ALL LITERATURE SEARCH TERMS · US Modafinil (1998)- Mean (SD) is pooled data of Modafinil 200mg and...

v. June 15, 2020

SUPPLEMENTAL MATERIALS

ALL LITERATURE SEARCH TERMS PICO 1 PubMed Search String: ("Disorders of Excessive Somnolence"[Mesh] OR "Narcolepsy"[Mesh] OR “Narcolepsy Type 1” [All Fields] OR “Hypocretin deficiency

syndrome” [All Fields] OR “narcolepsy-cataplexy” [All Fields] OR “narcolepsy with cataplexy” [All Fields] OR “Narcolepsy Type 2” [All Fields] OR

“Narcolepsy without cataplexy” [All Fields]) AND ("Adult"[Mesh] OR "Adolescent"[Mesh] OR "Child"[Mesh]) AND "Humans"[Mesh] AND

("Amphetamines"[Mesh] OR “amphetamines”[All Fields] OR "armodafinil" [Supplementary Concept] OR “armodafinil”[All Fields] OR

"Clarithromycin"[Mesh] OR “clarithromycin”[All Fields] OR "Flumazenil"[Mesh] OR “flumazenil”[All Fields] OR "Carnitine"[Mesh] OR “L-

carnitine”[All Fields] OR "Methylphenidate"[Mesh] or “methylphenidate”[All Fields] OR "modafinil" [Supplementary Concept] OR “modafinil”[All

Fields] OR "Orexins"[Mesh] OR “Orexin A”[All Fields] OR "reboxetine" [Supplementary Concept] OR “reboxetine”[All Fields] OR

"Ritanserin"[Mesh] OR “ritanserin”[All Fields] OR "Serotonin Uptake Inhibitors"[Mesh] OR "selective serotonin reuptake inhibitors"[All Fields] OR

"Selegiline"[Mesh] OR “selegiline”[All Fields] OR “JZP-110” OR “Solriamfetol” OR "Sodium Oxybate"[Mesh] OR “sodium oxybate”[All Fields] OR

"Antidepressive Agents, Tricyclic"[Mesh] OR “tricyclic antidepressants” [All Fields] OR "Venlafaxine Hydrochloride"[Mesh] OR “venlafaxine”[All

Fields] OR "Drug-Related Side Effects and Adverse Reactions"[Mesh] OR "Prescription Drug Misuse"[Mesh] OR "Growth and

Development"[Mesh] OR "Adolescent Development"[Mesh] OR "Child Development"[Mesh] OR "Drug Tolerance"[Mesh] OR “toxicity”

[Subheading]) AND ("Clinical Trial"[ptyp] OR "Clinical Trial, Phase I"[ptyp] OR "Clinical Trial, Phase II"[ptyp] OR "Clinical Trial, Phase III"[ptyp]

OR "Clinical Trial, Phase IV"[ptyp] OR "Comparative Study"[ptyp] OR "Controlled Clinical Trial"[ptyp] OR "Evaluation Studies"[ptyp] OR

"Multicenter Study"[ptyp] OR "Observational Study"[ptyp] OR "Pragmatic Clinical Trial"[ptyp] OR "Randomized Controlled Trial"[ptyp] OR

"Validation Studies"[ptyp]) AND English[lang]

PICO 2 PubMed Search String: ("Disorders of Excessive Somnolence"[Mesh] OR "Hypersomnolence, Idiopathic"[Mesh] OR “Idiopathic Hypersomnia” [All Fields] OR “Idiopathic CNS hypersomnolence” [All Fields]) AND ("Adult"[Mesh] OR "Adolescent"[Mesh] OR "Child"[Mesh]) AND "Humans"[Mesh] AND ("Amphetamines"[Mesh] OR “amphetamines”[All Fields] OR "armodafinil" [Supplementary Concept] OR “armodafinil”[All

Fields] OR "Clarithromycin"[Mesh] OR “clarithromycin”[All Fields] OR "Flumazenil"[Mesh] OR “flumazenil”[All Fields] OR "Thyroxine"[Mesh] OR

