Roth 2006a 5 weeks placebo 8 274 2.9% ramelteon 13 274 4.7%
Zammit 2007 5 weeks placebo 2 131 1.5% ramelteon 11 139 7.9%
Zammit 2004c ~6 weeks placebo 3 99 3.0% eszopiclone 16 209 7.7%
Ancoli-Israel 2010
3 months placebo 4 194 2.1% eszopiclone 5 194 2.6%
Herring 2016 - trial 1a
3 months placebo 13 384 3.4% suvorexant 13 254 5.1%
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Trial Duration Group 1 n N % Group 2 n N %
Herring 2016 - trial 2
3 months placebo 12 383 3.1% suvorexant 20 239 8.4%
Krystal 2003 6 months placebo 5 195 2.6% eszopiclone 54 593 9.1%
Study 303 6 months placebo 5 319 1.6% lemborexant 68 628 10.8%
Walsh 2007d 6 months placebo 9 280 3.2% eszopiclone 48 548 8.8% a Herring et al (2016) also report than less than 2% of patients experienced somnolence in the following 4-6 months randomized extension period. b It is not clear whether the AEs were reported for the double-blind treatment period, or also included the follow-up period (Black 2017: 28 days, McCall 2006: 5-7 days). The double-blind treatment duration is reported here. c Only treatment-related events were reported. d Number of events, rather than number of patients experiencing at least one was reported. AE, adverse event; ER, extended release; IR, immediate release; n, number of patients with at least one event; N, number of patients at risk; NR, not reported.
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Supplementary Table 37. Results of individual studies, percentage experiencing at least one dizziness event data
Trial Duration Group 1 n N % Group 2 n N %
Scharf 1990b 1 week placebo 0 80 0.0% estazolam 2 81 2.5%
Black 2017 ~2 weeksa placebo 10 177 5.6% zolpidem-IR 3 168 1.8%
Hajak 2009 2 weeks placebo 4 142 2.8% zolpidem-IR 14 150 9.3%
McCall 2006 2 weeksa placebo 2 128 1.6% eszopiclone 9 136 6.6%
Rosenberg 1994
2 weeks zolpidem-IR
1 71 1.4% triazolam 0 68 0.0%
Study 201 2 weeks placebo 3 56 5.4% lemborexant 2 70 2.9%
Uchiyama 2011
2 weeks placebo 0 482 0.0% ramelteon 3 489 0.6%
Walsh 1998b 2 weeks placebo 0 34 0.0% zaleplon 3 67 4.5%
triazolam 3 31 9.7%
Yan 2013 2 weeks estazolam NR
<2% brotizolam NR
>2%
Roth 2006b 3 weeks placebo 6 110 5.5% zolpidem-ER 12 102 11.8%
Walsh 2008 3 weeks placebo 3 106 3% zolpidem-ER 8 99 8%
Dorsey 2004 4 weeks placebo 0 73 0.0% zolpidem-IR 6 68 8.8%
Fry 2000 4 weeks placebo 10 119 8.0% zolpidem-IR 16 116 14.0%
zaleplon 15 238 6.3%
Lahmeyer 1997
~4 weeks placebo 2 53 4% zolpidem-IR 2 44 5%
Pinto 2016 4 weeks zopiclone 12 130 9.2% eszopiclone 21 128 16.4%
Study 304 ~4 weeks placebo 4 209 1.9% lemborexant 5 534 0.9%
zolpidem-ER 8 263 3.0%
Hajak 1994c 4 weeks placebo 82 298 27.5% zopiclone 169 612 27.6%
flunitrazepam
83 290 28.6% triazolam 91 307 29.6%
Roth 2006a 5 weeks placebo 18 274 6.6% ramelteon 23 274 8.4%
Scharf 1994 5 weeks placebo 0 24 0.0% zolpidem-IR 3 26 11.5%
Zammit 2007 5 weeks placebo 5 131 3.8% ramelteon 5 139 3.6%
Zammit 2004b
~6 weeks placebo 4 99 4.0% eszopiclone 8 209 3.8%
Ancoli-Israel 2010
3 months placebo 3 194 1.5% eszopiclone 8 194 4.1%
Herring 2016 - trial 1
3 months placebo 11 384 2.9% suvorexant 8 254 3.1%
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Trial Duration Group 1 n N % Group 2 n N %
Herring 2016 - trial 2
3 months placebo 8 383 2.1% suvorexant 7 239 2.9%
Krystal 2003 6 months placebo 6 195 3.1% eszopiclone 58 593 9.8%
Mayer 2009 6 months placebo 5 223 2.2% ramelteon 7 228 3.1%
Study 303 6 months placebo 6 319 1.9% lemborexant 9 628 1.4% a It is not clear whether the AEs were reported for the double-blind treatment period, or also included the follow-up period (Black 2017: 28 days, McCall 2006: 5-7 days). The double-blind treatment duration is reported here. b Only treatment-related events were reported. c Number of events, rather than number of patients experiencing at least one was reported. AE, adverse event; ER, extended release; IR, immediate release; n, number of patients with at least one event; N, number of patients at risk; NR, not reported.
