Efficacy of pharmacotherapy for obstructive sleep apnoea in adults: a systematic review and network meta-analysis

Thomas Gaisl, MD1 · Sarah R. Haile, PhD2 · Sira Thiel1 · Martin Osswald, MSc1

· Prof Malcolm Kohler, MD1

1 Department of Pulmonology, University Hospital Zurich, Zurich, Switzerland2 Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Zurich,

Switzerland

Methods.................................................................................................................................................. 2

Inclusion criteria.................................................................................................................................. 2

Identification of trials........................................................................................................................... 2

Selection of trials and data extraction.................................................................................................2

Table 1. Search results by database before and after duplication......................................................3

Table 2. Final search terms used for the database «Medline»............................................................4

Table 3. Final search terms used for the database «EMBASE».........................................................5

Table 4. Final search terms used for the database «Cochrane Library »............................................6

Table 5. Final search terms used for the database « PsycINFO».......................................................7

Table 6. Final search terms used for the database «Web of Science»...............................................9

Table 7. Final search terms used for the database «ClinicalTrials.gov»...........................................10

Table 8. Final search terms used for the database «WHO ICTRP»..................................................10

Table 9. PRISMA checklist................................................................................................................11

Results................................................................................................................................................. 13

Figure 1. Funnel plots for included studies........................................................................................13

Figure 2. Treatment effects for each included trial............................................................................14

Figure 3. Predicted effects on AHI by drug category.........................................................................15

Figure 4. Predicted effects on ODI by drug category........................................................................16

Figure 5. Observed mean difference in AHI of included studies.......................................................17

Figure 6. Observed mean difference in ODI of included studies.......................................................18

Table 10. Currently ongoing studies.................................................................................................19

Table 11. Risk of bias of included trials.............................................................................................20

Figure 6. Proportion of bias...............................................................................................................21

Table 12. Details and classification of included RCTs......................................................................22

Table 13. Inclusion and exclusion criteria of included RCTs.............................................................25

References........................................................................................................................................... 34

Page 1 of 38

MethodsInclusion criteriaTo be included in the meta-analysis, trials must have measured and reported variables of OSA

severity during unenforced sleep (e.g. AHI, oxygen desaturation index) at a follow-up visit

and preferably also at baseline or reported a treatment effect for this outcome. Both parallel

and crossover RCTs and only trial reports in humans and published in English, German and

French were considered for eligibility.

Identification of trialsThe electronic literature search as well as the reporting of the trials was performed according

to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)

statement.1 The literature search was performed independently by two of the authors (TG and

ST) using the following databases from their inception June 1st 2018: MEDLINE, EMBASE,

the Cochrane Central Register of Controlled Trials (CENTRAL) Issue 3. Medical Subject

Headings for OSA were applied and RCTs were identified using the RCT-filter and/or the

Cochrane Collaboration highly sensitive search strategy (sensitivity-maximizing and

precision-maximizing version).2 We used an adaptive search algorithm for optimization,

meaning that as soon as an eligible study for this review was identified, the drug was added to

the search and the whole search was repeated. Additionally, preceding systematic reviews3-7

and bibliographies of included trials and reports were screened for potentially eligible studies

that might have been missed via the database search.

Selection of trials and data extractionThe screening and data extraction of potentially eligible studies was completed by two authors

(TG and MO). Disagreements in study identification and in extracted data between

investigators were resolved by discussion and consensus. For each included study, relevant

data were extracted independently using a standardized electronic spreadsheet according to

the study protocol. The relevant drugs and the corresponding studies were systematically

examined by pharmacist (MO) who classified the drugs by their proposed mechanism and

target receptors independently of the proposed mechanism of the original paper. Two authors

(TG and MO) evaluated the risk of bias in each study included in the meta-analysis using the

Cochrane Collaboration tool for assessing risk of bias.8 The primary outcome was the change

in objectively assessed OSA-severity parameters (i.e. AHI, oxygen desaturation index) from

baseline to follow-up.

Page 2 of 38

Table 1. Search results by database before and after duplication. The final search was performed on June 01, 2018.

De-duplication

Before After

Databases

Medline (including Epub Ahead of Print, In-Process & Other Non-Indexed Citations) - www.ncbi.nlm.nih.gov/pubmed/ 913 896

Embase (including conference abstracts) - www.embase.com 3,025 2,291

Cochrane - www.cochranelibrary.com 1,681 577

Web of Science - apps.webofknowledge.com 1,954 950

PsycInfo - www.apa.org/pubs/databases/psycinfo 338 198

All records 7,911 4,912

Registries

Clinicaltrials.gov - clinicaltrials.gov 275 136

ICTRP WHO - who.int/trialsearch 254 114

All registries 529 250

Page 3 of 38

Table 2. Final search terms used for the database «Medline». Accessed via Ovid® - www.ovid.com/ (including Epub Ahead of Print, In-Process & Other Non-Indexed Citations).

# Search terms Results

1 (exp Sleep Apnoea Syndromes/ or ((sleep or nocturnal) adj3 (apnoea* or apnoea* or obstructive)).ti,ab. or (hypopnoea* or hypopnoea* or OSA or OSAS or SHS or SAHS or OSAH or OSAHS).ti,ab. or 'sleep-disordered breathing'.ti,ab.) not exp colonoscopy/ not exp Tonsillectomy/

43,292

2 exp Drug Therapy/ or exp Benzodiazepines/ or expAnalgesics, Opioid/ or (drug* or medic* or pharmaceuticalor pharmaco*).ti,ab. or (non-benzodiazepine* ornonbenzodiazepine* or Zaleplon or Zolpidem orEszopiclone or Zopiclone or Triazolam or Nitrazepam orFlurazepam or Loprazolam or Lormetazepam orTemazepam or Estazolam or Oxazepam or Alprazolam orLorazepam or Clonazepam or Quazepam or Diazepam orMidazolam or Buprenorphine or Dipipanone or Diamorphine or Alfentanyl or Remifentanyl or remifentanilor Fentanyl or Methadone or Oxycodone or Papaveretumor Pentazocine or Pethidine or Tramadol or Codeine orMeptazinol or sodium oxybate or ramelteon or Rozeremor Gabapentin or Pregabalin or Melatonin or hypnotic* oropiate* or opioid* or analgesic* or sedative*).ti,ab. or(Acetazolamide or Adalimumab or Almitrine orAminophylline or Buspirone or Carbocysteine orCilazapril or Clonidine or Desipramine or Desloratadineor Donepezil or Doxapram or Dronabinol or Eszopicloneor Fenofibrate or Flumazenil or Fluoxetine or Fluticasoneor Liraglutide or Medroxyprogesterone or Mibefradil orMirtazapine or 'Mometasone furoate' or Montelukast orNaloxone or Naltrexone or Ondansetron or Paroxetine orPhentermine or Phosphocholinamin or Physostigmine orPioglitazone or Protriptyline or Sabeluzole or Salmeterolor Spironolactone or Surfactant or Temazepam orTestosterone or Theophylline or Tiagabine or Topiramateor Tramazoline or Trazodone or Xylometazoline orZonisamide).ti,ab.

4,407,594

3 1 and 2 8,343

4 (randomized controlled trial or controlled clinical trial).pt. or randomized.ab. or placebo.ab. or clinical trials as topic.sh. or randomly.ab. or trial.ti.

1,154,235

5 3 and 4 1,001

6 5 not (animals not humans).sh. not ((exp child/ or exp infant/ or exp adolescent/) not exp adult/)

928

7 limit 6 to (english or german or french or spanish) 913

Page 4 of 38

Table 3. Final search terms used for the database «EMBASE» https://www.embase.com/ (including conference abstracts)

# Search terms Results

1 ('sleep disordered breathing'/exp OR (((sleep OR nocturnal) NEAR/3 (apnoea* OR apnoea* ORobstructive)):ti,ab) OR hypopnoea*:ti,ab OR hypopnoea*:ti,ab OR osa:ti,ab OR osas:ti,ab ORshs:ti,ab OR sahs:ti,ab OR osah:ti,ab OR osahs:ti,ab OR 'sleep-disordered breathing':ti,ab)NOT 'colonoscopy'/exp NOT 'tonsillectomy'/exp

73,113

2 'drug therapy'/exp OR 'benzodiazepine derivative'/exp OR 'narcotic analgesic agent'/exp ORdrug*:ti,ab OR medic*:ti,ab OR pharmaceutical:ti,ab OR pharmaco*:ti,ab OR 'nonbenzodiazepine*':ti,ab OR nonbenzodiazepine*:ti,ab OR zaleplon:ti,ab OR zolpidem:ti,ab ORzopiclone:ti,ab OR triazolam:ti,ab OR nitrazepam:ti,ab OR flurazepam:ti,ab OR loprazolam:ti,abOR lormetazepam:ti,ab OR estazolam:ti,ab OR oxazepam:ti,ab OR alprazolam:ti,ab ORlorazepam:ti,ab OR clonazepam:ti,ab OR quazepam:ti,ab OR diazepam:ti,ab ORmidazolam:ti,ab OR buprenorphine:ti,ab OR dipipanone:ti,ab OR diamorphine:ti,ab ORalfentanyl:ti,ab OR remifentanyl:ti,ab OR remifentanil:ti,ab OR fentanyl:ti,ab ORmethadone:ti,ab OR oxycodone:ti,ab OR papaveretum:ti,ab OR pentazocine:ti,ab ORpethidine:ti,ab OR tramadol:ti,ab OR codeine:ti,ab OR meptazinol:ti,ab OR 'sodiumoxybate':ti,ab OR ramelteon:ti,ab OR rozerem:ti,ab OR gabapentin:ti,ab OR pregabalin:ti,ab ORmelatonin:ti,ab OR hypnotic*:ti,ab OR opiate*:ti,ab OR opioid*:ti,ab OR analgesic*:ti,ab ORsedative*:ti,ab OR acetazolamide:ti,ab OR adalimumab:ti,ab OR almitrine:ti,ab ORaminophylline:ti,ab OR buspirone:ti,ab OR carbocysteine:ti,ab OR cilazapril:ti,ab ORclonidine:ti,ab OR desipramine:ti,ab OR desloratadine:ti,ab OR donepezil:ti,ab ORdoxapram:ti,ab OR dronabinol:ti,ab OR eszopiclone:ti,ab OR fenofibrate:ti,ab ORflumazenil:ti,ab OR fluoxetine:ti,ab OR fluticasone:ti,ab OR liraglutide:ti,ab ORmedroxyprogesterone:ti,ab OR mibefradil:ti,ab OR mirtazapine:ti,ab OR 'mometasonefuroate':ti,ab OR montelukast:ti,ab OR naloxone:ti,ab OR naltrexone:ti,ab OR ondansetron:ti,abOR paroxetine:ti,ab OR phentermine:ti,ab OR phosphocholinamin:ti,ab OR physostigmine:ti,abOR pioglitazone:ti,ab OR protriptyline:ti,ab OR sabeluzole:ti,ab OR salmeterol:ti,ab ORspironolactone:ti,ab OR surfactant:ti,ab OR temazepam:ti,ab OR testosterone:ti,ab ORtheophylline:ti,ab OR tiagabine:ti,ab OR topiramate:ti,ab OR tramazoline:

