supplementary materials comparative efficacy of

15 April 2021

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



months: fixed effects ........................................................................................... 61



Supplementary Table 22. Differences in sWASO across the network (minutes) at

4 weeks: random effects ..................................................................................... 63


3 months: fixed effects ........................................................................................ 65


6 months: fixed effects ........................................................................................ 66

Supplementary Table 25. Differences in sSOL across the network (minutes) at 4






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Supplementary Table 28. Differences in ISI total score across the network at 4






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


10 where higher score indicates better quality of sleep) at 3 months: fixed effects

............................................................................................................................ 76


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


at least one dizziness event data ........................................................................ 84


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

15 April 2021

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


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


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


Mean age (years)


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


Mean age (years)


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


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


MC, DB, PC

Americas, Australia, Europe, Asia, South Africa

3 months 56.6 35% Adult (18–65 years) and older ≥65 years


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


Mean age (years)


sSOL≥30 minutes for a minimum of 3 months

Leppik 1997 48

MC, DB, PC, AC


Chronic insomnia of at least 3 months

placebo = 84



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



sTST ≤6.5hrs per night

sSOL >30 minutes for at least 1 month

placebo = 128


Pinto 2016 51

SC, DB, AC

Brazil 4 weeks 47.4 25% 20-64 years

Symptomatic insomnia ≥3 months



Randall 2012 52

DB, PC



placebo = 47

zolpidem-IR, 5/10 mg = 44

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Study Study type


Mean age (years)


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



Roth 2006a 55

MC, DB, PC

USA 5 weeks 72.4 31% Older (≥65 years)

Primary insomnia (DSM-IV-Tre) ≥ 3 months

placebo = 274



Roth 2006b 56

MC, DB, PC

USA, Canada, Australia

3 weeks 44.3 42% 18-64 years


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, 15mgb = 25

Scharf 2005 59

MC, DB, PC



sTST ≤6.5 hours

sSOL>30mins for at least 1 month

placebo = 80



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Study Study type


Mean age (years)


Soares 2006 62

MC, DB, PC

NR 4 weeks 49.1 0% Female 40-60 years


sTST ≤6 hours

sSOL >45mins ≥3 times per week, ≥1 month

placebo = 209


Study 201 60

MC, DB, PC


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




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



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


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Study Study type


Mean age (years)


ISI>=13 lemborexant, 10mg = 269


Tsutsui 2001 63

MC, DB, AC

Japan 2 weeks 42.2 35% Primary insomnia experiencing difficulties sleeping more than 3 times per week



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


Voshaar 2004 66

MC, DB, AC

Netherlands

4 weeks 46.1 33% 18-64 years

Primary insomnia (DSM-III-R)


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


Mean age (years)


PC, AC

sTST = 4-6 hours at least 3 nights per week


Walsh 1998b 69

MC, DB, PC, AC


Primary insomnia (DSM-IIIR)

placebo = 34

zaleplon, 5mg = 34

zaleplon, 10mg = 33


Walsh 2000 70

MC, DB, PC

USA 5 weeks 42.1 26% 18–65 years


placebo = 57

zaleplon, 10mg = 56

Walsh 2007 71

MC, DB, PC



sTST ≤6.5 hours and

sSOL>30 mins ≥ 1 month

placebo = 280


Walsh 2008 72

MC, DB, PC

Argentina Canada, USA, Mexico, Europe

3 weeks 70.2 43% Older (65-87 years)


sWASO ≥1, ≥ 3 nights per week and

Time spent in bed = 6.5-9 hours

placebo = 106


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


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Study Study type


Mean age (years)


sTST = 4-6 hours

sSOL ≥30 minutes for ≥3-months


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


sTST ≤6.5hrs

sSOL≥30min for ≥ 1 month

placebo = 99

eszopiclone, 3 mg = 105

eszopiclone, 2 mg = 104

Zammit 2007 77

MC, DB, PC



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?


Unclear Unclear Yes Yesa Unclear Yesf Yes, Yes, NR Yesg


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


Yes Yes Yes Yes No No Yes, Yes, Yes Yesg

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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

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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



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

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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

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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

15 April 2021

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



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



Trial-level

Timepoint Statistic Group 2 – Group 1 N Mean difference se difference

Black 2017


Change zolpidem-IR - placebo 345 6.0d 5.10d

15 April 2021

3 months


Mayer 2009

Average of last 2 nights of month 3


6 months


Mayer 2009



Randall 2012

Average of 2 nights in month 8


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.