“levothyroxine”[All Fields] OR "Mazindol"[Mesh] OR "Mazindol"[All Fields] OR "Methylphenidate"[Mesh] or “methylphenidate”[All Fields] OR

"modafinil" [Supplementary Concept] OR “modafinil”[All Fields] OR "1-(3-(3-(4-chlorophenyl)propoxy)propyl)piperidine" [Supplementary

Concept] OR “pitolisant”[All Fields] OR "Sodium Oxybate"[Mesh] OR “JZP-110” OR “Solriamfetol” OR “sodium oxybate”[All Fields] OR

“scheduled naps”[All Fields]) AND ("Clinical Trial"[ptyp] OR "Clinical Trial, Phase I"[ptyp] OR "Clinical Trial, Phase II"[ptyp] OR "Clinical Trial,

Phase III"[ptyp] OR "Clinical Trial, Phase IV"[ptyp] OR "Comparative Study"[ptyp] OR "Controlled Clinical Trial"[ptyp] OR "Evaluation

Studies"[ptyp] OR "Multicenter Study"[ptyp] OR "Observational Study"[ptyp] OR "Pragmatic Clinical Trial"[ptyp] OR "Randomized Controlled

Trial"[ptyp] OR "Validation Studies"[ptyp]) AND English[lang]

PICO 3 PubMed Search String: ("Disorders of Excessive Somnolence"[Mesh] OR "Kleine-Levin Syndrome"[Mesh] OR “Kleine-Levin Syndrome” [All Fields] OR “Recurrent

hypersomnia” [All Fields] OR “periodic hypersomnolence” [All Fields]) AND ("Adult"[Mesh] OR "Adolescent"[Mesh] OR "Child"[Mesh]) AND

"Humans"[Mesh] AND ("Amantadine"[Mesh] OR "Amantadine"[All Fields] OR "Serotonin Uptake Inhibitors"[Mesh] OR "selective serotonin

reuptake inhibitors"[All Fields] OR "Antidepressive Agents, Tricyclic"[Mesh] OR “tricyclic antidepressants” [All Fields] OR "Venlafaxine

Hydrochloride"[Mesh] OR “venlafaxine”[All Fields] OR "Clarithromycin"[Mesh] OR “clarithromycin”[All Fields] OR "Valproic Acid"[Mesh] OR

"Valproic Acid"[All Fields] OR "Carbamazepine"[Mesh] OR "Carbamazepine"[All Fields] OR "Phenytoin"[Mesh] OR "Phenytoin"[All Fields] OR

"Lithium Carbonate"[Mesh] OR "Lithium Carbonate"[All Fields] OR "Melatonin"[Mesh] OR "Melatonin"[All Fields] OR "Risperidone"[Mesh] OR

"Risperidone"[All Fields] OR "Amphetamines"[Mesh] OR “amphetamines”[All Fields] OR "armodafinil" [Supplementary Concept] OR

“armodafinil”[All Fields] OR "Methylphenidate"[Mesh] or “methylphenidate”[All Fields] OR "modafinil" [Supplementary Concept] OR

“modafinil”[All Fields] OR “supportive care”[All Fields]) AND ("Clinical Trial"[ptyp] OR "Clinical Trial, Phase I"[ptyp] OR "Clinical Trial, Phase

II"[ptyp] OR "Clinical Trial, Phase III"[ptyp] OR "Clinical Trial, Phase IV"[ptyp] OR "Comparative Study"[ptyp] OR "Controlled Clinical Trial"[ptyp]

OR "Evaluation Studies"[ptyp] OR "Multicenter Study"[ptyp] OR "Observational Study"[ptyp] OR "Pragmatic Clinical Trial"[ptyp] OR

"Randomized Controlled Trial"[ptyp] OR "Validation Studies"[ptyp]) AND English[lang]

PICO 4 PubMed Search String: ("Disorders of Excessive Somnolence"[Mesh] OR “hypersomnia”[All Fields] OR “Hypersomnia Associated with a Psychiatric Disorder” [All

Fields] OR “Hypersomnia not due to substance or known physiological condition” [All Fields] OR “nonorganic hypersomnia” [All Fields] OR