6,686,564

3 1 AND 2 19,939

4 'crossover procedure':de OR 'double-blind procedure':de OR 'randomized controlled trial':deOR 'single-blind procedure':de OR random*:de,ab,ti OR factorial*:de,ab,ti ORcrossover*:de,ab,ti OR ((cross NEXT/1 over*):de,ab,ti) OR placebo*:de,ab,ti OR ((doubl*NEAR/1 blind*):de,ab,ti) OR ((singl* NEAR/1 blind*):de,ab,ti) OR assign*:de,ab,ti ORallocat*:de,ab,ti OR volunteer*:de,ab,ti

2,235,952

5 3 AND 4 3,249

6 5 NOT ([animals]/lim NOT [humans]/lim) NOT (([infant]/lim OR [child]/lim OR [adolescent]/lim)NOT ([adult]/lim OR [aged]/lim))

3,065

7 6 AND ([english]/lim OR [german]/lim OR [french]/lim OR [spanish]/lim) 3,025

Page 5 of 38

Table 4. Final search terms used for the database «Cochrane Library » http://cochranelibrary-wiley.com/

# Search terms Results

1 ((sleep or nocturnal) near/3 (apnoea* or apnoea* or obstructive)):ti,ab,kw or hypopnoea* or

hypopnoea* or OSA or OSAS or SHS or SAHS or OSAH or OSAHS or "sleep-disordered

breathing":ti,ab,kw (Word variations have been searched)

5,511

2 (drug* or medic* or pharmaceutical or pharmaco* or "non-benzodiazepine*" ornonbenzodiazepine* or Zaleplon or Zolpidem or Eszopiclone or Zopiclone or Triazolamor Nitrazepam or Flurazepam or Loprazolam or Lormetazepam or Temazepam orEstazolam or Oxazepam or Alprazolam or Lorazepam or Clonazepam or Quazepam orDiazepam or Midazolam or Buprenorphine or Dipipanone or Diamorphine or Alfentanylor Remifentanyl or remifentanil or Fentanyl or Methadone or Oxycodone or Papaveretumor Pentazocine or Pethidine or Tramadol or Codeine or Meptazinol or "sodium oxybate"or ramelteon or Rozerem or Gabapentin or Pregabalin or Melatonin or hypnotic* oropiate* or opioid* or analgesic* or sedative* or Acetazolamide or Adalimumab orAlmitrine or Aminophylline or Buspirone or Carbocysteine or Cilazapril or Clonidine orDesipramine or Desloratadine or Donepezil or Doxapram or Dronabinol or Eszopiclone orFenofibrate or Flumazenil or Fluoxetine or Fluticasone or Liraglutide orMedroxyprogesterone or Mibefradil or Mirtazapine or "Mometasone furoate" orMontelukast or Naloxone or Naltrexone or Ondansetron or Paroxetine or Phentermine orPhosphocholinamin or Physostigmine or Pioglitazone or Protriptyline or Sabeluzole orSalmeterol or Spironolactone or Surfactant or Temazepam or Testosterone orTheophylline or Tiagabine or Topiramate or Tramazoline or Trazodone or Xylometazolineor Zonisamide):ti,ab,kw (Word variations have been searched)

507,078

3 1 AND 2 1,681

Page 6 of 38

Table 5. Final search terms used for the database « PsycINFO» https://www.ebsco.com/

# Search terms Results

1 DE "Sleep Apnoea" OR TI ( ((sleep OR nocturnal) N3 (apnoea* OR apnoea* OR obstructive)) OR (hypopnoea* OR hypopnoea* OR OSA OR OSAS OR SHS OR SAHS OR OSAH OR OSAHS OR sleep-disordered breathing) ) OR AB ( ((sleep OR nocturnal) N3 (apnoea* OR apnoea* OR obstructive)) OR (hypopnoea* OR hypopnoea* OR OSA OR OSAS OR SHS OR SAHS OR OSAH OR OSAHS OR sleep-disordered breathing) )

6,269

2 DE ( "Drug Therapy" OR "Benzodiazepines" OR "Alprazolam" OR "Chlordiazepoxide" OR "Clonazepam" OR "Diazepam" OR "Flunitrazepam" OR "Flurazepam" OR "Lorazepam" OR "Midazolam" OR "Nitrazepam" OR "Oxazepam" OR "Opiates" OR "Buprenorphine" OR "Codeine" OR "Endogenous Opiates" OR "Fentanyl" OR "Heroin" OR "Morphine" OR "Papaverine" ) OR TI ( (drug* OR medic* OR pharmaceutical OR pharmaco* OR non-benzodiazepine* or nonbenzodiazepine* OR Zaleplon OR Zolpidem OR Eszopiclone OR Zopiclone OR Triazolam OR Nitrazepam OR Flurazepam OR Loprazolam OR Lormetazepam OR Temazepam OR Estazolam OR Oxazepam OR Alprazolam OR Lorazepam OR Clonazepam OR Quazepam OR Diazepam OR Midazolam OR Buprenorphine OR Dipipanone OR Diamorphine OR Alfentanyl OR Remifentanyl OR remifentanil OR Fentanyl OR Methadone OR Oxycodone OR Papaveretum OR Pentazocine OR Pethidine OR Tramadol OR Codeine OR Meptazinol OR sodium oxybate OR ramelteon OR Rozerem OR Gabapentin OR Pregabalin OR Melatonin OR hypnotic* OR opiate* or opioid* OR analgesic* OR sedative* OR Acetazolamide OR Adalimumab OR Almitrine OR Aminophylline OR Buspirone OR Carbocysteine OR Cilazapril OR Clonidine OR Desipramine OR Desloratadine OR Donepezil OR Doxapram OR Dronabinol OR Eszopiclone OR Fenofibrate OR Flumazenil OR Fluoxetine OR Fluticasone OR Liraglutide OR Medroxyprogesterone OR Mibefradil OR Mirtazapine OR Mometasone furoate OR Montelukast OR Naloxone OR Naltrexone OR Ondansetron OR Paroxetine OR Phentermine OR Phosphocholinamin OR Physostigmine OR Pioglitazone OR Protriptyline OR Sabeluzole OR Salmeterol OR Spironolactone OR Surfactant OR Temazepam OR Testosterone OR Theophylline OR Tiagabine OR Topiramate OR Tramazoline OR Trazodone OR Xylometazoline OR Zonisamide) ) OR AB ( (drug* OR medic* OR pharmaceutical OR pharmaco* OR non-benzodiazepine* or nonbenzodiazepine* OR Zaleplon OR Zolpidem OR Eszopiclone OR Zopiclone OR Triazolam OR Nitrazepam OR Flurazepam OR Loprazolam OR Lormetazepam OR Temazepam OR Estazolam OR Oxazepam OR Alprazolam OR Lorazepam OR Clonazepam OR Quazepam OR Diazepam OR Midazolam OR Buprenorphine OR Dipipanone OR Diamorphine OR Alfentanyl OR Remifentanyl OR remifentanil OR Fentanyl OR Methadone OR Oxycodone OR Papaveretum OR Pentazocine OR Pethidine OR Tramadol OR Codeine OR Meptazinol OR sodium oxybate OR ramelteon OR Rozerem OR Gabapentin OR Pregabalin OR Melatonin OR hypnotic* OR opiate* or opioid* OR analgesic* OR sedative* OR Acetazolamide OR Adalimumab OR Almitrine OR Aminophylline OR Buspirone OR Carbocysteine OR Cilazapril OR Clonidine OR Desipramine OR Desloratadine OR Donepezil OR Doxapram OR Dronabinol OR Eszopiclone OR Fenofibrate OR Flumazenil OR Fluoxetine OR Fluticasone OR Liraglutide OR Medroxyprogesterone OR Mibefradil OR Mirtazapine OR Mometasone furoate OR Montelukast OR Naloxone OR Naltrexone OR Ondansetron OR Paroxetine OR Phentermine OR

582,327

Page 7 of 38

# Search terms Results

Phosphocholinamin OR Physostigmine OR Pioglitazone OR Protriptyline OR Sabeluzole OR Salmeterol OR Spironolactone OR Surfactant OR Temazepam OR Testosterone OR Theophylline OR Tiagabine OR Topiramate OR Tramazoline OR Trazodone OR Xylometazoline OR Zonisamide) )

3 1 AND 2 1,663

4 DE ( "Treatment Effectiveness Evaluation" OR "Treatment Outcomes" OR "Placebo" OR "Followup Studies" ) OR TI ( placebo* OR random* OR "comparative stud*" OR (clinical N3 trial*) OR (research N3 design) OR (evaluat* N3 stud*) OR (prospectiv* N3 stud*) OR ((singl* OR doubl* OR trebl* OR tripl*) N3 (blind* OR mask*)) ) OR AB ( placebo* OR random* OR "comparative stud*" OR (clinical N3 trial*) OR (research N3 design) OR (evaluat* N3 stud*) OR (prospectiv* N3 stud*) OR ((singl* OR doubl* OR trebl* OR tripl*) N3 (blind* OR mask*)) )

380,841

5 3 AND 4 341

6 LA english OR german OR french OR spanish 4,374,193

7 5 AND 6 338

Page 8 of 38

Table 6. Final search terms used for the database «Web of Science» http://apps.webofknowledge.com/

# Search terms Results

1 TOPIC: (((sleep OR nocturnal) NEAR/3 (apnoea* OR apnoea* OR obstructive)) OR {hypopnoea* OR hypopnoea* OR OSA OR OSAS OR SHS OR SAHS OR OSAH OR OSAHS OR "sleep-disorderedbreathing"))lndexes=SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH, BKCI-S, BKCI-SSH, ESC/, CCR-EXPANDED, ICTimespan=All years