15 April 2021

Supplementary Table 5. Results of individual studies, sTST data (minutes)

4 weeks


Study 303 Last 7 nights of month





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




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

15 April 2021

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


Fry 2000 Week 4 actual placebo 107 364.3d 6.14f zaleplon 203 368.2d 4.46f


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


actual placebo 224a

340.3 4.04 ramelteon 227a 342.2 4.04

Randall 2012

average of 2 nights in month 1


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

15 April 2021

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


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


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


3 months


Study 303 last 7 nights of month


15 April 2021


average over last 2 weeks of month 3



average over last 2 weeks of month 3


Ancoli-Israel 2010


Krystal 2003



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


6 months


Study 303 last 7 nights of month


Krystal 2003



Mayer 2009


actual placebo 224a

349.5 4.35 ramelteon 227a 345.4 4.34

Randall 2012



Walsh 2007



15 April 2021

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.

15 April 2021

Supplementary Table 6. Results of individual studies, WASO (PSG) data (minutes)

4 weeks



Change placebo 52 -38.2 4.70 lemborexant 68 -50.7 4.10



zolpidem-ER 263 -37.7 2.22


Month 1 Change placebo 272b -18.7 2.58 suvorexant 185b -45.0 3.14



McCall 2006

2 weeks Change placebo 128a -12.5 3.17 eszopiclone 136a -25.3 3.46

Randall 2012


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


Actual placebo 131 56.4 3.11 ramelteon 139 59.9 3.04


Black 2017 Average of nights 15-16


Roth 2006b


Change zolpidem-ER – placebo 199 -16.0 3.72

Walsh 2008



15 April 2021

3 months


Herring 2016 – Trial 1




6 months


Randall 2012



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

15 April 2021

Supplementary Table 7. Results of individual studies, sWASO data (minutes)

4 weeks


Study 201 Days 8-15 change placebo 56 -31.6 5.17 lemborexant 68 -49.7 4.73


change placebo 297 -17.2 3.10 lemborexant 590 -23.4 2.17



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



change placebo 365b -17.9 1.84 suvorexant 244b -23.3 2.24




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


15 April 2021

Dorsey 2004

Week 4 actual placebo 73 47.0 4.72 zolpidem-IR 68 29.0 5.30

Krystal 2003



Mayer 2009


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


Zammit 2004





change zolpidem-IR - placebo 345 -12.7h 3.11h

3 months




15 April 2021


Average over last 2 weeks of month 3





Ancoli-Israel 2010

Week 12 actual placebo 194 73.0 4.00 eszopiclone 194 55 4

Krystal 2003



Mayer 2009



Walsh 2007



6 months




Krystal 2003



Mayer 2009



Randall 2012


actual placebo 47c 59.6 7.64 zolpidem-IR 44c 52.3 8.79

Walsh 2007

Average of 4 weeks in month 6


15 April 2021

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

15 April 2021

Supplementary Table 8. Results of individual studies, LPS (PSG) data (minutes)

4 weeks






zolpidem-ER 250 -7.5 2.22


Month 1 Change placebo 272 -23.3 1.84 suvorexant 185 -33.6 2.22



McCall 2006


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



Pinto 2016 Day 28 Actual zopiclone 97 15.7d 1.99d eszopiclone 102 10.6d 1.17d

Randall 2012



Scharf 1994



Walsh 2000

Average of first 2 nights of week 4

Actual placebo 47 36.1 3.63 zaleplon 50 30.1 4.26

15 April 2021

Walsh 1998b


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


Zammit 2007




Black 2017 Average of nights 15-16

Change zolpidem-IR - placebo 345 -10.5f 3.4f

Roth 2006b



Walsh 2008



3 months






Mayer 2009



15 April 2021

6 months


Mayer 2009



Randall 2012



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

15 April 2021

Supplementary Table 9. Results of individual studies, sSOL data (minutes)

4 weeks


Study 201 Days 8-15 Change placebo 56 -13.5 3.77 lemborexant 68 -26.8 3.70





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



Change placebo 365b -11.7 1.79 suvorexant 244b -17.1 2.17




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


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

15 April 2021

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


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



Roth 2006a


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

15 April 2021

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)


Walsh 1998a


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



Zammit 2007




change zolpidem-IR - placebo 345 -6.1d 2.40d

3 months










15 April 2021

Ancoli-Israel 2010

Week 12 Actual placebo 194 59.0 4.00 eszopiclone 194 47.0 4.00

Krystal 2003



Mayer 2009


Walsh 2007



6 months




Krystal 2003



Mayer 2009


Randall 2012



Walsh 2007



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:

15 April 2021

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.