“pseudohypersomnia” [All Fields] OR “pseudonarcolepsy” [All Fields] OR “Hypersomnia Due to a Medical Disorder” [All Fields] OR

"Hypersomnolence, Idiopathic"[Mesh] OR “Idiopathic Hypersomnia” [All Fields] OR “Idiopathic CNS hypersomnolence” [All Fields] OR "Kleine-

Levin Syndrome"[Mesh] OR “Kleine-Levin Syndrome” [All Fields] OR “Recurrent hypersomnia” [All Fields] OR “periodic hypersomnolence” [All

Fields] OR "Narcolepsy"[Mesh] OR “Narcolepsy Type 1” [All Fields] OR “Hypocretin deficiency syndrome” [All Fields] OR “narcolepsy-

v. June 15, 2020

cataplexy” [All Fields] OR “narcolepsy with cataplexy” [All Fields] OR “Narcolepsy Type 2” [All Fields] OR “Narcolepsy without cataplexy” [All

Fields]) AND ("Adult"[Mesh] OR "Adolescent"[Mesh] OR "Child"[Mesh]) AND "Humans"[Mesh] AND ("Amantadine"[Mesh] OR "Amantadine"[All

Fields] OR "Amphetamines"[Mesh] OR “amphetamines”[All Fields] OR "Valproic Acid"[Mesh] OR "Valproic Acid"[All Fields] OR

"Carbamazepine"[Mesh] OR "Carbamazepine"[All Fields] OR "Phenytoin"[Mesh] OR "Phenytoin"[All Fields] OR "armodafinil" [Supplementary

Concept] OR “armodafinil”[All Fields] OR "Clarithromycin"[Mesh] OR “clarithromycin”[All Fields] OR "Flumazenil"[Mesh] OR “flumazenil”[All

Fields] OR "Thyroxine"[Mesh] OR “levothyroxine”[All Fields] OR "Carnitine"[Mesh] OR “L-carnitine”[All Fields] OR "Lithium Carbonate"[Mesh]

OR "Lithium Carbonate"[All Fields] OR "Mazindol"[Mesh] OR "Mazindol"[All Fields] OR "Melatonin"[Mesh] OR "Melatonin"[All Fields] OR

"Methylphenidate"[Mesh] or “methylphenidate”[All Fields] OR "modafinil" [Supplementary Concept] OR “modafinil”[All Fields] OR

"Orexins"[Mesh] OR “Orexin A”[All Fields] OR "reboxetine" [Supplementary Concept] OR “reboxetine”[All Fields] OR "Risperidone"[Mesh] OR

"Risperidone"[All Fields] OR "Ritanserin"[Mesh] OR “ritanserin”[All Fields] OR "1-(3-(3-(4-chlorophenyl) propoxy) propyl) piperidine"

[Supplementary Concept] OR “pitolisant”[All Fields] OR "Serotonin Uptake Inhibitors"[Mesh] OR "selective serotonin reuptake inhibitors"[All

Fields] OR "Antidepressive Agents, Tricyclic"[Mesh] OR “tricyclic antidepressants” [All Fields] OR "Venlafaxine Hydrochloride"[Mesh] OR

“venlafaxine”[All Fields] OR “JZP-110” OR “Solriamfetol” OR “Serotonin and Noradrenaline Reuptake Inhibitors”[Mesh] OR "Venlafaxine

Hydrochloride"[Mesh] OR “Sodium Oxybate”[Mesh] OR “sodium oxybate”[All Fields] OR “Antidepressive Agents, Tricyclic”[Mesh] OR “tricyclic

antidepressants” [All Fields] OR “scheduled naps”[All Fields] OR "Caffeine"[Mesh] OR “caffeine”[All Fields] OR “supportive care”[All Fields])

AND

("Clinical Trial"[ptyp] OR "Clinical Trial, Phase I"[ptyp] OR "Clinical Trial, Phase II"[ptyp] OR "Clinical Trial, Phase III"[ptyp] OR "Clinical Trial,