59,435

2 TOPIC: ((drug* OR medic* OR pharmaceutical OR pharmaco* OR "non-benzodiazepine*" OR nonbenzodiazepine* OR Zaleplon OR Zolpidem OR Eszopiclone OR Zopiclone OR Triazolam ORNitrazepam OR Flurazepam OR Loprazolam OR LORmetazepam OR Temazepam OR EstazolamOR Oxazepam OR Alprazolam OR LORazepam OR Clonazepam OR Quazepam OR Diazepam ORMidazolam OR BuprenORphine OR Dipipanone OR Diamorphine OR Alfentanyl ORRemifentanyl OR remifentanil OR Fentanyl OR Methadone OR Oxycodone OR Papaveretum ORPentazocine OR Pethidine OR Tramadol OR Codeine OR Meptazinol OR "sodium oxybate" ORramelteon OR Rozerem OR Gabapentin OR Pregabalin OR Melatonin OR hypnotic* OR opiate*OR opioid* OR analgesic' OR sedative* OR Acetazolamide OR Adalimumab OR Almitrine OR Aminophylline OR Buspirone OR Carbocysteine OR Cilazapril OR Clonidine OR Desipramine OR Desloratadine OR Donepezil OR Doxapram OR Dronabinol OR Eszopiclone OR Fenofibrate OR Flumazenil OR Fluoxetine OR Fluticasone OR Liraglutide OR Medroxyprogesterone ORMibefradil OR Mirtazapine OR "Mometasone furoate" OR Montelukast OR Naloxone OR Naltrexone OR Ondansetron OR Paroxetine OR Phentermine OR Phosphocholinamin OR Physostigmine OR Pioglitazone OR Protriptyline OR Sabeluzole OR Salmeterol OR Spironolactone OR Surfactant OR Temazepam OR Testosterone OR Theophylline OR Tiagabine OR Topiramate OR Tramazoline OR Trazodone OR Xylometazoline OR Zonisamide))lndexes=SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH, BKCI-S, BKC/-SSH, ESC/, CCR-EXPANDED, /CTimespan=All years

3,945,541

3 1 AND 2 lndexes=SC/-EXPANDED, SSC/, A&HCI, CPC/-S, CPC/-SSH, BKCI-S, BKC/-SSH, ESC/, CCR-EXPANDED, /CTimespan=All years

9,048

4 TOPIC: ((random* OR factorial* OR crossover* OR cross NEAR/1 over* OR placebo* OR doubl* 3NEAR/1 blind* OR sing!* NEAR/1 blind• OR assign* OR allocat" OR volunteer*)) ORTITLE: (trial)lndexes=SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH, BKCI-S, BKCI-SSH, ESC/, CCR-EXPANDED, ICTimespan=All years

2,833,265

5 4 AND 3 lndexes=SC/-EXPANDED, SSC/, A&HCI, CPC/-S, CPC/-SSH, BKCI-S, BKC/-SSH, ESC/, CCR-EXPANDED, /CTimespan=All years

1,960

6 4 AND 3 Refined by: LANGUAGES: ( ENGLISH OR GERMAN OR FRENCH OR SPANISH) lndexes=SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH, BKCI-S, BKCI-SSH, ESC/, CCR-EXPANDED, ICTimespan=All years

1,954

Page 9 of 38

Table 7. Final search terms used for the database «ClinicalTrials.gov»https://clinicaltrials.gov/ct2/search/advanced

# Search terms

Condition or disease "sleep apnoea" OR "sleep apnoea" OR "obstructive sleep" OR "sleep-disordered breathing" OR hypopnoea OR hypopnoea

Other terms drug* OR medicat* OR pharmaceutical OR pharmaco* OR "non benzodiazepine*" OR nonbenzodiazepine* OR hypnotic* OR opiate* OR opioid* OR analgesic* OR sedative* OR placebo*

Study type Interventional Studies (Clinical Trials)

Recruitment status All studies

Age Adult, Senior

Table 8. Final search terms used for the database «WHO ICTRP»International Clinical Trials Registry Platform by the World Health Organization (WHO ICTRP) http://apps.who.int/trialsearch/AdvSearch.aspx

# Search terms

Title "sleep apnoea" OR "sleep apnoea" OR "obstructive sleep" OR "sleep-disordered breathing" OR hypopnoea OR hypopnoea

Intervention drug* OR medicat* OR pharmaceutical OR pharmaco* OR "non benzodiazepine*" OR nonbenzodiazepine* OR hypnotic* OR opiate* OR opioid* OR analgesic* OR sedative* OR placebo*

Recruitment status All

Phases All

Page 10 of 38

Table 9. PRISMA 2009 checklist.Adapted from Moher D et al. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(6):e1000097

Section/topic # Checklist item Reported

TITLE Title 1 Identify the report as a systematic review, meta-

analysis, or both. YES

ABSTRACT Structured summary 2 Provide a structured summary including, as applicable:

background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number.

YES

INTRODUCTION Rationale 3 Describe the rationale for the review in the context of

what is already known. YES

Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS).

YES

METHODS Protocol and registration 5 Indicate if a review protocol exists, if and where it can

be accessed (e.g., Web address), and, if available, provide registration information including registration number.

YES

Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale.

YES

Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.

YES

Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.

YES

Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis).

YES

Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.

YES

Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made.

YES

Risk of bias in individual studies

12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.

YES

Page 11 of 38

Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means). YES

Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I2) for each meta-analysis.

YES

Page 1 of 2

Section/topic # Checklist item Reported

Risk of bias across studies 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies).

YES

Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating which were pre-specified.

NA

RESULTS Study selection 17 Give numbers of studies screened, assessed for

eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram.

YES

Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations.

YES

Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12).

YES

Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.

YES

Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency. YES

Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15). YES

Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]).

NA

DISCUSSION Summary of evidence 24 Summarize the main findings including the strength of

evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers).

YES

Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias).

YES

Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research.

YES

FUNDING Funding 27 Describe sources of funding for the systematic review

and other support (e.g., supply of data); role of funders for the systematic review.

YES

Page 12 of 38

Results

Figure 1. Funnel plots and network-map for included studies.

AHI (left) and oxygen desaturation index (right)

Page 13 of 38

Figure 2. Treatment effects for each included trial.Considering all drugs included in the systematic review, patients treated with medication had AHI that was on average 4·8 (-4·8, 95% CI -6·9 to -2·7, p < 0·0001) points lower than patients treated without medication. Removing the 6 studies which reported change from baseline resulted in similar results (mean difference AHI -4·4, 95% CI -6·8 to -2·1, p = 0·0002). Heterogeneity between the studies was quite high (I2 40% AHI and 58% ODI).

Page 14 of 38

Figure 3. Predicted effects on AHI by drug category.We also considered a simpler model, which only adjusted for the medication category and not the category itself. Most of the effects on AHI were not statistically significant. Only antidepressants and antihypertensives had an observed association with AHI (-8·1, 95% CI -15·4 to -0·9, p = 0·028) and ODI (drug combinations only manifested an association for AHI, not ODI).

Page 15 of 38

Figure 4. Predicted effects on ODI by drug category.Both antihypertensives (-22·1, -32·1 to -12·1, p < 0·001) and antidepressants (-11·5, -17·1 to -5·9, p<0·001) had a statistically significant effect on ODI.

Page 16 of 38

Figure 5. Observed mean difference in AHI of included studies. Most studies included in this review failed to achieve statistical significance for AHI even with very large effect sizes, even if the observed effect size was larger than 5, or worse, larger than 10.

Page 17 of 38

Figure 6. Observed mean difference in ODI of included studies.

Page 18 of 38

Table 10. Currently ongoing studies Dated October 2018.

Investigator Year of registration Intervention Proposed

mechanism

Bayer AG9 2018 BAY2253651 Muscle tone

Therapix Biosciences Ltd. 10 2018 THX-110 Ventilatory drive

David Andrew Wellman, Brigham and Women's Hospital11

2016 (completed by

2018)

Atomoxetine and Oxybutynin unclear

David Andrew Wellman, Brigham and Women's Hospital12

2017 DAW1033D unclear

Robert L. Owens, University of California, San Diego13 2015 Melatonin Oxidative stress

University of South Florida14 2015

Oxymetazoline Hydrochloride /

Fluticasone Propionate

Airway diameter

Page 19 of 38

Table 11. Risk of bias of included trials.Evaluated using the Cochrane Risk of Bias tool.

Study

Selection bias Performance bias

Detection bias

Attrition bias

Reporting bias

Randomsequence generation

Allocation c

oncealment

Blindingof

participantsand

personnel

Blinding of outcome

assessment

Incompleteoutcome

dataSelevtivereporting

Acar et al. 201315 unclear low low low unclear unclearAtkinson et al. 198516 unclear unclear low unclear unclear unclearBerry et al. 199917 unclear unclear low unclear low lowBlackman et al. 201618 low low low low low lowBrownell et al. 198219 unclear unclear unclear low low lowBruckert et al. 201020 unclear unclear unclear unclear low lowCarley et al. 200721 unclear unclear unclear unclear low lowCarley et al. 201822 low low low low low lowCarter et al. 201623 unclear unclear low low low lowClarenbach et al. 200824 unclear unclear unclear low low lowCook et al. 198925 unclear unclear unclear unclear low lowDiamond et al. 198226 unclear unclear unclear unclear unclear unclearEckert et al. 201127 low low low low low lowEdwards et al. 201228 unclear unclear high low low lowEskandari et al. 201429 low unclear low low low lowEskandari et al. 201830 low high high low low lowEspinoza et al. 198731 unclear unclear unclear unclear low lowFerber et al. 199332 unclear unclear unclear unclear low lowGrote et al. 200033 low unclear low low low lowHedner et al. 199634 unclear unclear unclear low low lowHedner et al. 200335 unclear unclear low low low lowHedner et al. 200536 unclear unclear unclear unclear unclear unclearHein et al. 200037 unclear unclear low low low lowHeitmann et al. 199838 unclear unclear unclear unclear low lowHoyos et al. 201239 low low low low low lowIssa 199240 unclear unclear unclear low low lowJokic et al. 199841 unclear unclear low unclear low lowKiley et al. 200442 unclear unclear unclear low low lowKoutsourelakis et al. 201343 low low low low low lowKraiczi et al. 199944 low unclear low low low lowLi et al. 201645 low unclear low unclear low lowLiu et al. 201646 low unclear high low low lowMaari et al. 201447 unclear unclear unclear unclear low unclearMangin et al. 198348 high unclear unclear unclear low lowMarshall et al. 200849 low low low low low lowMartino et al. 199950 unclear unclear high high unclear unclearMendleson et al. 199151 unclear unclear unclear unclear unclear unclearMoraes et al. 200852 low low low low low lowMorrell et al. 200253 unclear unclear high low low unclearMulloy et al. 199254 unclear unclear unclear low low lowPrasad et al. 201055 unclear unclear unclear low low low

Page 20 of 38

Rasche et al. 199956 unclear unclear unclear unclear unclear unclearSchönhofer et al. 199657 unclear unclear high unclear low lowSmales et al. 201558 low unclear low low low lowSmith et al. 201759 unclear unclear unclear unclear unclear unclearStepanski et al. 198860 unclear unclear unclear unclear low lowStradling et al. 200361 unclear unclear unclear unclear unclear unclearSukys-Claudino et al. 201262 low unclear low low low lowSuratt et al. 198663 unclear unclear unclear unclear low lowTaranto-Montemurro et al. 201664 low low low low low low

Taranto-Montemurro et al. 201765 low low low low low low

Torvaldsson et al. 200566 unclear low low unclear low lowWang et al. 201167 unclear unclear low low low lowWhyte et al. 198868 unclear unclear unclear unclear low lowWinslow et al. 201269 unclear unclear low low low lowWu et al. 201670 low unclear high low high unclearYang et al. 201671 low high high high unclear unclear

Figure 6. Proportion of bias.Summary of proportion of trials at low, unclear and high risk of bias in each domain of the Cochrane Collaboration’s tool for assessing risk of bias.