15 April 2021

Supplementary Table 10. Results of individual studies, SE (PSG) data (%)

4 weeks







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


Actual placebo 47b 79.8 1.43 zolpidem-IR 44b 86.3 1.25

Scharf 1994



Zammit 2004


Zammit 2007




Roth 2006b


Change zolpidem-ER – placebo 199 3.0 1.3

Walsh 2008


Change zolpidem-ER – placebo 199 2.3 1.2

15 April 2021

6 months


Randall 2012


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

15 April 2021

Supplementary Table 11. Results of individual studies, sSE data (%)


4 weeks



Study 303 Average of last 7 nights of month





3 months



6 months



ER, extended release; N, number of patients; se, standard error; sSE, subjective sleep efficiency

15 April 2021

Supplementary Table 12. Results of individual studies, ISI total score data (scale: 0 to 28 where lower score reflects lower severity)


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


month 1 change placebo 360b -2.9 0.23 suvorexant 241b -4.0 0.26


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


3 months



Month 3 change placebo 339 -4.6 0.26 suvorexant 228 -5.7 0.31

15 April 2021



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



6 months


Walsh 2007



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.

15 April 2021

Supplementary Table 13. Results of individual studies, quality of sleep transformed into 1 (poor) to 10 (excellent) scale

4 weeks







Hajak 2009 Week 2 (average) Change placebo 128 0.8 0.11 zolpidem-IR 140 1.6 0.11







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


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


Fry 2000 Week 4 Actual placebo 107 6.4 0.15 zaleplon 203 6.3 0.11


15 April 2021

Hedner 2000


Krystal 2003 Average of weeks 1-4


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


McCall 2006 2 weeks Actual placebo 128 6.7 0.14 eszopiclone 136 7.3 0.14

Randall 2012



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


Walsh 1998a


trazodone 98 5.7 0.21

Zammit 2004

Average of nights 1,15,29,43 and 44


Zammit 2007

Week 5 Actual placebo 131 6.0 0.09 ramelteon 139 6.1 0.09


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

15 April 2021

3 months














Walsh 2007 Month 3 (average of 4 weeks)


6 months








Randall 2012



Walsh 2007 Month 6 (average of 4 weeks)


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:

15 April 2021

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

15 April 2021

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

15 April 2021

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

15 April 2021

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

15 April 2021

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

15 April 2021

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,


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)

15 April 2021

Lemborexant 3 months 6 months

vs

Comparator sTST, min sWASO,


sQUAL (scale 1-10) sTST, min sWASO,


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

15 April 2021

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)

15 April 2021

placebo lemborex

ant suvorexa

nt zolpidem

-IR zolpidem

-ER eszopiclo


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)


ER, extended release; IR, immediate release; sTST, subjective total sleep time

15 April 2021

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)


sTST, subjective total sleep time

15 April 2021

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)


IR, immediate release; sTST, subjective total sleep time

15 April 2021

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)

15 April 2021

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)


ER, extended release; IR, immediate release; sWASO, subjective wake time after sleep onset

15 April 2021

Supplementary Table 23. Differences in sWASO across the network (minutes) at 3 months: fixed effects


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)


sWASO, subjective wake time after sleep onset

15 April 2021

Supplementary Table 24. Differences in sWASO across the network (minutes) at 6 months: fixed effects


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)


IR, immediate release; sWASO, subjective wake time after sleep onset

15 April 2021

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)

15 April 2021

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)


ER, extended release; IR, immediate release; sSOL, subjective sleep onset latency

15 April 2021

Supplementary Table 26. Differences in sSOL across the network (minutes) at 3 months: fixed effects


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)


sSOL, subjective sleep onset latency

15 April 2021

Supplementary Table 27. Differences in sSOL across the network (minutes) at 6 months: fixed effects


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)


IR, immediate release; sSOL, subjective sleep onset latency

15 April 2021

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

15 April 2021

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)


ISI, Insomnia Severity Index

15 April 2021

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)


ISI, Insomnia Severity Index

15 April 2021

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)

15 April 2021

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

15 April 2021

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 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)


sQUAL, subjective quality of sleep

15 April 2021

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 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)


IR, immediate release; sQUAL, subjective quality of sleep

15 April 2021

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


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%

15 April 2021


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.