Phase IV"[ptyp] OR "Comparative Study"[ptyp] OR "Controlled Clinical Trial"[ptyp] OR "Evaluation Studies"[ptyp] OR "Multicenter Study"[ptyp]

OR "Observational Study"[ptyp] OR "Pragmatic Clinical Trial"[ptyp] OR "Randomized Controlled Trial"[ptyp] OR "Validation Studies"[ptyp]) AND

English[lang]

EXCLUSION CRITERIA Exclusion criteria are applied during the abstract review of all retrieved publications. Studies that meet any of the exclusion criteria are rejected from the systematic review: A. Publication type

a. Book and book chapters b. Conference abstracts c. Dissertations d. Editorials e. Letters to the editor f. Methods papers g. Review papers

B. Study type

a. Animal research C. Language non-English

D. Sample size < 10 subjects with disease E. Main study objective is NOT evaluating the efficacy/effectiveness of interventions of interest

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Pharmacological therapy

a) Anticonvulsant (Carbamazepine, Phenytoin,

Valproic acid)

b) Antimanic Agent (Lithium Carbonate)

c) Anti-Parkinson Agent (Amantadine)

d) Antipsychotic (Risperidone)

e) Benzodiazepine receptor agonists (Eszopiclone,

Zaleplon, Zolpidem)

f) Benzodiazepine receptor antagonist (Flumazenil)

g) Benzodiazepines (Temazepam, Triazolam)

h) Central Nervous System Depressant (Sodium

oxybate)

i) Central Nervous System Stimulant (Amphetamines

and related preparations, Armodafinil,

Methylphenidate and related preparations,

Modafinil)

j) Combination therapy

k) Dietary Supplement (L-carnitine)

l) Dietary Supplement (L-carnitine)

m) H3 receptor inverse agonist (Pitolisant)

n) Macrolide (Clarithromycin)

o) Monoamine oxidase inhibitors/B (Selegiline)

p) Norepinephrine Reuptake Inhibitor (Atomoxetine)

q) Selective dopamine and norepinephrine reuptake

inhibitor (Solriamfetol [JZP-110])

r) Selective serotonin reuptake inhibitors (Citalopram,

Escitalopram, Fluoxetine, Paroxetine, Sertraline)

s) Serotonin/Norepinephrine Reuptake Inhibitor

(Venlafaxine)

t) Skeletal Muscle Relaxant (R-baclofen/ baclofen)

u) Thyroid Product (Levothyroxine)

v) Tricyclic antidepressants (Amitriptyline, Amoxapine,

Clomipramine, Doxepin, Imipramine, Maprotiline,

Nortriptyline, Trimipramine)

Behavioral therapy

a) Exercise

b) Scheduled naps/sleep extension

c) Sleep hygiene

d) Supportive care

e) Trigger avoidance

Immunotherapy

a) Intravenous immunoglobulin

b) Plasmapheresis

c) Steroids

F. Studies that focus on comorbid disorders: OSA, circadian rhythm sleep disorders, insufficient sleep,

medication side-effects.

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INCLUSION CRITERIA Inclusion criteria are applied during the full publication review of all accepted studies. Full publications that meet all inclusion criteria will be accepted as evidence to use in the systematic review. G. Outcomes of interest (must meet at least 1)

1. Accident risk 2. Cataplexy 3. Cognitive performance 4. Difficulty waking in the morning 5. Disease severity 6. Excessive daytime sleepiness 7. Fatigue 8. Mood 9. Quality of life 10. Poor work/school performance/attendance 11. Sleep inertia

H. For RCTs: compares interventions vs. placebo, compares intervention vs. intervention For observational studies longitudinally examines the effects of intervention

I. Hypersomnia diagnosis: ICSD, DSM, other hypersomnolence criteria/symptoms that would require task force adjudication

ABBREVIATIONS

BFI Brief Fatigue Inventory

CGI Clinical Global Index (CGI)