Page 21 of 38

Table 12. Details and classification of included RCTs.

Author and year

Bro

ncho

dila

tor

Para

sym

path

omim

eti

cA

ntih

yper

tens

iv

Oth

er

Opi

oide

ant

idot

e

Hyp

notic

Sex

ster

oid

Nas

al d

econ

gest

ant

Ant

iem

etic

Ant

idia

betic

Stim

ulan

t

Ant

icon

vula

nt

Ant

idep

ress

ant

Description Target

Acar et al. 201315 1 Antihistamine / topical corticosteroid Histamine receptor H1/ Glucocorticoid receptor

Atkinson et al. 198516 1 (competitive) Opiate receptor antagonist Opioid receptor

Berry et al. 199917 1 Selective seretonin reuptake inhibitor (SSRI) (antidepressant) Serotonine transporter (SERT)

Blackman et al. 201618 1 Incretin mimetic (antidiabetic) Glucagon-like peptide-1 receptor (GLP-1)

Brownell et al. 198219

1 (Non-sedating) Tricyclic antidepressant (TCA)

SERT, Norepinephrine transporter (NET), 5-Hydroxytryptophan (5HT) 2a, (Histamine (H) 1 and muscarinic acetylcholine (mACh) receptors)

Bruckert et al. 2010201 Fibrate (cholesterol lowering drug)

Peroxisome proliferator-activated receptor-alpha (PPARalpha)

Carley et al. 200721 1 Noradrenergic and specific serotonergic antidepressant (NaSSA) (atypical antidepressant) alfa2 antagonist -> induce NA release

(Noradrenergic and serotonin receptors) 5-HT2-R antagonist

Carley et al. 201822 1 Tetrahydrocannabinol (antiemetic) Cannabinoid receptor CB1 (and CB2)

Carter et al. 201623 1 Z-compound (hypnotic) GABA-A receptor

Clarenbach et al. 200824 1 Local vasoconstrictor (nasal decongestant) α2-adrenoreceptor

Cook et al. 198925 1 Progesterone (contraceptive) Progesterone, androgen, and glucocorticoid receptors

Diamond et al. 198226 1 (competitive) Opiate receptor antagonist Opioid receptor

Eckert et al. 201127 1 Z-compound (hypnotic) GABA-A receptor

Edwards et al. 201228 1 Carbonic anhydrase inhibitor Carbonic anhydrase

Eskandari et al. 2014291 Sodium channel blocker (anticonvulsant)

Voltage dependant sodium channel and T-type calcium channel

Eskandari et al. 201830 1 Carbonic anhydrase inhibitor Carbonic anhydrase

Espinoza et al. 198731 1 1 Xanthine (bronchodilator) Phosphodiesterase / adenosine receptor

Page 22 of 38

Author and year

Bro

ncho

dila

tor

Para

sym

path

omim

eti

cA

ntih

yper

tens

iv

Oth

er

Opi

oide

ant

idot

e

Hyp

notic

Sex

ster

oid

Nas

al d

econ

gest

ant

Ant

iem

etic

Ant

idia

betic

Stim

ulan

t

Ant

icon

vula

nt

Ant

idep

ress

ant

Description Target

Ferber et al. 199332 1 (competitive) Opiate receptor antagonist Opioid-receptor

Fiori et al. 201572 1 Diuretic (Antimineralocorticoid, Loop diuretic) Mineralocorticoid receptor / Na-K-Cl cotransporter

Grote et al. 200033 1 Angiotensin converting encyme Inhibitor (ACE inhibitor) (antihypertensive) Angiotensin-converting enzyme

Hedner et al. 199634 1 Acetylcholinesterase inhibitor (AChEI) (parasympathomimetic) Acetylcholinesterase

Hedner et al. 200335 1 1 NMDA receptor antagonist (neuroprotective) (Alzheimer-dementia) NMDA-receptor

Hedner et al. 200536 1 AChEI (parasympathomimetic) Acetylcholinesterase

Hein et al. 200037 1 1 Xanthine (bronchodilator) Phosphodiesterase / adenosine receptor

Heitmann et al. 199838 1 Calcium channel blocker (antihypertensive) T-type calcium channels

Hoyos et al. 201239 1 Androgen (steroide) Androgen receptor

Issa 199240 1 alfa2 receptor agonist (antihypertensive) α2 adrenoreceptor and imidazoline receptor

Jokic et al. 199841 1 Mineral Oil (lubricating and coating agent)

Kiley et al. 200442 1 topical Corticosteride (Anti-inflammatory) Glucocorticoid receptor

Koutsourelakis et al. 201343 1 alpha-Sympathomimetic/ Corticosteroide α adrenoreceptor/ Glucocorticoid receptor

Kraiczi et al. 199944 1 SSRI (antidepressant) SERT

Li et al. 201645 1 Acetylcholinesterase inhibitor (parasympathomimetic) Acetylcholinesterase

Liu et al. 201646 1 Thiazolidinedione (antidiabetic) Peroxisome proliferator-activated receptor gamma

Maari et al. 201447 1 Tumor necrosis fractor (TNF) alfa inhibitor (humaner monoclonaler AB) TNFα

Mangin et al. 198348 1 (Diphenylmethylpiperazine derivative) (respiratory stimulant) Peripheral chemoreceptors

Marshall et al. 2008491

Noradrenergic and specific serotonergic antidepressant (NaSSA) (atypical antidepressant) alfa2 antagonist -> induce NA release / Glycolysis inhibitor

Noradrenergic and serotonin receptors

Martino et al. 199950 1 1 Xanthine (bronchodilator) Phosphodiesterase / adenosine receptor

Mendleson et al. 199151 1 selective partial agonists at 5-HT1A (anxiolytic) 5-HT1A

Moraes et al. 200852 1 Acetylcholinesterase inhibitor (parasympathomimetic) Acetylcholinesterase

Page 23 of 38

Author and year

Bro

ncho

dila

tor

Para

sym

path

omim

eti

cA

ntih

yper

tens

iv

Oth

er

Opi

oide

ant

idot

e

Hyp

notic

Sex

ster

oid

Nas

al d

econ

gest

ant

Ant

iem

etic

Ant

idia

betic

Stim

ulan

t

Ant

icon

vula

nt

Ant

idep

ress

ant

Description Target

Morrell et al. 200253 1 Detergent physical surface properties

Mulloy et al. 199254 1 1 Xanthine (bronchodilator) Phosphodiesterase / adenosine receptor

Prasad et al. 201055 1 5-HT3 rezeptor antagonist (Antiemetic) 5-HT3

Prasad et al. 201055 1 SSRI (antidepressant) SERT

Rasche et al. 199956 1 Long-Acting β2 Adrenergic Agonists (LABA) (bronchodilator) β2-adrenoreceptor

Schönhofer et al. 199657 1 Benzodiazepin-antagonist GABA-A receptor

Smales et al. 201558 1 Seotonin antagonist and reuptake inhibitor (SARI) (antidepressant) 5-HT2 and SERT

Smith et al. 201759 1 Leukotriene receptor antagonists (LTRA) (bronchodilator) / Corticosteroide (anti-inflammatory)

Leukotriene receptor (LT1)/ glucocorticoid receptor

Stepanski et al. 198860 1 (Non-sedating) Tricyclic antidepressant (TCA) SERT, NET, 5HT2a, (H1 and mACh)

Stradling et al. 200361 1 5-HT3 receeptor antagonist (Antiemetic) 5-HT3

Sukys-Claudino et al. 201262 1 Acetylcholinesterase inhibitor (parasympathomimetic) Acetylcholinesterase

Suratt et al. 198663 1 Morpholin derivate (respiratory stimulant) Peripheral chemoreceptorsTaranto-Montemurro et al. 201664 1 GABA agonist (anticonvulsant) GABA receptor

Taranto-Montemurro et al. 201765 1 (Non-sedating) Tricyclic antidepressant (TCA) SERT, NET, 5HT2a, (H1 and

mACh)

Torvaldsson et al. 200566 1 1 NMDA receptor antagonist NMDA receptorWang et al. 201167 1 GABA agonist (hypnotic) GABA-A receptor

Whyte et al. 198868 1 (Non-sedating) TCA SERT, NET, 5HT2a, (H1 and mACh)

Whyte et al. 198868 1 1 Carbonic anhydrase inhibitor Carbonic anhydrase

Winslow et al. 201269 1 1 Amphetamin (appetite depressant)/ glutamate antagonist (anticonvulsive) TAAR1/ glutamate receptor

Wu et al. 201670 1 Mucolytic not clarified

Yang et al. 201671 1 Aldosteron-antagonist (steroid) (antihypertensive) Aldosterone receptor

Page 24 of 38

Table 13. Inclusion and exclusion criteria of included RCTs.

Author and year

Inclusion age

(years)

Characteristics (OSA)

+ requirementsExclusion criteria Funding / conflict of interest

Phar

mac

eutic

al

com

pany

/ in

dust

ry

Acar et al. 201315 30-50 OSA (AHI≥15) + allergic

rhinitis

Patients with infectious or occupational rhinitis, any known systemic diseases, major anatomic deformity, being under treatment for AR, and drug use that may affect sleep quality

unknown

Atkinson et al. 198516 unclear 70% of patients had OSA (not

defined) No exclusion criteria statedNational Institutes of Health General Clinical Research Center grant and NIH grant of the Diabetes Research and Training Center, University of Virginia

Berry et al. 199917 ≥18 OSA (AHI>60) No exclusion criteria stated unknown

Blackman et al. 201618

18-64 OSA (AHI≥15) + BMI≥30 Treatment with glucagon-like peptide-1 (GLP-1) receptor agonists (including liraglutide or exenatide), dipeptidyl peptidase-4 (DPP-4) inhibitors or insulin within the last 3 months prior to screening. Diagnosis of type 1 or type 2 diabetes per judgement of the investigator. Glycated hemoglobin (HbA1c) ≥6.5% (screening value). Significant craniofacial abnormalities that may be causing OSA. Respiratory and neuromuscular diseases that could interfere with the results of the trial in the opinion of the investigator. Known diagnosis prior to screening of periodic limb movement disorder. Use of central stimulants, hypnotics, mirtazepine, opioids, trazodone within the previous 3 months prior to screening. Obesity induced by other endocrinologic disorders (eg, Cushing Syndrome). Treatment with medications within 3 months prior to screening that in the opinion of the investigator may cause significant weight gain. Weight loss attempts using herbal supplements or over-the-counter medications within 3 months prior to screening. Participation in an organized weight reduction program (current or within 3 months prior to screening). Treatment with pramlintide, sibutramine, orlistat, zonisamide, topiramate or phentermine within 3 month prior to screening. Previous surgical treatment for obesity; e.g., gastric banding procedure (excluding liposuction if performed more than one year before trial entry). Hypothyroidism/hyperthyroidism defined as thyroid-stimulating hormone (TSH) >6 mIU/L or <0.4 m IU/L. Calcitonin ≥50 ng/L at screening. Familial or personal history of Multiple Endocrine Neoplasia type 2 or familial Medullary Thyroid Carcinoma. Personal history of non-familial Medullary Thyroid Carcinoma. History of chronic pancreatitis or