15 April 2021

Supplementary Table 35. Results of individual studies, withdrawal due to adverse event data


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%


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%


Tsutsui 2001 2 weeks zolpidem-IR

18 211 8.5% zopiclone 23 225 10.2%

Uchiyama 2011b


Walsh 1998a 2 weeks placebo 2 104 1.9% zolpidem-IR 5 102 4.9%

trazodone 5 100 5.0%


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%


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%

15 April 2021


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%




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 2004 ~6 weeks placebo 0 99 0.0% eszopiclone 3 209 1.4%

Ancoli-Israel 2010







Mayer 2009d 6 months placebo 10 224 4.5% ramelteon 7 227 3.1%


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

15 April 2021

Supplementary Table 36. Results of individual studies, percentage experiencing at least one somnolence event data


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%



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%


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%


triazolam 1 31 3.2%


Walsh 2008 3 weeks placebo 5 106 5% zolpidem-ER 6 99 6%

Wang-Weigand 2011


Elie 1999 4 weeks placebo 1 126 0.8% zolpidem-IR 6 122 4.9%

zaleplon 9 241 3.7%


zaleplon 15 238 6.3%





Zammit 2004c ~6 weeks placebo 3 99 3.0% eszopiclone 16 209 7.7%

Ancoli-Israel 2010




15 April 2021






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.

15 April 2021

Supplementary Table 37. Results of individual studies, percentage experiencing at least one dizziness event data


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%


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%


Uchiyama 2011



triazolam 3 31 9.7%

Yan 2013 2 weeks estazolam NR

<2% brotizolam NR

>2%


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%


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%



Hajak 1994c 4 weeks placebo 82 298 27.5% zopiclone 169 612 27.6%

flunitrazepam

83 290 28.6% triazolam 91 307 29.6%


Scharf 1994 5 weeks placebo 0 24 0.0% zolpidem-IR 3 26 11.5%


Zammit 2004b

~6 weeks placebo 4 99 4.0% eszopiclone 8 209 3.8%

Ancoli-Israel 2010




15 April 2021





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.

15 April 2021

Supplementary Table 38. Results of individual studies, percentage experiencing at least one fall or accidental injury event data


Fall

Scharf 2005 2 weeks placebo 0 80 0.0% eszopiclone 0 151 0.0%





Ancoli-Israel 2010







Accidental injury




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.

15 April 2021

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

15 April 2021

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


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)

15 April 2021

placebo lembore

xant suvorexa

nt zolpidem

-IR zolpidem

-ER zopiclon

e eszopiclo


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)


AE, adverse event; ER; extended release; IR, immediate release

15 April 2021

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)


ER; extended release; IR, immediate release

15 April 2021

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)


ER, extended release; IR, immediate release

15 April 2021

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)


15 April 2021

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

15 April 2021

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

15 April 2021

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

15 April 2021

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

15 April 2021

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


zolpidem-ER

eszopiclone

trazodone

temazepam brotizolam

ramelteon

placebo

lemborexant

suvorexant

eszopiclone

ramelteon

placebo

lemborexant

zolpidem-IR

eszopiclone

ramelteon

15 April 2021

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)


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

15 April 2021

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)


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

15 April 2021

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

15 April 2021

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

15 April 2021

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

15 April 2021

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

15 April 2021

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

15 April 2021

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


zolpidem-ER

zopiclone

eszopiclone

zaleplon triazolam

ramelteon

placebo

lemborexant

suvorexant

eszopiclone

15 April 2021

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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B - A C - A D - A E - A F - A G - AB - E

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15 April 2021

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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15 April 2021

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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supplementary materials comparative efficacy of

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