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Supplementary Table 38. Results of individual studies, percentage experiencing at least one fall or accidental injury event data
Trial Duration Group 1 n N % Group 2 n N %
Fall
Scharf 2005 2 weeks placebo 0 80 0.0% eszopiclone 0 151 0.0%
Study 201 2 weeks placebo 0 56 0.0% lemborexant 0 70 0.0%
Walsh 2008 3 weeks placebo 0 106 0.0% zolpidem-ER 0 99 0.0%
Study 304 ~4 weeks placebo 0 209 0.0% lemborexant 4 534 0.7%
zolpidem-ER 0 263 0.0%
Ancoli-Israel 2010
3 months placebo 1 194 0.5% eszopiclone 2 194 1.0%
Herring 2016 - trial 1a
3 months placebo 5 384 1.3% suvorexant 2 254 0.8%
Herring 2016 - trial 2
3 months placebo 2 383 0.5% suvorexant 2 239 0.8%
Study 303 6 months placebo 10 319 3.1% lemborexant 10 628 1.6%
Accidental injury
McCall 2006 2 weeksb placebo 2 128 1.6% eszopiclone 4 136 2.9%
Soares 2006 4 weeks placebo 4 209 1.9% eszopiclone 2 201 1.0%
Krystal 2003 6 months placebo 11 195 5.6% eszopiclone 43 593 7.3%
Walsh 2007c 6 months placebo 17 280 6.1% eszopiclone 27 548 4.9% a Herring et al (2016) also report that no one in the placebo group and one person in the suvorexant group (out of 100, 1%) experienced a fall in the following 4-6 months randomized extension period. b It is not clear whether the AEs were reported for the double-blind treatment period, or also included the follow-up period (McCall 2006: 5-7 days). The double-blind treatment duration is reported here. c Number of events, rather than number of patients experiencing at least one was reported. The Cochrane review did not adjust for this. AE, adverse event; ER, extended release; n, number of patients with at least one event; N, number of patients at risk; NR, not reported.
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Supplementary Table 39. Odds ratios for SAE across the network: fixed effects
placebo lemborexant suvorexant zolpidem-ER eszopiclone ramelteon
placebo 1.38
(0.59, 3.66) 0.26
(0.06, 0.81) 4.40
(0.80, 28.06) 2.08
(0.86, 5.86) 3.37
(0.72, 26.02)
lemborexant 0.72
(0.27, 1.70) 0.18
(0.03, 0.79) 3.15
(0.62, 17.96) 1.51
(0.41, 5.75) 2.44
(0.39, 22.15)
suvorexant 3.86
(1.23, 17.84) 5.48
(1.26, 32.06) 17.63
(2.16, 183.70) 8.28
(1.87, 50.01) 13.74
(1.87, 162.80)
zolpidem-ER 0.23
(0.04, 1.24) 0.32
(0.06, 1.62) 0.06
(0.01, 0.46) 0.48
(0.06, 3.42) 0.78
(0.07, 10.76)
eszopiclone 0.48
(0.17, 1.16) 0.66
(0.17, 2.47) 0.12
(0.02, 0.54) 2.08
(0.29, 16.35) 1.61
(0.25, 14.86)
ramelteon 0.30
(0.04, 1.39) 0.41
(0.05, 2.54) 0.07
(0.01, 0.54) 1.28
(0.09, 14.54) 0.62
(0.07, 3.95)
Notes: data are posterior median odds ratio (95% credible interval) and are presented as column treatment versus row treatment
ER, extended release; SAE, serious adverse event
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Supplementary Table 40. Odds ratios for withdrawal due to AE across the network: fixed effects
placebo lembore
xant suvorexa
nt zolpidem
-IR zolpidem
-ER zopiclon
e eszopiclo
ne zaleplon trazodon
e flunitraz
epam estazola
m triazola
m temazep
am ramelteo
n
placebo
1.38 (0.69, 2.95)
0.56 (0.30, 1.01)
2.32 (1.52, 3.60)
3.45 (1.33, 9.60)
3.14 (1.83, 5.49)
1.61 (1.17, 2.24)
1.40 (0.80, 2.47)
2.43 (0.66, 8.35)
2.81 (0.92, 7.60)
0.46 (0.17, 1.21)
1.85 (0.87, 3.83)
1.93 (0.56, 5.85)
0.95 (0.54, 1.65)
lemborexant
0.72 (0.34, 1.45)
0.40 (0.15, 1.01)
1.68 (0.71, 3.81)
2.49 (0.94, 6.70)
2.27 (0.90, 5.54)
1.16 (0.51, 2.50)
1.01 (0.40, 2.48)
1.74 (0.39, 7.24)
2.01 (0.53, 6.87)
0.33 (0.10, 1.10)
1.33 (0.46, 3.66)
1.38 (0.33, 5.16)