This study was sponsored by Novo Nordisk A/S. The authors gratefully acknowledge the important contributions of the study participants, clinical trial personnel and the SCALE Sleep Apnoea study group. We thank Trine Kvist, PhD, employed by Novo Nordisk A/S, for performing the statistical analyses and reviewing the manuscript for accuracy. We also thank Irina Nayvelt, PhD, employed by Novo Nordisk Inc., for medical writing assistance and Watermeadow Medical, funded by Novo Nordisk, for editorial and administrative assistance.

yes

Page 25 of 38

Author and year

Inclusion age

(years)

Characteristics (OSA)

+ requirementsExclusion criteria Funding / conflict of interest

Phar

mac

eutic

al

com

pany

/ in

dust

ry

idiopathic acute pancreatitisBrownell et al. 198219 unclear OSA (not defined) No exclusion criteria stated Merck Sharpe and Dohme supplied drugs and placebo yes

Bruckert et al. 201020 18-70

OSA (AHI>10 in accordance with the Scottish

Intercollegiate Guidelines Network guideline 73) +

BMI≥25 kg/m2 + moderate hypertriglyceridemia

CPAP-treatment before inclusion. HbA1c >7.5%. Mean corpuscular volume >100 m3. history of: cerebrovascular disease, hypersensitivity to fibrates or alcohol abuse, endocrine disease (other than adequately controlled hypothyroidism), renal failure (plasma creatinine levels 4130 mmol/L), chronic liver disease (liver enzymes over twice the upper limit of the reference range), muscle disease (creatine phosphokinase over three times the upper limit of the reference range), symptomatic gall bladder or cardiopulmonary disease, neurological conditions requiring reatment, impaired visual field, or pregnancy. treatments likely to produce sleepiness.

Supported by a grant from Laboratories Fournier SA, Daix, France. yes

Carley et al. 200721 18-67 OSAS (AASM 1999

guideline)

Significant cardiovascular, endocrine, hematologic, metabolic, neurologic, psychiatric, pulmonary, renal disorder, or sleep disorder other than obstructive sleep apnoea (OSA), documented by history, physical, or laboratory examination. antihypertensive regimens. pregnancy, alcohol or drug abuse, a history of rotating or permanent night shift work within 6 months, and concomitant use of any central nervous system-active drug or any serotonergic drug.

NV Organon yes

Carley et al. 201822

21-65 OSA (AHI≥15 and ≤50) ESS <7, BMI> 45; motor vehicle accident or “near-miss” due to sleepiness (self-report) within 2 years; arterial oxygen saturation < 75% for more than 5% of total sleep time on baseline (screening) PSG; severe OSA that in the investigator’s judgment precluded delaying (re)institution of PAP treatment; prior upper airway surgery for snoring or OSA as an adult; significant defect in nasal patency due to anatomical abnormality or uncontrolled rhinitis; bariatric surgery within 2 years; medically managed weight-loss program within 6 months; noninvasive treatment for OSA within 1 month (self-report); history of shift work or rotating shifts within 1 month; any clinically significant uncontrolled cardiopulmonary, gastrointestinal, pancreatic, hepatic, renal, hematologic, endocrine (including type 1 diabetes), neurological, urogenital, psychiatric, or sleep disorder (other than OSA); seizure disorder; use of CNS active drugs; pregnancy; recreational drug use or positive urine drug

National Institutes of Health, National Heart Lung and Blood Institute Grant Number UM1-HL112856 and National Center for Advancing Translational Sciences, Grant Numbers UL1TR001422 and UL1TR002003. DWC is an inventor of intellectual property assigned to the University of Illinois at Chicago. Collectively, these patents and applications relate to treatment of sleep-related breathing disorders by cannabinoid drugs. The University of Illinois has granted an exclusive license to these and related international patents to RespireRx Pharmaceuticals. RespireRx pays annual fees to the University of Illinois to maintain this license and plans to develop drug treatments for sleep-related breathing disorders. Upon commercialization of cannabinoid drug(s) for this purpose, RespireRx will pay royalties to the University of Illinois at Chicago. In addition, DWC holds shares of common stock in RespireRx Pharmaceuticals. He has not been paid by, nor does he advise RespireRx Pharmaceuticals.

yes

Page 26 of 38

Author and year

Inclusion age

(years)

Characteristics (OSA)

+ requirementsExclusion criteria Funding / conflict of interest

Phar

mac

eutic

al

com

pany

/ in

dust

ry

screen; or clinically significant abnormality on complete blood count or liver function tests.

Carter et al. 201623 18-65 OSA (AHI>5) Mean oxygen saturation nadir ≤70%, medication which affects

breathing or muscle activity, pregnancy, allergies.

National Health and Medical Research Council (NHRMC) of Australia (1042493), an Australasian Sleep Association Rob Pierce Grant-in-Aid, and an Australian Lung Foundation/Ludwig Engel Grant-in-Aid for Physiological Research. S.G.C. is supported by a NHMRC NeuroSleep CREtop-up scholarship (1060992)

Clarenbach et al. 200824 unclear OSA (AHI>10) + ESS>8 +

chronic nasal congestion

Nasal surgery within the last 6 months. current treatment with nasal decongestants or topical steroids. sleep disorders other than obstructive sleep apnoea. internal medical or psychiatric disorders that interfered with sleep

Swiss National Science Foundation, Hartmann-Müller Stiftung Zurich, and Lung League Zurich, Switzerland

Cook et al. 198925 unclear OSA (≥30 AH per night) +

daytime sleepiness No exclusion criteria stated American Lung Associations of South Carolina, MUSC institutional grant No. CRO2, and the Upjohn company yes

Diamond et al. 198226 unclear OSA (not defined) No exclusion criteria stated unknown

Eckert et al. 201127 unclear OSA (AHI>5) + "low arousal

threshold" Severe oxygen desaturation (nadir overnight SaO2 <70 %)National Institutes of Health (NIH) and an unrestricted investigator-initiated research grant from Sepracor Pharmaceuticals.

yes

Edwards et al. 201228 unclear OSA (AHI>10)

any medication known to influence breathing, sleep/arousal or muscle physiology. history of renal failure, neuromuscular disease or other major neurological disorders, uncontrolled diabetes, heart failure, central sleep apnoea/Cheyne–Stokes respiration, uncontrolled hypertension, thyroid disease, or any other unstable medical condition

National Institutes of Health: 5R01HL048531-16, R01 HL085188-02, R01 HL090897-01A2, K24 HL 093218-01A1 and P01 HL 095491 and the American Heart Association: 0840159N, 0575028N. B.A.E. is supported by the Thoracic Society of Australia and New Zealand/Allenand Hanbury’s Respiratory Research Fellowship. S.A.S is supported by an American Heart Association fellowship (11POST7360012). D.J.E. is supported by American Heart Association and a NHMRC of Australia Overseas Biomedical Fellowship (510392).

Eskandari et al. 201429 unclear OSA (AHI>15) + BMI 27-35

kg/m2 + ESS >6

Seizure disorders, unstable cardiovascular, pulmonary or gastrointestinal disease, depression, alcohol or drug abuse, and medication interfering with the study protocol

This study was supported by research grants from the Swedish Heart and Lung Foundation (grant number 20120429), the Swedish Society of Medicine, and the Gothenburg Medical Society. The study medication was provided by Eisai Limited (Hatfield, UK); Eisai Limited was not involved in any other part of the study.

Eskandari et al. 201830 18-75

OSA (AHI>15) + Hypertension + BMI <30kg/m2 + ESS >6

Hypersensitivity to ongoing medication and/or with other sulfonamides, seizure disorders, unstable cardiovascular,pulmonary, or gastrointestinal disease, impairedrenal or hepatic function, depression, or any form of abuse.

Swedish Heart and Lung Foundation and an education grants from the Sahlgrenska University hospital. Dr. Grote and Dr. Hedner have an approved and a pending patent related to inhibition of carbonic anhydrase for the treatment of sleep apnoea.

Espinoza et al. unclear OSA (AHI>15) + daytime Previous medication: theophylline. Evidence of upper airway unknown

Page 27 of 38

Author and year

Inclusion age

(years)

Characteristics (OSA)

+ requirementsExclusion criteria Funding / conflict of interest

Phar

mac

eutic

al

com

pany

/ in

dust

ry

198731 sleepiness infection. Drugs for OSA (e.g. medroxyprogesterone)Ferber et al. 199332 unclear OSA (AHI>10) Severe pulmonary insufficiency or neuroendicrine abnormality unknown

Fiori et al. 201572 18-60 OSA (AHI>30) + BMI <35

kg/m2

CPAP, CSA, Chronic renal disease, peripheral venous or lymphatic insufficiency; use of diuretics and substances with action on the central or peripheral nervous system, such as benzodiazepines, hypnotics, anticonvulsants, antidepressants, appetite suppressants, amphetamines, antiparkinson agents, muscle relaxants, bronchodilators; stroke within the past 6 months or with incapacitating sequelae;

Institutional Research Incentive Fund. Funding was provided by Fundo de Incentivo a Pesquisa (FIPE-HCPA), Brazil.

Grote et al. 200033 35 - 65

OSA (not defined) + hypertension (according to

WHO criteria)Treatment for hypertension Merck KGa, Darmstadt, Germany, and Hofmann-La Roche Inc,

Basel, Switzerland yes

Hedner et al. 199634 25-65 OSA (ODI 4%≥10)

Coronary heart disease, previously known or treated cardiac arrhythmia of any type, myocardial infarction or stroke within 12 months before study enrolment, previous or present known or treated psychiatric disease, regular intake of bensodiazepines or related compounds. intolerance to cholinesterase inhibitory agents, myasthenia gravis. body weight exceeding 120% of ideal (Metropolitan scale), previously known renal or hepatic disease, and current alcohol or drug abuse

The Swedish Heart and Lung Foundation and Faculty grants from the University of Goteborg. J.H., Y.P., P.M. are owner in part of a patent addressing the use of physostigmine in sleep-disordered breathing

Hedner et al. 200335 unclear OSA (moderate to severe) No exclusion criteria stated Swedish Medical Research Council, The Swedish Heart and

Lung Foundation and by Jansen Pharmaceuticals. yes

Hedner et al. 200536 unclear OSA (moderate to severe) No exclusion criteria stated unknown

Hein et al. 200037 unclear OSA (AHI>5) + symptoms No exclusion criteria stated unknown

Heitmann et al. 199838 23-69

OSA (AHI≥5) + hypertension (sitting diastolic BP >95 and

<115 mmHg)

Malignant or secondary hypertension, major systemic disease and a history of alcohol or drug abuse. Concomitant antihypertensive medication or treatment which interfered with calcium antagonists

Hoffmann-La Roche AG, Grenzach-Whylen yes

Hoyos et al. 201239

≥18 OSA (AHI>10) + BMI >30kg/m2

Uncontrolled, concurrent medical or psychiatric illness; a minimum oxygen saturation <65% or AHI >80 events/h or requiring immediate continuous positive airway pressure treatment; the use of medications known to alter androgen action, sleep or body weight; contraindications to testosterone therapy or to deep intramuscular injections; a desire for paternity during the next 12 months; participation in sports

National Health and Medical Research Council of Australia (NHMRC) through a project grant (512499), a Centre for Clinical Research Excellence in Interdisciplinary Sleep Health (571421) and fellowships to CH, RK, DW, CP, RRG and PYL(512057, 633161, 571165, 571179, 202916 and 511929, respectively). Bayer Schering supplied study drug, matching placebo and $20 000 to date.

yes

Page 28 of 38

Author and year

Inclusion age

(years)

Characteristics (OSA)

+ requirementsExclusion criteria Funding / conflict of interest

Phar

mac

eutic

al

com

pany

/ in

dust

ry

that ban testosterone and require drug monitoring; fasting haematocrit >52%; prostate-specific antigen (PSA)>4 ng/ml; participation in another investigational drug trial in the previous 30 days; or concurrent treatment of sleep apnoea with continuous positive airway pressure or mandibular advancement devices.