CGI-C Clinical Global Impression of Change

CGI-Sleepiness Clinical Global Impression of Sleepiness

ESS Epworth Sleepiness Scale

ESS-CHAD Epworth Sleepiness Scale for Children and Adolescents

FOSQ Functional Outcomes of Sleep Questionnaire

FSS Fatigue Severity Scale

GIR Global Improvement Rating

JESS Epworth Sleepiness Scale; Japanese version

MSLT Multiple Sleep Latency Test

MWT Maintenance of Wakefulness Test

NT1 Narcolepsy Type 1

NT2 Narcolepsy Type 2

PGI-C Patient Global Impression of Change

RRT Reciprocal Reaction Time

SF-36 Short Form Health Survey-36

SSS Stanford Sleepiness Scale

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ADULT POPULATION

PICO 1: Narcolepsy Intervention: ARMODAFINIL

Outcome: EXCESSIVE DAYTIME SLEEPINESS

Table S1. ESS determined excessive daytime sleepiness in an observational study, in response to Armodafinil in adult patients

unspecified narcolepsy.

Study Study Design Study duration

No. of subjects Data (mean, SD)

Pre- Post Difference, [CI] Intervention

Comparator

Pre Post Pre-treatment Post treatment

Pre-treatment

Post treatment

Schwartz 2010

Open-label, flexible-dose study

12 months 49

28 16.3 (3.5) Not provided N/A N/A -4.7 (−7.41, −1.93)*

*This data was provided in publication; not calculated.

Table S2. MWT (change from baseline) determined excessive daytime sleepiness, in response to Armodafinil (various doses) vs.

placebo in adult patients with unspecified narcolepsy



Pre-Post difference (CI)

Armodafinil Placebo

Armodafinil Placebo Pre-treatment (pooled)

Change from

baseline

Pre-treatment

Change from

baseline

Harsh 2006

Multicenter double-blind study

12 weeks 118

58 11.22 ± 6.52 1.75 ± 5.43 12.5 ± 6.6 -1.56 ± 7.62 3.31 (1.12- 5.50)

Change from baseline in MWT- Mean (SD) estimated from graph and represents pooled data of 2 timepoints.

Outcome: DISEASE SEVERITY

Table S3. CGI- C determined disease severity in an RCT, in response to Armodafinil (various doses) in adult patients with unspecified

narcolepsy.

Study Study Design Study

duration


Mean Difference Intervention

Placebo

Post intervention Pre-Rx % improvement Pre-Rx % improvement

Harsh 2006 RCT 12 weeks Armodafinil- 132 Placebo- 64

N/A 71% N/A 33% 38%

Outcome: ACCIDENT RISK

Table S4. Diary based mean reduction in number of patients who reported mistakes, near misses, and accidents in an RCT, in

response to Armodafinil (various doses) in adult patients with unspecified narcolepsy.


duration


Mean Difference (reduction)

Intervention

Placebo

Post intervention Pre-Rx Post Rx Pre-Rx Post Rx Harsh 2006 RCT 12 weeks Armodafinil- 132

Placebo- 64 N/A 36.5% N/A 10% 26.5%

Harsh 2006 Pooled data of different doses

v. June 15, 2020

Outcome: FATIGUE

Figure S1. BFI determined (Global) Fatigue, in response to Armodafinil (various doses) vs. placebo in adult patients with unspecified

narcolepsy

This data depicts the mean change (improvement) from baseline.

Outcome: SLEEP QUALITY

Table S5. Sleep efficiency (assessed by polysomnography) determined sleep quality in an RCT, in response to Armodafinil (various

doses) in adult patients with unspecified narcolepsy


duration


Mean difference (% difference in

improvement

Intervention

Placebo

Post intervention Pre-Rx (%)

Post Rx (% improvement)

Pre-Rx (%)

Post Rx (% improvement)

Harsh 2006 RCT 12 weeks Armodafinil- 131 Placebo- 63

81.3 ± 12.8

83.4 ±12.3 (2.1%)

81.3 ±12.8

80.9 ± 12.7 (-0.4%)

2.50 [-1.28, 6.28] 2.5 %

Harsh 2006 Pooled data of different doses

Table S6. Summary of Findings table for Armodafinil for the treatment of Narcolepsy in adults.