0.68 (0.27, 1.67)
suvorexant
1.78 (0.99, 3.38)
2.48 (0.99, 6.64)
4.15 (2.00, 8.92)
6.20 (2.01, 20.48)
5.62 (2.51, 13.00)
2.87 (1.47, 5.86)
2.50 (1.11, 5.83)
4.34 (1.04, 17.31)
5.00 (1.42, 16.34)
0.83 (0.26, 2.61)
3.31 (1.27, 8.64)
3.45 (0.87, 12.34)
1.69 (0.74, 3.93)
zolpidem-IR
0.43 (0.28, 0.66)
0.60 (0.26, 1.42)
0.24 (0.11, 0.50)
1.49 (0.52, 4.51)
1.35 (0.82, 2.26)
0.69 (0.41, 1.15)
0.60 (0.34, 1.08)
1.05 (0.29, 3.49)
1.21 (0.40, 3.23)
0.20 (0.07, 0.57)
0.80 (0.39, 1.57)
0.83 (0.25, 2.43)
0.41 (0.20, 0.82)
zolpidem-ER
0.29 (0.10, 0.75)
0.40 (0.15, 1.06)
0.16 (0.05, 0.50)
0.67 (0.22, 1.93)
0.91 (0.28, 2.75)
0.47 (0.16, 1.28)
0.40 (0.13, 1.23)
0.70 (0.14, 3.33)
0.80 (0.18, 3.27)
0.13 (0.03, 0.52)
0.53 (0.15, 1.79)
0.55 (0.11, 2.43)
0.27 (0.09, 0.83)
zopiclone
0.32 (0.18, 0.55)
0.44 (0.18, 1.12)
0.18 (0.08, 0.40)
0.74 (0.44, 1.22)
1.10 (0.36, 3.51)
0.51 (0.29, 0.90)
0.45 (0.22, 0.91)
0.77 (0.20, 2.80)
0.90 (0.31, 2.20)
0.15 (0.05, 0.44)
0.59 (0.27, 1.21)
0.61 (0.17, 1.93)
0.30 (0.14, 0.65)
eszopiclone
0.62 (0.45, 0.85)
0.86 (0.40, 1.95)
0.35 (0.17, 0.68)
1.44 (0.87, 2.41)
2.15 (0.78, 6.28)
1.95 (1.11, 3.49)
0.87 (0.46, 1.65)
1.51 (0.40, 5.34)
1.75 (0.56, 4.83)
0.29 (0.10, 0.79)
1.15 (0.52, 2.48)
1.20 (0.34, 3.76)
0.59 (0.31, 1.12)
zaleplon
0.72 (0.40, 1.24)
0.99 (0.40, 2.52)
0.40 (0.17, 0.90)
1.66 (0.93, 2.97)
2.47 (0.81, 7.89)
2.25 (1.10, 4.62)
1.15 (0.61, 2.16)
1.73 (0.44, 6.48)
2.00 (0.59, 6.01)
0.33 (0.11, 1.00)
1.32 (0.55, 3.08)
1.38 (0.37, 4.54)
0.68 (0.30, 1.48)
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placebo lembore
xant suvorexa
nt zolpidem
-IR zolpidem
-ER zopiclon
e eszopiclo
ne zaleplon trazodon
e flunitraz
epam estazola
m triazola
m temazep
am ramelteo
n
trazodone
0.41 (0.12, 1.51)
0.57 (0.14, 2.55)
0.23 (0.06, 0.96)
0.96 (0.29, 3.43)
1.43 (0.30, 7.36)
1.30 (0.36, 5.02)
0.66 (0.19, 2.51)
0.58 (0.15, 2.28)
1.15 (0.23, 5.71)
0.19 (0.04, 0.95)
0.76 (0.19, 3.18)
0.79 (0.15, 4.19)
0.39 (0.10, 1.61)
flunitrazepam
0.36 (0.13, 1.09)
0.50 (0.15, 1.90)
0.20 (0.06, 0.71)
0.83 (0.31, 2.51)
1.24 (0.31, 5.56)
1.12 (0.45, 3.19)
0.57 (0.21, 1.79)
0.50 (0.17, 1.68)
0.87 (0.18, 4.36)
0.17 (0.04, 0.72)
0.66 (0.23, 2.09)
0.69 (0.15, 3.02)
0.34 (0.11, 1.17)
estazolam
2.16 (0.83, 5.87)
3.02 (0.91, 10.44)
1.21 (0.38, 3.85)
5.03 (1.75, 14.90)
7.51 (1.92, 30.98)
6.81 (2.25, 21.29)
3.48 (1.26, 9.92)
3.03 (1.00, 9.51)
5.25 (1.05, 25.67)
6.04 (1.39, 24.95)
4.00 (1.18, 13.65)
4.16 (0.87, 18.42)
2.04 (0.67, 6.40)
triazolam
0.54 (0.26, 1.15)
0.75 (0.27, 2.17)
0.30 (0.12, 0.79)
1.25 (0.64, 2.57)
1.87 (0.56, 6.66)
1.69 (0.83, 3.65)
0.87 (0.40, 1.92)
0.76 (0.32, 1.82)
1.31 (0.31, 5.25)
1.52 (0.48, 4.42)
0.25 (0.07, 0.85)
1.05 (0.30, 3.22)
0.51 (0.20, 1.30)
temazepam
0.52 (0.17, 1.79)
0.72 (0.19, 3.05)
0.29 (0.08, 1.15)
1.20 (0.41, 4.08)
1.81 (0.41, 8.84)
1.63 (0.52, 5.88)
0.83 (0.27, 2.97)
0.73 (0.22, 2.72)
1.26 (0.24, 6.88)
1.45 (0.33, 6.58)
0.24 (0.05, 1.15)
0.96 (0.31, 3.35)
0.49 (0.14, 1.91)
ramelteon
1.06 (0.60, 1.86)
1.47 (0.60, 3.75)
0.59 (0.25, 1.34)
2.46 (1.22, 5.02)
3.66 (1.21, 11.69)
3.33 (1.53, 7.34)
1.70 (0.89, 3.27)
1.48 (0.67, 3.30)
2.57 (0.62, 10.02)
2.96 (0.85, 9.37)
0.49 (0.16, 1.50)
1.96 (0.77, 4.91)
2.04 (0.52, 7.06)
Notes: data are posterior median odds ratio (95% credible interval) and are presented as column treatment versus row treatment
AE, adverse event; ER; extended release; IR, immediate release
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Supplementary Table 41. Odds ratios for somnolence across the network: fixed effects