Issa 199240 unclear OSA (not defined) High resting blood pressure (untreted or treated with antihypertensive drugs) unknown

Jokic et al. 199841 unclear OSA (AHI>5 + daytime

sleepiness or AHI>10)Nasal obstruction, swallowing difficulties, or any history of aspiration Heart and Stroke Foundation of Saskatchewan

Kiley et al. 200442 ≥18 56% OSA (AHI≥10) and 44%

non-OSA + rhinitis Fixed nasal obstruction GlaxoWellcome plc yes

Koutsourelakis et al. 201343 unclear OSA (AHI>10) + normal nasal

resistance

Recent surgery in the upper airway, more than three central apnoeas per hour or 5% of total apnoeas, use of medications known to influence nasal resistance (antihistamine and decongestants, etc.), upper or lower respiratory tract disease, including a history of nasal allergy, smoking, treatment of OSA with continuous positive airway pressure (CPAP) during the course of the study

unknown

Kraiczi et al. 199944 25-65 OSA (ODI≥10)

Known psychiatric disease, regular intake of CNS-active drugs, symptomatic coronary heart disease, intolerance to paroxetine, alcohol or drug abuse, as well as general reasons for ineligibility as judged by the investigators

Supported by grants from the Swedish Medical Research Council, the Medical Faculty of Goteborg University, the Swedish Heart and Lung Foundation and Novo Nordisk Pharma AB, Malmö, Sweden.

yes

Li et al. 201645 18-70 OSA (AHI>5)

Presence of pulmonary, cardiac, neurological or other active severe medical or psychiatric diseases; current use of continuous positive airway pressure therapy. known allergy to donepezil, currently smoking, or taking alcohol>3 oz per day

ResMed, Inc. provided a philanthropic donation to the UC San Diego in support of the UCSD sleep center. award and the American Heart Association (15SDG25890059)

Liu et al. 201646 30-70OSA (AHI≥9) + "characteristic

symptoms" + BMI 25-40 kg/m2 + insulin resistancy

History of type 2 diabetes (or use of antidiabetic drugs), cardiovascular, kidney or liver diseases, or prior treatment for OSA

This research was funded by NIH grants, NHLBI MapGen, and supported by a Human Health Service grant. This work was supported through a Patient-Centered Outcomes Research Institute (PCORI) Pilot Project Program Award Sustainable Methods, Algorithms, and Research Tools for Delivering Optimal Care Study

Maari et al. 201447 18-80 OSA (AHI>15) + Psoriasis

(BSA>5%)

Medical treatment for sleep apnoea in the 6 months preceding day 0 or any nonbiologic systemic therapy, biological therapy, topical treatments or phototherapy for the treatment of psoriasis within 30, 90, 14 or 14 days prior to day 0, espectively

Innovaderm Research, Montreal, QC, Canada yes

Mangin et al. 198348 unclear OSA (not defined) No exclusion criteria stated unknown

Page 29 of 38

Author and year

Inclusion age

(years)

Characteristics (OSA)

+ requirementsExclusion criteria Funding / conflict of interest

Phar

mac

eutic

al

com

pany

/ in

dust

ry

Marshall et al. 200849 >21 OSA (AHI 10-40) +

BMI≤34kg/m2 + ESS>10

CPAP-treatment before inclusion. Smokers. Potential pregnancy. clinically significant comorbidity, including any unstable cardiovascular, gastrointestinal, metabolic, pulmonary, renal, neurologic, hepatic, hematologic, immunologic, endocrine, or neoplastic disease; had uncontrolled hypertension; had a urrent diagnosis of any psychiatric illness or substance abuse disorder according to DSM IV criteria; were pregnant or lactating; or had severe craniofacial abnormalities.

Cypress Bioscience. Ron Grunstein is supported by National Health and Medical Research Council of Australia Practitioner Fellowships.

yes

Martino et al. 199950 unclear OSA (planned therapy for

CPAP) Respiratory infection, allergic rhinitis or asthma None

Mendleson et al. 199151 unclear OSA (not defined) No exclusion criteria stated unknown

Moraes et al. 200852 unclear OSA (AHI>5) + mild-to-

moderate Alzheimer disease

Presence of other causes of dementia; MRI compatible with other etiology of dementia. pulmonary, cardiac, and other current severe medical or psychiatric diseases

Fundação de Amparo à Pesquisa do Estado de São Paulo

Morrell et al. 200253 unclear OSA (AHI>10) No exclusion criteria stated Veterans Adminisration Medical Research Services and

National Heart, Lung and Blood Institute.

Mulloy et al. 199254 unclear OSA (AHI>15)

History of cardiac or hepatic disorders, taking hypnotics or sedatives, or any medication known to interfere with the absorption or metabolism of theophylline. substantial alcohol intake (>20 units per week)

unknown

Prasad et al. 201055 21-65 OSA (AH≥10)

Arterial oxygen saturation <75% for more than 5% of total sleep time. severe OSA that precluded withdrawal of PAP treatment. history of shift work or rotating shifts within preceding 1 month. history of any surgical treatment for OSA at any time or other major surgery within 6 months. participation in any form of medically managed weight loss program within 6 months. clinically significant cardiopulmonary, gastrointestinal, pancreatic, hepatic, renal, hematologic, endocrine (including type 1 diabetes), neurological, urogenital, psychiatric, or sleep disorder other than OSA. use of any central nervous system-active drug or serotonergic drug, pregnancy, alcohol or recreational drug use, positive plasma drug screen, or clinically significant abnormality on complete blood count.

BTG International, which holds a license from University of Illinois at Chicago to issued and pending patents relevant to the combined use of ondansetron and fluoxetine to treat sleep apnoea. Investigational Drug Service from a pharmacy. Investigational ondansetron was manufactured by GlaxoSmithKline and fluoxetine was manufactured by Eli Lily. Dr Logan is a full time Vice President of BTG International, the study sponsor. Dr Carley serves as anunpaid Director for SteadySleep Rx Co., and holds stock in this company. Drs Carley and Radulovacki are inventors on patents and patent applications that disclose the use of serotonin antagonists and reuptake inhibitors to treat sleep apnoea. Dr Carley and Dr Radulovacki have received research support from SteadySleep Rx Co. Dr Radulovacki holds stock in SteadySleep Rx Co.

yes

Rasche et al. 199956

>18 OSA (AHI>5) + excessive daytime sleepiness

asthma or chronic obstructive pulmonary disease. left heart insufficiency, a body mass index >40 kg/m2, evidence of alcohol and/or drug abuse as well as females who were

Glaxo Wellcome, London, United Kingdom yes

Page 30 of 38

Author and year

Inclusion age

(years)

Characteristics (OSA)

+ requirementsExclusion criteria Funding / conflict of interest

Phar

mac

eutic

al

com

pany

/ in

dust

ry

pregnant or lactating or likely to become pregnant during the study. hypersensitivity to 2-agonists, or currently receiving beta-blocker therapy.

Schönhofer et al. 199657 unclear OSA (AHI>40)

History of seizure, arrhythmia, impaired renal or hepatic function, and patients taking medication with effects on the central nervous system

unknown

Smales et al. 201558 unclear OSA (AHI>10) No exclusion criteria stated

Supported by the National Institutes of Health grants K24 HL 093,218 (A.M.) and 1 P01 HL 095,491 (A.M.), the Harvard Catalyst Clinical Research Center grant UL1 RR 025758–01, and the National Health and Medical Research Council of Australia’s CJ Martin Overseas Biomedical Fellowship 1035115 (B.A.E.).

Smith et al. 201759 >21 OSA (AHI 5-10) No exclusion criteria stated unknown

Stepanski et al. 198860 unclear OSA (AI>10) + daytime

sleepiness No exclusion criteria stated unknown

Stradling et al. 200361 unclear OSA (ODI 4% 10-40) No exclusion criteria stated unknown

Sukys-Claudino et al. 201262 35-65 OSA (AHI>10) + OSAS

(AASM 1999 guideline)

CPAP-treatment before inclusion. BMI >35 kg/m2. Smoking. Psychiatric, neurological, cardiovascular, or pulmonary disease

Conselho Nacional de Desenvolvimento em Pesquisa (CNPQ), Sao Paulo, Brazil. AFIP (Associação Fundo de Incentivo à Pesquisa)

Suratt et al. 198663 unclear OSA (not defined) No exclusion criteria stated A. H. Robins Company Industry

Taranto-Montemurro et al. 201664

18-75 OSA (AHI>10) Medications known to influence breathing or sleep–wake physiology, history of epilepsy

This research project received generous philanthropic funding from Fan Hongbing, President of OMPA Corporation, Kaifeng, China. This work was also supported by the American Heart Association, National Institutes of Health grants as well as the Harvard Catalyst Clinical Research Center.