References: Harsh 2006 (A); Schwartz 2010 (B)

Outcomes [Tool] Quality of the evidence

(GRADE)

Absolute Difference

Armodafinil vs Placebo or Pre- Post difference

No of

Participants

(studies)

Excessive daytime sleepiness*

[Epworth Sleepiness Score]

⊕◯◯◯

VERY LOW B

The mean ESS score pre-post difference was 4.70 points lower1 [1.93 to 7.41 points

lower].

28

(1 non-RCT) B

Excessive daytime sleepiness* [Maintenance of Wakefulness Test]

⊕⊕⊕◯

MODERATE A

The mean change from baseline in the MWT score in the Armodafinil group was an

estimated 3.31 minutes higher1 [1.12 min to 5.50 min higher] compared to placebo.

176

(1 RCT) A

Disease severity* (CGI-C scores)

⊕⊕⊕⊕

HIGH

The mean in % improvement in CGI-c scores in the armodafinil group was 38%.when

compared to placebo.

196

(1 RCT) A

Accident risk ⊕⊕⊕⊕

HIGH

The mean reduction in number of patients reporting mistakes/accidents was 26.5% in

the armodafinil group.1

118

(1 RCT) A

Fatigue

[Brief Fatigue Inventory]

⊕⊕⊕◯

MODERATE A

The mean BFI score in the Armodafinil group was 1.10 points lower1 [1.72 points to 0.48

points lower] compared to placebo.

176

(1 RCT) A

Sleep Quality

[Sleep efficiency]

⊕⊕⊕⊕

HIGH

The % improvement in sleep efficiency in the armodafinil group was 2.5 % when

compared to placebo.

194

(1 RCT) A

* Critical Outcome 1 Meets the clinical significance threshold 2 Does not meet the clinical significance threshold A 95% CI crosses clinical significance threshold B Small sample size

Intervention: CLOMIPRAMINE


Table S7. ESS determined excessive daytime sleepiness, in response to Clomipramine in adult patients with unspecified narcolepsy




Comparator


Pre-treatment

Post treatment

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Chen 1995

Observational 16 16 18.9±3.7 15.7± 5.2 N/A N/A -3.20 [-6.33, -0.07]

Table S8. Summary of Findings table for Clomipramine for the treatment of Narcolepsy in adults.

References: Chen 1995 (A)


(GRADE)

Absolute Difference


No of

Participants

(studies)

Excessive daytime sleepiness* [Epworth Sleepiness Scale]

⊕◯◯◯

VERY LOW B


lower].

16

(1 non-RCT) A


Intervention: DEXTROAMPHETAMINE


Table S9. ESS determined excessive daytime sleepiness, in response to dextroamphetamine in adult patients with unspecified

narcolepsy




Comparator


Pre-treatment

Post treatment

Chen 1995

Observational Unspecified 60 60 20.1 ± 2.7 15.1 ± 5.6 N/A N/A -5.00 [-6.57, -3.43]

Outcome: CATAPLEXY (FREQUENCY AND SEVERITY)

Table S10. Self-rating scales determined daily cataplexy rate, in response to dextroamphetamine (various doses) in adult patients with

unspecified narcolepsy




Comparator


Pre-treatment

Post treatment

Shindler1985

Observational 4 weeks 20 20 2.1 ± 2.68 1.4 ± 4.2 N/A N/A 0.70 [-1.48, 2.88]

Schindler 1985- Data converted from Mean (SE) to Mean (SD).

Table S11. Summary of Findings table for Dextroamphetamine for the treatment of Narcolepsy in adults.

References: Shindler 1985 (A); Chen1995 (B)

Outcomes [Tool] Quality of the

evidence

(GRADE)

Absolute Difference

Dexamphetamine vs Placebo or Pre- Post difference

No of

Participants

(studies)

Excessive Daytime Sleepiness*

[Epworth Sleepiness Scale]

⊕◯◯◯

VERY LOW A

The mean pre-post difference in ESS in adult patients on dextroamphetamine was 5.0

points lower1 [ 3.43 points to 6.57 points lower]

60 patients

(1 non-RCT) B

Cataplexy*

[Episodes per day]

⊕◯◯◯

VERY LOW A

The mean pre-post % difference in the daily cataplexy rate was 33%1 20 patients

(1 non- RCT) A

* Critical Outcome

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1 Meets the clinical significance threshold 2 Does not meet the clinical significance threshold A Small sample size

Intervention: L-CARNITINE


Figure S2. JESS determined excessive daytime sleepiness, in response to L-Carnitine in adult patients with NT1

Miyagawa 2013 is a randomized, double-blind, cross-over and placebo-controlled trial.