placebo lemborexant suvorexant zolpidem-IR zolpidem-
ER eszopiclone zaleplon trazodone estazolam triazolam ramelteon
placebo 7.73
(4.17, 15.71) 2.15
(1.26, 3.70) 2.32
(1.43, 3.85) 2.65
(1.36, 5.32) 2.19
(1.27, 4.02) 1.51
(0.85, 2.73) 3.71
(1.82, 7.61) 0.59
(0.20, 1.77) 2.79
(0.78, 9.73) 2.77
(1.65, 4.85)
lemborexant 0.13
(0.06, 0.24) 0.28
(0.11, 0.63) 0.30
(0.13, 0.67) 0.34
(0.16, 0.69) 0.28
(0.12, 0.68) 0.19
(0.08, 0.46) 0.48
(0.18, 1.24) 0.08
(0.02, 0.27) 0.36
(0.08, 1.46) 0.36
(0.15, 0.83)
suvorexant 0.47
(0.27, 0.79) 3.61
(1.58, 8.73) 1.08
(0.52, 2.26) 1.23
(0.52, 2.96) 1.02
(0.47, 2.28) 0.70
(0.32, 1.56) 1.72
(0.71, 4.23) 0.27
(0.08, 0.93) 1.29
(0.33, 5.05) 1.29
(0.61, 2.80)
zolpidem-IR 0.43
(0.26, 0.70) 3.35
(1.50, 7.85) 0.93
(0.44, 1.92) 1.14
(0.50, 2.68) 0.95
(0.45, 2.05) 0.65
(0.39, 1.08) 1.60
(0.82, 3.09) 0.25
(0.08, 0.84) 1.20
(0.36, 3.96) 1.20
(0.58, 2.52)
zolpidem-ER 0.38
(0.19, 0.73) 2.91
(1.45, 6.29) 0.81
(0.34, 1.92) 0.87
(0.37, 2.02) 0.83
(0.34, 2.03) 0.57
(0.23, 1.39) 1.40
(0.52, 3.73) 0.22
(0.06, 0.80) 1.05
(0.25, 4.34) 1.05
(0.44, 2.50)
eszopiclone 0.46
(0.25, 0.79) 3.53
(1.48, 8.61) 0.98
(0.44, 2.12) 1.05
(0.49, 2.24) 1.20
(0.49, 2.94) 0.69
(0.30, 1.55) 1.68
(0.67, 4.19) 0.27
(0.08, 0.92) 1.26
(0.31, 5.00) 1.26
(0.57, 2.78)
zaleplon 0.66
(0.37, 1.17) 5.14
(2.17, 12.74) 1.42
(0.64, 3.14) 1.54
(0.92, 2.55) 1.75
(0.72, 4.33) 1.46
(0.64, 3.32) 2.45
(1.11, 5.44) 0.39
(0.11, 1.35) 1.84
(0.53, 6.21) 1.84
(0.84, 4.10)
trazodone 0.27
(0.13, 0.55) 2.10
(0.81, 5.69) 0.58
(0.24, 1.42) 0.63
(0.32, 1.22) 0.72
(0.27, 1.94) 0.59
(0.24, 1.50) 0.41
(0.18, 0.90) 0.16
(0.04, 0.59) 0.75
(0.19, 2.90) 0.75
(0.31, 1.85)
estazolam 1.70
(0.56, 5.01) 13.27
(3.72, 47.69) 3.67
(1.07,12.22) 3.96
(1.18,13.00) 4.53
(1.25,16.26) 3.76
(1.09,12.82) 2.57
(0.74, 8.83) 6.32
(1.70,23.15) 4.73
(0.89,24.74) 4.74
(1.40,15.94)
triazolam 0.36
(0.10, 1.28) 2.80
(0.69, 11.89) 0.77
(0.20, 3.06) 0.83
(0.25, 2.81) 0.96
(0.23, 4.02) 0.79
(0.20, 3.21) 0.54
(0.16, 1.89) 1.33
(0.35, 5.22) 0.21
(0.04, 1.13) 1.00
(0.26, 3.97)
ramelteon 0.36
(0.21, 0.61) 2.79
(1.21, 6.68) 0.77
(0.36, 1.64) 0.84
(0.40, 1.73) 0.96
(0.40, 2.28) 0.79
(0.36, 1.75) 0.54
(0.24, 1.19) 1.33
(0.54, 3.25) 0.21
(0.06, 0.72) 1.00
(0.25, 3.90)
Notes: data are posterior median odds ratio (95% credible interval) and are presented as column treatment versus row treatment
ER; extended release; IR, immediate release
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Supplementary Table 42. Odds ratios for dizziness across the network: fixed effects
placebo lemborexant suvorexant zolpidem-IR zolpidem-ER zopiclone eszopiclone zaleplon triazolam ramelteon
placebo 0.66
(0.32, 1.35) 1.23
(0.61, 2.43) 1.94
(1.18, 3.25) 2.31
(1.22, 4.49) 1.80
(0.66, 5.05) 3.52
(1.90, 7.20) 0.85
(0.42, 1.72) 2.16
(0.36, 11.46) 1.37
(0.83, 2.29)
lemborexant 1.52
(0.74, 3.12) 1.86
(0.68, 5.03) 2.94
(1.23, 7.13) 3.50
(1.56, 8.09) 2.74
(0.79, 9.53) 5.37
(2.07, 14.60) 1.29
(0.47, 3.53) 3.26
(0.48, 20.13) 2.08
(0.86, 5.04)
suvorexant 0.81
(0.41, 1.65) 0.54
(0.20, 1.47) 1.58
(0.68, 3.78) 1.89
(0.74, 4.94) 1.48
(0.44, 5.08) 2.89
(1.14, 7.75) 0.70
(0.26, 1.87) 1.76
(0.26, 10.78) 1.12
(0.48, 2.67)
zolpidem-IR 0.52
(0.31, 0.85) 0.34
(0.14, 0.82) 0.63
(0.26, 1.48) 1.19
(0.53, 2.73) 0.93
(0.30, 2.93) 1.82
(0.81, 4.34) 0.44
(0.22, 0.85) 1.11
(0.19, 5.93) 0.71
(0.34, 1.45)
zolpidem-ER 0.43
(0.22, 0.82) 0.29
(0.12, 0.64) 0.53
(0.20, 1.35) 0.84
(0.37, 1.90) 0.78
(0.23, 2.61) 1.53
(0.61, 3.93) 0.37
(0.14, 0.95) 0.93
(0.14, 5.57) 0.59
(0.26, 1.34)