Taranto-Montemurro et al. 201765

18-65 OSA (AHI>15)Medications known to influence breathing in sleep or wake states (i.e. hypnotics, antipsychotics or anxiolytics), and psychostimulants, or muscle physiology (i.e. myorelaxant)

This research project received generous philanthropic funding from Fan Hongbing, President of OMPA Corporation, Kaifeng, China. This work was also supported by the National Institutes of Health grants as well as the Harvard Catalyst Clinical Research Center:

Torvaldsson et al. 200566

25-75 OSA (AHI>20) More than 10 episodes of oxygen desaturation below 50% or with signs of consistent incomplete resaturation to over 90% between episodes of desaturation. coronary heart disease, previously diagnosed or treated cardiac arrhythmia, previous or present clinically significant psychiatric disease, clinically significant chronic pulmonary, gastrointestinal, renal, neurological, metabolic, hematological or hepatic disease, a

AstraZeneca R & D, Södertälje, Sweden and by grants from The Swedish Heart and Lung Foundation and Faculty grants from the University of Göteborg.

yes

Page 31 of 38

Author and year

Inclusion age

(years)

Characteristics (OSA)

+ requirementsExclusion criteria Funding / conflict of interest

Phar

mac

eutic

al

com

pany

/ in

dust

ry

clinical situation where withdrawal of nCPAP treatment significantly would increase the risk for work or traffic accidents, intolerance to the investigative drug, recent alcohol or drug abuse as well as any other condition or oncomitant medication known to interfere with the efficacy or safety of the investigational drug

Wang et al. 201167 unclear OSA (AHI>5)

Uncontrolled concurrent medical or psychiatric illness, concurrent medications that are known to affect sleep respiration or interact with temazepam; medical conditions that would contraindicate temazepam; major sleep disorders such as periodic limb movement syndrome (PLMS) orirregular sleep patterns, such as shift-workers

unknown

Whyte et al. 198868 unclear OSA (AHI>15) + symptoms No exclusion criteria stated unknown

Winslow et al. 201269 30-65 OSA (AHI≥15) + BMI 30-40

kg/m2

Sleep disorder other than OSA syndrome, periodic limb movement arousal index > 10, uncontrolled or poorly controlled blood pressure (systolic > 160 mm Hg or diastolic > 100 mm Hg), or the presence or history of unstable angina, heart failure, cardiac valvulopathy, myocardial infarction, potentially life-threatening cardiac arrhythmia, or clinically significant abnormality on electrocardiogram.

This study was funded by VIVUS, Inc. Dr. Winslow has participated in clinical trials for and received research payment from Apnex, Boehringer Ingelheim, Cephalon, Eli Lilly, Forest, GlaxoSmithKline, Merck & Co., Novartis, Pfizer, Philips-Respironics, Sanofi-Aventis, Ventus, and VIVUS. He has served as an advisor and consultant for VIVUS and as a speaker for GlaxoSmithKline. Dr. Bowden and Ms. DiDonato are employees of VIVUS, Inc., the sponsor of the study. Dr. McCullough has participated in clinical trials and received research payment from VIVUS.

yes

Wu et al. 201670 18-65 OSA (AHI≥15) + non-

smokers

Could not tolerate carbocysteine or CPAP; a history of treatment for OSAS; an active acute or chronic infection; diagnosed with a cardiovascular, neuromuscular, peripheral vascular, or chronic respiratory disease; steroidal, nonsteroidal anti-inflammatory, or lipid-lowering drugs, vasodilators, cardiovascular medications, or other medications that lower oxidative stress; drugs that impair sleep.

Science and Technology Planning Project of Guangdong Province, China (2008B03031254).

Yang et al. 201671

30-70 OSA (AHI>15) + resistant hypertension

Secondary causes of hypertension except for OSA and hyperaldosteronism, such as renovascular hypertension, pheochromocytoma or Cushing’s syndrome, patients with recent (≤6 months) treatment of OSA, or 2 weeks of aldosterone eceptor antagonists, or with current (≤6 months) myocardial infarction or stroke, chronic congestive heart failure, chronic renal disease (creatinine clearance rate <60 mL/min × 1.73 m2), severe respiratory diseases (chronic

unknown

Page 32 of 38

Author and year

Inclusion age

(years)

Characteristics (OSA)

+ requirementsExclusion criteria Funding / conflict of interest

Phar

mac

eutic

al

com

pany

/ in

dust

ry

obstructive ulmonary disease, branchial asthma), spironolactone contraindications (allergic to spironolactone), plasma potassium ≥5.0 mmol/L, women during pregnancy and maternity, liver dysfunction, hyponatremia, acidosis, breast enlargement, and menstrual disorders

Page 33 of 38

Table 14. Reported REM stages (% of total sleep time) of 31 RCTs at follow-up.We also considered a potential effect on sleep stages, which might explain a different AHI at follow up. Of 58 eligible studies, 31 reported data on REM stages. However, the effect of the intervention on REM stages was not statistically significant (-1.01, 95% CI -8.34 to +7.15, p = 0.523). Changes in AHI did not correlate with changes in REM sleep (r=0.69, p= 0.480).

Author REM(%) follow-up(intervention)

REM(%) follow-up(control)

Sukys-Claudino et al. 2012 25.2 31.2Eckert et al. 2011 11 10Clarenbach et al. 2008 10 11Moraes et al. 2008 15.9 9.7Carley et al. 2007 22.2 16.6Kiley et al. 2004 10.9 10.5Hedner et al. 1996 16 10Kraiczi et al. 1999 9.7 12.9Rasche et al. 1999 21.4 22.2Heitmann et al. 1998 18.1 21.7Jokic et al. 1998 28.6 22.8Mulloy et al. 1992 11 12Whyte et al. 1988 23 19Espinoza et al. 1987 6.2 9.6Suratt et al. 1986 2.75 4.25Mangin et al. 1983 9 9Brownell et al. 1982 9.7 23.4Hedner et al. 2005 17.3 12.9Atkinson et al. 1985 1.6 8.8Torvaldsson et al. 2005 9.4 14Carley et al. 2018 23 18.7Taranto-Montemurro et al. 2016 6.7 12.7Taranto-Montemurro et al. 2017 2 14.5Liu et al. 2016 22.2 22.2Li et al. 2016 15 13.5Smales et al. 2015 17.5 17.9Edwards et al. 2012 9.4 10.4Berry et al. 1999 3.2 6.2Schönhofer et al. 1996 7 7Wang et al. 2011 8.41 12.06Carter et al. 2016 8 8

Page 34 of 38

References

1. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. Bmj. 2009;339:b2700.

2. Lefebvre C, Manheimer E, Glanville J. Chapter 6: Searching for studies. In: Higgins JPT, Green S, eds. Cochrane Handbook for Systematic Reviews of Intervensions. London, England: Cochrane Collaboration. 2011.

3. Kohler M, Bloch KE, Stradling JR. Pharmacological approaches to the treatment of obstructive sleep apnoea. Expert Opin Investig Drugs. 2009;18(5):647-656.

4. Lin CM, Huang YS, Guilleminault C. Pharmacotherapy of obstructive sleep apnoea. Expert Opin Pharmacother. 2012;13(6):841-857.

5. Mason M, Welsh EJ, Smith I. Drug therapy for obstructive sleep apnoea in adults. Cochrane Database Syst Rev. 2013(5):CD003002.

6. White DP. Pharmacologic Approaches to the Treatment of Obstructive Sleep Apnoea. Sleep Med Clin. 2016;11(2):203-212.

7. Kohler M, Stradling JR. Pitfalls of clinical trials on pharmacological treatment for obstructive sleep apnoea: future directions. Expert Opin Investig Drugs. 2011;20(8):1033-1037.

8. Higgins J, Altman D, Sterne J. Chapter 8: Assessing risk of bias in included studies. In: Higgins JPT, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions. London, England: Cochrane Collaboration. 2011.

9. AG B. Obstructive Sleep Apnoea (OSA) Treated With a Potassium Channel Inhibitor (SANDMAN). 2018; https://clinicaltrials.gov/ct2/show/NCT03603678. Accessed 22.10.2018, 2018.

10. Ltd. TB. A Study to Examine the Efficacy of a Therapeutic THX-110 for Obstructive Sleep Apnoea. 2018; https://clinicaltrials.gov/ct2/show/NCT03646552. Accessed 22.10.2018, 2018.

11. David Andrew Wellman BaWsH. Atomoxetine and Oxybutynin in Obstructive Sleep Apnoea (ATOSA). 2016; https://clinicaltrials.gov/ct2/show/NCT02908529. Accessed 22.10.2018, 2018.

12. David Andrew Wellman BaWsH. DAW1033D in Obstructive Sleep Apnoea (OSAstimD). 2017; https://clinicaltrials.gov/ct2/show/NCT03383887. Accessed 22.10.2018, 2018.

13. University of California SD. The Effect of Melatonin on Sleep and Ventilatory Control in Obstructive Sleep Apnoea. 2015; https://clinicaltrials.gov/ct2/show/NCT02484300. Accessed 22.10.2018, 2018.

14. Florida UoS. Effect of Oxymetazoline Hydrochloride in Combination With Fluticasone Propionate on the Apnoea Hypopnoea Index (AHI) in Subject With Persistent Nasal Congestion and Mild Obstructive Sleep Apnoea. 2015; clinicaltrials.gov. Accessed 22.10.2018, 2018.

15. Acar M, Cingi C, Sakallioglu O, San T, Fatih Yimenicioglu M, Bal C. The effects of mometasone furoate and desloratadine in obstructive sleep apnoea syndrome patients with allergic rhinitis. American journal of rhinology & allergy. 2013;27(4):e113-116.

16. Atkinson RL, Suratt PM, Wilhoit SC, Recant L. Naloxone improves sleep apnoea in obese humans. Int J Obes. 1985;9(4):233-239.

17. Berry RB, Yamaura EM, Gill K, Reist C. Acute effects of paroxetine on genioglossus activity in obstructive sleep apnoea. Sleep. 1999;22(8):1087-1092.

18. Blackman A, Foster GD, Zammit G, et al. Effect of liraglutide 3.0 mg in individuals with obesity and moderate or severe obstructive sleep apnoea: the SCALE Sleep Apnoea randomized clinical trial. International journal of obesity (2005). 2016;40(8):1310-1319.

19. Brownell LG, West P, Sweatman P, Acres JC, Kryger MH. Protriptyline in obstructive sleep apnoea: a double-blind trial. The New England journal of medicine. 1982;307(17):1037-1042.

20. Bruckert E, Duchene E, Bonnefont-Rousselot D, et al. Proof of concept study: does fenofibrate have a role in sleep apnoea syndrome? Curr Med Res Opin. 2010;26(5):1185-1192.

21. Carley DW, Olopade C, Ruigt GS, Radulovacki M. Efficacy of mirtazapine in obstructive sleep apnoea syndrome. Sleep. 2007;30(1):35-41.

22. Carley DW, Prasad B, Reid KJ, et al. Pharmacotherapy of Apnoea by Cannabimimetic Enhancement, the PACE Clinical Trial: Effects of Dronabinol in Obstructive Sleep Apnoea. Sleep. 2018;41(1).

23. Carter SG, Berger MS, Carberry JC, et al. Zopiclone Increases the Arousal Threshold without Impairing Genioglossus Activity in Obstructive Sleep Apnoea. Sleep. 2016;39(4):757-766.

Page 35 of 38

24. Clarenbach CF, Kohler M, Senn O, Thurnheer R, Bloch KE. Does nasal decongestion improve obstructive sleep apnoea? Journal of sleep research. 2008;17(4):444-449.

25. Cook WR, Benich JJ, Wooten SA. Indices of severity of obstructive sleep apnoea syndrome do not change during medroxyprogesterone acetate therapy. Chest. 1989;96(2):262-266.