Outcome: QUALITY OF LIFE

Figure S3. SF-36; Mental health summary scores in an RCT, in response to L-carnitine in adult patients with NT1

Miyagawa 2013 is a randomized, double-blind, cross-over and placebo-controlled trial

Outcome: FATIGUE Figure S4. SF-36; Vitality scores in an RCT, in response to L-carnitine in adult patients with NT1

Miyagawa 2013 is a randomized, double-blind, cross-over and placebo-controlled trial

Table S12. Summary of Findings table for L-Carnitine for the treatment of NT1 in adults.

References: Miyagawa 2013 (A)


evidence

(GRADE)

Absolute Difference

L-Carnitine vs Placebo or Pre- Post difference

No of

Participants

(studies)



⊕⊕⊕◯

MODERATE A

The mean ESS score in the L-Carnitine group was 0.00 points higher2 [1.96 lower to

1.96 points higher] compared to placebo

28 patients

(1 RCT) A

Quality of life *

[Short Form Health Survey (SF-36) - mental

component score]

⊕⊕⊕◯

MODERATE A

The mean SF-36 Mental health scores in Narcolepsy Type 1 patients in the L-carnitine

group was 0.50 points higher [3.46 points lower to 4.46 points higher] compared to

placebo2

28 patients

(1 RCT) A

Fatigue [Short

Form Health Survey (SF-36) - Energy and vitality

component]

⊕⊕⊕◯

MODERATE A

The mean SF-36 energy/vitality component score in the L-Carnitine group was 2.00

points higher [3.50 points lower to 7.50 points higher] compared to placebo2

28 patients

(1 RCT) A

* Critical Outcome 1 Meets the clinical significance threshold 2 Does not meet the clinical significance threshold A Small sample size

v. June 15, 2020

Intervention: METHYLPHENIDATE


Table S13. GIR scale determined disease severity in response to methylphenidate in adult patients with unspecified narcolepsy

Study Study Design

Study

duration

No. of subjects Intervention Placebo

Improvement Pre Post Pre-

treatment

Post

treatment

Pre-treatment Post treatment

Reinish 1994 Observational-

prospective

cohort

4-300 wks 11 11 N/A N/A N/A N/A 89.7%

*This data was provided in publication; not calculated.

Table S14. Summary of Findings table for Methylphenidate for the treatment of Narcolepsy in adults.

References: Reinish 1994 (A)


evidence

(GRADE)

Absolute Difference

Methylphenidate vs Placebo or Pre- Post difference

No of

Participants

(studies)

Disease Severity*

[Treatment rating scale]

⊕◯◯◯

VERY LOW A

A marked improvement on the GIR was noted in 89.7% of the patients in response

to methylphenidate.

11 patients

(1 non-RCT) A


Intervention: MODAFINIL


Figure S5. ESS determined excessive daytime sleepiness, in response to Modafinil (various doses) vs. placebo in adult patients with

NT1.

Joo 2010 is a cross over study

Table S15. ESS determined excessive daytime sleepiness, in an observational study in response to Modafinil (various doses) in adult

patients with NT1.


duration



Comparator


Pre-treatment

Post treatment

Lavault 2011

Cross-sectional study

N/A 68 110 17.1 ± 4.2 14.9 ± 4.9 N/A N/A -2.20[-3.55, -0.85]

v. June 15, 2020

Figure S6. ESS determined excessive daytime sleepiness, in response to Modafinil (various doses) vs. placebo in adult patients with