zopiclone 0.55
(0.20, 1.53) 0.37
(0.10, 1.26) 0.68
(0.20, 2.30) 1.08
(0.34, 3.33) 1.28
(0.38, 4.28) 1.96
(0.93, 4.32) 0.47
(0.14, 1.61) 1.19
(0.15, 8.38) 0.76
(0.24, 2.35)
eszopiclone 0.28
(0.14, 0.53) 0.19
(0.07, 0.48) 0.35
(0.13, 0.88) 0.55
(0.23, 1.24) 0.65
(0.25, 1.63) 0.51
(0.23, 1.08) 0.24
(0.09, 0.62) 0.61
(0.09, 3.64) 0.39
(0.16, 0.87)
zaleplon 1.17
(0.58, 2.37) 0.77
(0.28, 2.11) 1.44
(0.53, 3.85) 2.27
(1.17, 4.48) 2.71
(1.05, 7.14) 2.12
(0.62, 7.38) 4.15
(1.61, 11.24) 2.53
(0.43, 13.10) 1.60
(0.68, 3.81)
triazolam 0.46
(0.09, 2.75) 0.31
(0.05, 2.06) 0.57
(0.09, 3.80) 0.90
(0.17, 5.35) 1.07
(0.18, 7.14) 0.84
(0.12, 6.52) 1.65
(0.27, 11.04) 0.40
(0.08, 2.30) 0.63
(0.11, 4.02)
ramelteon 0.73
(0.44, 1.20) 0.48
(0.20, 1.16) 0.90
(0.38, 2.09) 1.42
(0.69, 2.90) 1.69
(0.75, 3.88) 1.32
(0.43, 4.13) 2.59
(1.15, 6.10) 0.62
(0.26, 1.47) 1.58
(0.25, 9.03)
Notes: data are posterior median odds ratio (95% credible interval) and are presented as column treatment versus row treatment
ER, extended release; IR, immediate release
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Supplementary Table 43. Odds ratios for falls and/or accidental injury across the network: fixed effects
placebo lemborexant suvorexant eszopiclone
placebo 0.68 (0.30, 1.61) 0.85 (0.21, 2.90) 1.27 (0.73, 2.28)
lemborexant 1.47 (0.62, 3.33) 1.23 (0.25, 5.48) 1.86 (0.67, 5.08)
suvorexant 1.18 (0.34, 4.70) 0.81 (0.18, 4.08) 1.50 (0.39, 6.70)
eszopiclone 0.79 (0.44, 1.37) 0.54 (0.20, 1.50) 0.67 (0.15, 2.58)
Notes: data are posterior median odds ratio (95% credible interval) and are presented as column treatment versus row treatment
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Supplementary Table 44. Comparison of each treatment with placebo: NMA safety results
Intervention Odds ratio Hazard ratio
vs placebo SAE Withdrawal due to AE Somnolence Dizziness Falls/ injury SAE
Withdrawal due to AE Somnolence Dizziness Falls/ injury
lemborexant 1.38 (0.59, 3.66)
1.38 (0.69, 2.95)
7.73 (4.17, 15.71)
0.66 (0.32, 1.35)
0.68 (0.30, 1.61)
1.38 (0.59, 3.64)
1.38 (0.70, 2.94)
7.41 (4.03, 14.92)
0.66 (0.32, 1.33)
0.68 (0.30, 1.60)
suvorexant 0.26 (0.06, 0.81)
0.56 (0.30, 1.01)
2.15 (1.26, 3.70)
1.23 (0.61, 2.43)
0.85 (0.21, 2.90)
0.26 (0.06, 0.81)
0.57 (0.30, 1.01)
2.11 (1.26, 3.59)
1.22 (0.61, 2.41)
0.85 (0.21, 2.89)
zolpidem-IR NA 2.32 (1.52, 3.60)
2.32 (1.43, 3.85)
1.94 (1.18, 3.25) NA NA 2.27
(1.50, 3.48) 2.26
(1.41, 3.71) 1.89
(1.17, 3.12) NA
zolpidem-ER 4.40 (0.80, 28.06)
3.45 (1.33, 9.60)
2.65 (1.36, 5.32)
2.31 (1.22, 4.49) NA
4.35 (0.80, 27.33)
3.40 (1.33, 9.41)
2.59 (1.35, 5.12)
2.26 (1.22, 4.32) NA
zopiclone NA 3.14 (1.83, 5.49) NA 1.80
(0.66, 5.05) NA NA 3.02 (1.79, 5.19) NA 1.83
(0.70, 4.92) NA
eszopiclone 2.08 (0.86, 5.86)
1.61 (1.17, 2.24)
2.19 (1.27, 4.02)
3.52 (1.90, 7.20)
1.27 (0.73, 2.28)
2.08 (0.87, 5.79)
1.58 (1.16, 2.16)
2.15 (1.27, 3.90)
3.42 (1.86, 6.96)
1.26 (0.74, 2.26)
zaleplon NA 1.40 (0.80, 2.47)
1.51 (0.85, 2.73)
0.85 (0.42, 1.72) NA NA 1.38
(0.81, 2.42) 1.49
(0.85, 2.66) 0.86
(0.44, 1.70) NA
trazodone NA 2.43 (0.66, 8.35)
3.71 (1.82, 7.61) NA NA NA 2.38
(0.66, 7.92) 3.42
(1.77, 6.67) NA NA
flunitrazepam NA 2.81 (0.92, 7.60) NA NA NA NA 2.72
(0.90, 7.30) NA NA NA
estazolam NA 0.46 (0.17, 1.21)
0.59 (0.20, 1.77) NA NA NA 0.47
(0.18, 1.20) 0.60
(0.21, 1.75) NA NA
triazolam NA 1.85 (0.87, 3.83)
2.79 (0.78, 9.73)
2.16 (0.36, 11.46) NA NA 1.83
(0.87, 3.70) 2.67
(0.78, 8.95)
2.12 (0.38, 10.69)
NA
temazepam NA 1.93 (0.56, 5.85) NA NA NA NA 1.91
(0.56, 5.61) NA NA NA