26. Diamond E, Druz W, D’Souza V, JT. S. Effect of Naloxone in obstructive sleep apnoea. American Review of Respiratory Disease. 1982;125(Suppl 4):235.

27. Eckert DJ, Owens RL, Kehlmann GB, et al. Eszopiclone increases the respiratory arousal threshold and lowers the apnoea/hypopnoea index in obstructive sleep apnoea patients with a low arousal threshold. Clinical science. 2011;120(12):505-514.

28. Edwards BA, Sands SA, Eckert DJ, et al. Acetazolamide improves loop gain but not the other physiological traits causing obstructive sleep apnoea. The Journal of physiology. 2012;590(5):1199-1211.

29. Eskandari D, Zou D, Karimi M, Stenlof K, Grote L, Hedner J. Zonisamide reduces obstructive sleep apnoea: a randomised placebo-controlled study. The European respiratory journal. 2014;44(1):140-149.

30. Eskandari D, Zou D, Grote L, Hoff E, Hedner J. Acetazolamide Reduces Blood Pressure and Sleep-Disordered Breathing in Patients With Hypertension and Obstructive Sleep Apnoea: A Randomized Controlled Trial. Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine. 2018;14(3):309-317.

31. Espinoza H, Antic R, Thornton AT, McEvoy RD. The effects of aminophylline on sleep and sleep-disordered breathing in patients with obstructive sleep apnoea syndrome. The American review of respiratory disease. 1987;136(1):80-84.

32. Ferber C, Duclaux R, Mouret J. Naltrexone improves blood gas patterns in obstructive sleep apnoea syndrome through its influence on sleep. Journal of sleep research. 1993;2(3):149-155.

33. Grote L, Wutkewicz K, Knaack L, Ploch T, Hedner J, Peter JH. Association between blood pressure reduction with antihypertensive treatment and sleep apnoea activity. Am J Hypertens. 2000;13(12):1280-1287.

34. Hedner J, Grunstein R, Eriksson B, Ejnell H. A double-blind, randomized trial of sabeluzole--a putative glutamate antagonist--in obstructive sleep apnoea. Sleep. 1996;19(4):287-289.

35. Hedner J, Kraiczi H, Peker Y, Murphy P. Reduction of sleep-disordered breathing after physostigmine. American journal of respiratory and critical care medicine. 2003;168(10):1246-1251.

36. Hedner J, Kraiczi H, Peker Y, Grote L. Reduction of sleep apnoea after the orally available cholinesterase inhibitor donepezil. Sleep medicine. 2005;6(2):54-55.

37. Hein H, Behnke G, Jorres RA, Magnussen H. The therapeutic effect of theophylline in mild obstructive sleep Apnoea/Hypopnoea syndrome: results of repeated measurements with portable recording devices at home. Eur J Med Res. 2000;5(9):391-399.

38. Heitmann J, Grote L, Knaack L, Kohler U, Hinder M, Peter JH. Cardiovascular effects of mibefradil in hypertensive patients with obstructive sleep apnoea. Eur J Clin Pharmacol. 1998;54(9-10):691-696.

39. Hoyos CM, Killick R, Yee BJ, Grunstein RR, Liu PY. Effects of testosterone therapy on sleep and breathing in obese men with severe obstructive sleep apnoea: a randomized placebo-controlled trial. Clinical endocrinology. 2012;77(4):599-607.

40. Issa FG. Effect of clonidine in obstructive sleep apnoea. The American review of respiratory disease. 1992;145(2 Pt 1):435-439.

41. Jokic R, Klimaszewski A, Mink J, Fitzpatrick MF. Surface tension forces in sleep apnoea: the role of a soft tissue lubricant: a randomized double-blind, placebo-controlled trial. American journal of respiratory and critical care medicine. 1998;157(5 Pt 1):1522-1525.

42. Kiely JL, Nolan P, McNicholas WT. Intranasal corticosteroid therapy for obstructive sleep apnoea in patients with co-existing rhinitis. Thorax. 2004;59(1):50-55.

43. Koutsourelakis I, Minaritzoglou A, Zakynthinos G, Vagiakis E, Zakynthinos S. The effect of nasal tramazoline with dexamethasone in obstructive sleep apnoea patients. The European respiratory journal. 2013;42(4):1055-1063.

44. Kraiczi H, Hedner J, Dahlof P, Ejnell H, Carlson J. Effect of serotonin uptake inhibition on breathing during sleep and daytime symptoms in obstructive sleep apnoea. Sleep. 1999;22(1):61-67.

45. Li Y, Owens RL, Sands S, et al. The Effect of Donepezil on Arousal Threshold and Apnoea-Hypopnoea Index. A Randomized, Double-Blind, Cross-Over Study. Annals of the American Thoracic Society. 2016;13(11):2012-2018.

Page 36 of 38

46. Liu A, Kim SH, Ariel D, et al. Does enhanced insulin sensitivity improve sleep measures in patients with obstructive sleep apnoea: a randomized, placebo-controlled pilot study. Sleep medicine. 2016;22:57-60.

47. Maari C, Bolduc C, Nigen S, Marchessault P, Bissonnette R. Effect of adalimumab on sleep parameters in patients with psoriasis and obstructive sleep apnoea: a randomized controlled trial. The Journal of dermatological treatment. 2014;25(1):57-60.

48. Mangin P, Krieger J, Kurtz D. [Effect of oral almitrine on the sleep apnoea syndrome]. Rev Fr Mal Respir. 1983;11(6):899-906.

49. Marshall NS, Yee BJ, Desai AV, et al. Two randomized placebo-controlled trials to evaluate the efficacy and tolerability of mirtazapine for the treatment of obstructive sleep apnoea. Sleep. 2008;31(6):824-831.

50. Di Martino E, Saadi R, Emmerling O, Werner E. [Drug therapy of sleep apnoea syndromes: results of short-term treatment with theophylline]. Laryngorhinootologie. 1999;78(3):120-124.

51. Mendelson WB, Maczaj M, Holt J. Buspirone administration to sleep apnoea patients. J Clin Psychopharmacol. 1991;11(1):71-72.

52. Moraes W, Poyares D, Sukys-Claudino L, Guilleminault C, Tufik S. Donepezil improves obstructive sleep apnoea in Alzheimer disease: a double-blind, placebo-controlled study. Chest. 2008;133(3):677-683.

53. Morrell MJ, Arabi Y, Zahn BR, Meyer KC, Skatrud JB, Badr MS. Effect of surfactant on pharyngeal mechanics in sleeping humans: implications for sleep apnoea. The European respiratory journal. 2002;20(2):451-457.

54. Mulloy E, McNicholas WT. Theophylline in obstructive sleep apnoea. A double-blind evaluation. Chest. 1992;101(3):753-757.

55. Prasad B, Radulovacki M, Olopade C, Herdegen JJ, Logan T, Carley DW. Prospective trial of efficacy and safety of ondansetron and fluoxetine in patients with obstructive sleep apnoea syndrome. Sleep. 2010;33(7):982-989.

56. Rasche K, Duchna HW, Lauer J, et al. Obstructive Sleep Apnoea and Hypopnoea Efficacy and Safety of a Long-Acting beta2-Agonist. Sleep & breathing = Schlaf & Atmung. 1999;3(4):125-130.

57. Schonhofer B, Kohler D. Benzodiazepine receptor antagonist (flumazenil) does not affect sleep-related breathing disorders. The European respiratory journal. 1996;9(9):1816-1820.

58. Smales ET, Edwards BA, Deyoung PN, et al. Trazodone Effects on Obstructive Sleep Apnoea and Non-REM Arousal Threshold. Annals of the American Thoracic Society. 2015;12(5):758-764.

59. Smith DF, Ishman SL, Spiceland CP, Romaker AM. Effects of medical therapy on mild obstructive sleep apnoea in adult patients. Sleep. 2017;40(Abstract Suppl):A208.

60. Stepanski EJ, Conway WA, Young DK, Zorick FJ, Wittig RM, Roth T. A double-blind trial of protriptyline in the treatment of sleep apnoea syndrome. Henry Ford Hosp Med J. 1988;36(1):5-8.

61. Stradling J, Smith D, Radulovacki M, Carley D. Effect of ondansetron on moderate obstructive sleep apnoea, a single night, placebo-controlled trial. Journal of sleep research. 2003;12(2):169-170.

62. Sukys-Claudino L, Moraes W, Guilleminault C, Tufik S, Poyares D. Beneficial effect of donepezil on obstructive sleep apnoea: a double-blind, placebo-controlled clinical trial. Sleep medicine. 2012;13(3):290-296.

63. Suratt PM, Wilhoit SC, Brown ED, Findley LJ. Effect of doxapram on obstructive sleep apnoea. Bull Eur Physiopathol Respir. 1986;22(2):127-131.

64. Taranto-Montemurro L, Sands SA, Edwards BA, et al. Desipramine improves upper airway collapsibility and reduces OSA severity in patients with minimal muscle compensation. The European respiratory journal. 2016;48(5):1340-1350.

65. Taranto-Montemurro L, Sands SA, Edwards BA, et al. Effects of Tiagabine on Slow Wave Sleep and Arousal Threshold in Patients With Obstructive Sleep Apnoea. Sleep. 2017;40(2).

66. Torvaldsson S, Grote L, Peker Y, Basun H, Hedner J. A randomized placebo-controlled trial of an NMDA receptor antagonist in sleep-disordered breathing. Journal of sleep research. 2005;14(2):149-155.

67. Wang D, Marshall NS, Duffin J, et al. Phenotyping interindividual variability in obstructive sleep apnoea response to temazepam using ventilatory chemoreflexes during wakefulness. Journal of sleep research. 2011;20(4):526-532.

68. Whyte KF, Gould GA, Airlie MA, Shapiro CM, Douglas NJ. Role of protriptyline and acetazolamide in the sleep apnoea/hypopnoea syndrome. Sleep. 1988;11(5):463-472.

Page 37 of 38

69. Winslow DH, Bowden CH, DiDonato KP, McCullough PA. A randomized, double-blind, placebo-controlled study of an oral, extended-release formulation of phentermine/topiramate for the treatment of obstructive sleep apnoea in obese adults. Sleep. 2012;35(11):1529-1539.

70. Wu K, Su X, Li G, Zhang N. Antioxidant Carbocysteine Treatment in Obstructive Sleep Apnoea Syndrome: A Randomized Clinical Trial. PloS one. 2016;11(2):e0148519.

71. Yang L, Zhang H, Cai M, et al. Effect of spironolactone on patients with resistant hypertension and obstructive sleep apnoea. Clinical and experimental hypertension (New York, NY : 1993). 2016;38(5):464-468.

72. Fiori CZ, Martinez D, Goncalves SC, Montanari CC, Fuchs FD. Effect of diuretics and sodium-restricted diet on sleep apnoea severity: study protocol for a randomized controlled trial. Trials. 2015;16:188.

Page 38 of 38