brotizolam NA NA NA NA NA NA NA NA NA NA
ramelteon 3.37 (0.72, 26.02)
0.95 (0.54, 1.65)
2.77 (1.65, 4.85)
1.37 (0.83, 2.29) NA 3.37
(0.72,26.07) 0.95
(0.54, 1.65) 2.73
(1.64, 4.76) 1.35
(0.83, 2.22) NA
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Intervention Odds ratio Hazard ratio
vs placebo SAE Withdrawal due to AE Somnolence Dizziness Falls/ injury SAE
Withdrawal due to AE Somnolence Dizziness Falls/ injury
Data are median odds ratio or hazard ratio of each intervention vs placebo with 95% CrI from fixed effects NMA. Statistically significant differences (95% CrI excluding 1) are highlighted in bold font CrI, credible interval; ER, extended release; IR, immediate release; SAE, serious adverse event; NA, not available; NMA, network meta-analysis; vs, versus
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Supplementary Table 45. β for interaction in older subgroup analysis
Outcome β for interaction in older subgroup analysis (posterior median, 95% credible interval)
Difference in TST (PSG) at 4 weeks, minutes –4.1 (–41.5, 43.1)
Difference in WASO (PSG), at 4 weeks, minutes –1.4 (–13.6, 9.7)
Difference in LPS (PSG) at 4 weeks, minutes 2.7 (–9.5, 15.5)
Difference in SE (PSG) at 4 weeks, % 0.7 (–5.8, 7.3)
Difference in sTST at 4 weeks, minutes –0.14 (–8.07, 7.68)
Difference in sWASO at 4 weeks, minutes –4.5 (–15.2, 5.0)
Difference in sSOL at 4 weeks, minutes –1.2 (–7.4, 5.2)
Difference in ISI total score (0-28 point scale where lower score indicates lower severity) at 4 weeks
1.2 (–0.8, 2.9)
sQUAL (1 to 10 point scale where higher score indicates better quality of sleep) at 4 weeks
0.0 (–0.3, 0.3)
Odds ratio for SAE 0.52 (0.08, 3.02)
Odds ratio for withdrawal due to AE 0.59 (0.35, 1.01)
Odds ratio for somnolence 0.48 (0.26, 0.87)
Odds ratio for dizziness 0.93 (0.46, 1.91)
Odds ratio for fall and accidental injury 2.89 (0.69, 15.75)
AE, adverse event; ISI, Insomnia Severity Index; LPS, latency to persistent sleep; min, minutes; PSG, polysomnographic; SAE , serious adverse event; SE, sleep efficiency; sQUAL, subjective quality of sleep; sSOL, subjective sleep onset latency, TST, total sleep time; WASO, wake time after sleep onset
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Supplementary Figure 1. Network diagrams for included studies reporting WASO (PSG), LPS (PSG) and SE (PSG) at 4 weeks
WASO (PSG)
LPS (PSG)
SE (PSG)
The width of the lines is proportional to the number of studies comparing each pair of treatments, and the size of each circle is proportional to the number of studies investigating that treatment. Zolpidem denotes zolpidem-IR
ER, extended release; IR, immediate release; LPS, latency to persistent sleep; PSG, polysomnographic; SE, sleep efficiency; WASO, wake after sleep onset
placebo
lemborexant
suvorexant
zolpidem-IR
zolpidem-ER
eszopiclone
ramelteon
placebo
lemborexant
suvorexantzolpidem-IR
zolpidem-ER
zopiclone
eszopiclone
zaleplon triazolam
ramelteon
placebo
lemborexant
zolpidem-IR
zolpidem-ER
zopiclone
eszopiclone
triazolam
ramelteon
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Supplementary Figure 2. Network diagrams for included studies reporting sTST and sWASO at 4 weeks, 3 months and 6 months
sTST (4 weeks)
sTST (3 months)
sTST (6 months)
sWASO (4 weeks)
sWASO (3 months)
sWASO (6 months)
The width of the lines is proportional to the number of studies comparing each pair of treatments, and the size of each circle is proportional to the number of studies investigating that treatment.
ER, extended release; IR, immediate release; sTST, subjective total sleep time; sWASO, subjective wake after sleep onset
placebo
lemborexant
suvorexant
zolpidem-IR
zolpidem-ER
eszopiclone
zaleplon
trazodone
triazolam
temazepam
brotizolam
ramelteon
placebo
lemborexant
suvorexant
eszopiclone
ramelteon
placebo
lemborexant
zolpidem-IR
eszopiclone
ramelteon
placebo
lemborexant
suvorexantzolpidem-IR
zolpidem-ER
eszopiclone
trazodone
temazepam brotizolam
ramelteon
placebo
lemborexant
suvorexant
eszopiclone
ramelteon
placebo
lemborexant
zolpidem-IR
eszopiclone
ramelteon
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Supplementary Figure 3. Network diagram for included studies reporting sSOL and ISI total score at 4 weeks, 3 months and 6 months
sSOL (4 weeks)
sSOL (3 months)
sSOL (6 months)
ISI (4 weeks)
ISI (3 months)
ISI (6 months)
The width of the lines is proportional to the number of studies comparing each pair of treatments, and the size of each circle is proportional to the number of studies investigating that treatment.
ER, extended release; IR, immediate release; ISI, Insomnia Severity Index; sSOL, subjective sleep onset latency
placebo
lemborexant
suvorexant
zolpidem-IR
zolpidem-ER
eszopiclone
zaleplon
trazodone
triazolamtemazepam
ramelteon
placebo
lemborexant
suvorexant
eszopiclone
ramelteon
placebo
lemborexant
zolpidem-IR
eszopiclone
ramelteon
placebo
lemborexantsuvorexant
zolpidem-ER
zopiclone eszopiclone
placebo
lemborexant
suvorexant
eszopiclone
placebo
lemborexant
eszopiclone
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Supplementary Figure 4. Network diagram for included studies reporting sQUAL at 4 weeks, 3 months and 6 months
sQUAL (4 weeks)
sQUAL (3 months)
sQUAL (6 months)
The width of the lines is proportional to the number of studies comparing each pair of treatments, and the size of each circle is proportional to the number of studies investigating that treatment.
ER, extended release; IR, immediate release; sQUAL, subjective quality of sleep
placebo
lemborexant
suvorexant
zolpidem-IR
zolpidem-ER
eszopiclone
zaleplon
trazodone
estazolamtriazolam
ramelteon
placebo
lemborexant
suvorexant
eszopiclone
ramelteon
placebo
lemborexant
zolpidem-IR
eszopiclone
ramelteon
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Supplementary Figure 5. Ranking of suvorexant, zolpidem-IR, zolpidem-ER, zopiclone, eszopiclone and zaleplon on objective efficacy outcome measures at 4 weeks
ER, extended release; IR, immediate release; LPS, latency to persistent sleep; PSG; polysomnography; SE, sleep efficiency; TST, total sleep
time; WASO, wake after sleep onset
0
0.2
0.4
0.6
0.8
1
0 1 2 3 4 5 6 7 8 9 1rank
zolpidem-CR
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Supplementary Figure 6. Ranking of triazolam, ramelteon and placebo on objective efficacy outcome measures at 4 weeks
LPS, latency to persistent sleep; PSG; polysomnography; SE, sleep efficiency; TST, total sleep time; WASO, wake after sleep onset
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Supplementary Figure 7. Ranking of lemborexant, suvorexant, zolpidem-IR, zolpidem-ER, zopiclone and eszopiclone on subjective efficacy outcome measures at 4 weeks
ER, extended release; IR, immediate release; ISI, Insomnia Severity Index; sQUAL, subjective quality of sleep; sSOL, subjective sleep onset
latency; sTST, subjective total sleep time; sWASO, subjective wake after sleep onset
0
0.2
0.4
0.6
0.8
1
0 1 2 3 4 5 6 7 8 9 10 11 12rank
lemborexant
0
0.2
0.4
0.6
0.8
1
0 1 2 3 4 5 6 7 8 9 10 11 12rank
suvorexant
0
0.2
0.4
0.6
0.8
1
0 1 2 3 4 5 6 7 8 9 10 11 12rank
zolpidem-IR
0
0.2
0.4
0.6
0.8
1
0 1 2 3 4 5 6 7 8 9 10 11 12rank
zolpidem-CR
0
0.2
0.4
0.6
0.8
1
0 1 2 3 4 5 6 7 8 9 10 11 12rank
zopiclone
0
0.2
0.4
0.6
0.8
1
0 1 2 3 4 5 6 7 8 9 10 11 12rank
eszopiclone
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Supplementary Figure 8. Ranking of zaleplon, trazodone, estazolam, triazolam, temazepam and brotizolam on subjective efficacy outcome measures at 4 weeks
ISI, Insomnia Severity Index; sQUAL, subjective quality of sleep; sSOL, subjective sleep onset latency; sTST, subjective total sleep time; sWASO,
subjective wake after sleep onset
0
0.2
0.4
0.6
0.8
1
0 1 2 3 4 5 6 7 8 9 10 11 12rank
zaleplon
0
0.2
0.4
0.6
0.8
1
0 1 2 3 4 5 6 7 8 9 10 11 12rank
trazodone
0
0.2
0.4
0.6
0.8
1
0 1 2 3 4 5 6 7 8 9 10 11 12rank
estazolam
0
0.2
0.4
0.6
0.8
1
0 1 2 3 4 5 6 7 8 9 10 11 12rank
triazolam
0
0.2
0.4
0.6
0.8
1
0 1 2 3 4 5 6 7 8 9 10 11 12rank
temazepam
0
0.2
0.4
0.6
0.8
1
0 1 2 3 4 5 6 7 8 9 10 11 12rank
brotizolam
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Supplementary Figure 9. Ranking of ramelteon and placebo on subjective efficacy outcome measures at 4 weeks
ISI, Insomnia Severity Index; sQUAL, subjective quality of sleep; sSOL, subjective sleep onset latency; sTST, subjective total sleep time; sWASO,
subjective wake after sleep onset
0
0.2
0.4
0.6
0.8
1
0 1 2 3 4 5 6 7 8 9 10 11 12rank
ramelteon
0
0.2
0.4
0.6
0.8
1
0 1 2 3 4 5 6 7 8 9 10 11 12rank
placebo
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Supplementary Figure 10. Network diagrams for included studies reporting SAE, withdrawals due to AE, somnolence, dizziness and falls/accidental injury
SAE
Withdrawals due to AE
Somnolence
Dizziness
Falls and/or accidental injury
The width of the lines is proportional to the number of studies comparing each pair of treatments and the size of each circle is proportional to the number of studies investigating that treatment.
AE, adverse event; ER, extended release; IR, immediate release; SAE, serious adverse event
placebo
lemborexantsuvorexant
zolpidem-ER
eszopiclone ramelteon
placebo
lemborexant
suvorexant
zolpidem-IRzolpidem-ER
zopiclone
eszopiclone
zaleplon
trazodone
flunitrazepam
estazolam triazolam
temazepam
ramelteon
placebo
lemborexant
suvorexant
zolpidem-IR
zolpidem-ER
eszopiclone
zaleplon
trazodone
estazolamtriazolam
ramelteon
placebo
lemborexant
suvorexantzolpidem-IR
zolpidem-ER
zopiclone
eszopiclone
zaleplon triazolam
ramelteon
placebo
lemborexant
suvorexant
eszopiclone
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Supplementary Figure 11. Comparison-adjusted funnel plots for WASO, LPS and SE (all PSG) at 4 weeks
WASO
Treatments: [A] placebo; [B] lemborexant; [C] suvorexant; [D] zolpidem-IR; [E] zolpidem-ER; [F] eszopiclone; [G] ramelteon
LPS
Treatments: [A] placebo; [B] lemborexant; [C] suvorexant; [D] zolpidem-IR; [E] zolpidem-ER; [F] zopiclone; [G] eszopiclone; [H] zaleplon; [I] triazolam; [J] ramelteon
SE
Treatments: [A] placebo; [B] lemborexant; [C] zolpidem-IR; [D] zolpidem-ER; [E] zopiclone; [F] eszopiclone; [G] triazolam; [H] ramelteon.
ER, extended release; IR, immediate release; LPS, latency to persistent sleep; PSG, polysomnographic; SE, sleep efficiency; WASO, wake time after sleep onset
Note, generally comparisons are of active intervention vs placebo or newer vs older intervention. Thus the left hand side of the figure indicates studies where the newer treatment is more effective than placebo or older treatments compared with the comparison-specific pooled effect.
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Page 107
Supplementary Figure 12. Comparison-adjusted funnel plots for sTST, sWASO, sSOL and sQUAL at 4 weeks
sTST
sWASO
Treatments: [A] placebo; [B] lemborexant; [C] suvorexant; [D] zolpidem-IR; [E] zolpidem-ER; [F] eszopiclone; [G] trazodone; [H] temazepam; [I] brotizolam; [J] ramelteon
sSOL
Treatments: [A] placebo; [B] lemborexant; [C] suvorexant; [D] zolpidem-IR; [E] zolpidem-ER; [F] eszopiclone; [G] zaleplon; [H] trazodone; [I] triazolam; [J] temazepam; [K] ramelteon
sQUAL
Treatments: [A] placebo; [B] lemborexant; [C] suvorexant; [D] zolpidem-IR; [E] zolpidem-ER; [F] eszopiclone; [G] zaleplon; [H] trazodone; [I] estazolam; [J] triazolam; [K] ramelteon
ER, extended release; IR, immediate release; sQUAL, subjective quality of sleep; sSOL, subjective sleep onset latency; sTST, subjective total sleep time; sWASO, subjective wake time after sleep onset
Note, generally comparisons are of active intervention vs placebo or newer vs older intervention. Thus, generally the left hand side of the figure indicates studies where the newer treatment is more effective than placebo or older treatments compared with the comparison-specific pooled effect.
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Page 108
Supplementary Figure 13. Comparison-adjusted funnel plot for SAE, withdrawals due to AE, somnolence and dizziness
SAE
Treatments: [A] placebo; [B] lemborexant; [C] suvorexant; [D] zolpidem-ER; [E] eszopiclone; [F] ramelteon
Withdrawals due to AE
Somnolence
Treatments: [A] placebo; [B] lemborexant; [C] suvorexant; [D] zolpidem-IR; [E] zolpidem-ER; [F] eszopiclone; [G] zaleplon; [H] trazodone; [I] estazolam; [J] triazolam; [K] ramelteon
Dizziness
Treatments: [A] placebo; [B] lemborexant; [C] suvorexant; [D] zolpidem-IR; [E] zolpidem-ER; [F] zopiclone; [G] eszopiclone; [H] zaleplon; [I] triazolam; [J] ramelteon
AE, adverse event; ER, extended release; IR, immediate release; SAE, serious adverse event
Note, generally comparisons are of active intervention vs placebo or newer vs older intervention. Thus the left hand side of the figure indicates studies where the newer treatment is safer than placebo or older treatments compared with the comparison-specific pooled effect.
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B - A C - A D - A E - A G - A H - AI - A J - A B - E D - H D - I G - FH - I