Saletu 2009 is a cross-over study Broughton 1997 is a cross over study and the Mean (SD) is pooled data of Modafinil 200mg and 400 mg US Modafinil (1998)- Mean (SD) is pooled data of Modafinil 200mg and 400 mg US Modafinil (2000)- Mean (SD) is pooled data of Modafinil 200mg and 400 mg

Table S16. ESS determined excessive daytime sleepiness, in an observational study in response to Modafinil (various doses) in adult

patients with unspecified narcolepsy


duration



Comparator


Pre-treatment

Post treatment

Mitler 2000 Observational; open label

40 weeks 471 471 16.5 ± 4.34 12.4 ± 4.34 N/A N/A -4.10 [-4.65, -3.55]

Schwartz 2003

Observational; open label

6 weeks 123 123 12.7 ± 5.5 11.8 ± 5.5 N/A N/A -0.90 [-2.27, 0.47]

Thorpy 2003


5 weeks 40 38 Not provided 9.79 ± 4.94 N/A N/A -

Figure S7. MWT determined excessive daytime sleepiness, in response to Modafinil (various doses) vs. placebo in adult patients with unspecified narcolepsy.

Saletu 2009 is a cross-over study Broughton 1997 is a cross over study and the Mean (SD) are pooled data of Modafinil 200mg and 400 mg US Modafinil (1998)- Mean (SD) is pooled data of Modafinil 200mg and 400 mg US Modafinil (2000)- Mean (SD) is pooled data of Modafinil 200mg and 400 mg

v. June 15, 2020

Table S17. MWT determined excessive daytime sleepiness, in response to Modafinil (various doses) vs. placebo in adult patients with

NT1.


duration

No. of subjects Data (mean, SD )

Pre- Post Difference, [CI]

Intervention

Placebo

Intervention Placebo Pre-treatment

Post treatment


Billiard 1994

Double-blind cross-over design

12 weeks 43 43 - 9.05 ± 6.56 - 6.96 ± 5.25 2.09 [-0.42, 4.60]

Billiard 1994- Values are estimates from figure.SD data calculated from SE provided.

Figure S8. MSLT determined excessive daytime sleepiness, in response to Modafinil (various doses) vs. placebo in adult patients with


US Modafinil (1998)- Mean (SD) is pooled data of Modafinil 200mg and 400 mg US Modafinil (2000)- Mean (SD) is pooled data of Modafinil 200mg and 400 mg

Outcome: CATAPLEXY

Table S18. Sleep diary determined cataplexy rate in response to Modafinil (various doses) vs. placebo in adult patients with




% difference in cataplexy reduction

Intervention

Placebo

Pts. on

modafinil

Pts on place

bo

Baseline Post treatment (% mean reduction)


Dauvilliers 2013

RCT 4 weeks 23 14 0.4 ± 0.6 0.26 ± 0.5 (35%)*

0·43 ± 0·7 0.39 ± 0.6 (10%)*

25%

Dauvilliers 2013- Post-hoc analysis


Figure S9. CGI determined disease severity, in response to Modafinil (various doses) vs. placebo in adult patients with NT1

Billiard 1994- crossover study. (Data appears to be in Mean (SD); though not specifically mentioned in paper)

v. June 15, 2020

Table S19. CGI determined disease severity in response to Modafinil (various doses) in adult patients with unspecified narcolepsy

Study Study Design

Study duratio

n


Improvement Intervention Placebo Pre-

treatment Post

treatment Pre-treatment Post treatment

US Modafinil in Narcolepsy Multicenter Study Group 1998

RCT 9 weeks 191 92 - - - - 72 %

Dauvilliers 2013 RCT 33 30 - - - - CGI-Change EDS: 86% CGI-C cataplexy: 29%

Black 2006 RCT 8 weeks 63 55 - - - - 19%

US Modafinil (1998)- Graphical estimate


Figure S10. SF-36 (Physical and mental health summary scores) determined excessive daytime sleepiness, in response to Modafinil

(various doses) vs. placebo in adult patients with unspecified narcolepsy

Beusterien 1999- Mean (SD) are pooled data of Modafinil 200mg and 400 mg. Since this is the same population, ignore the total mean and CI.

Table S20. SF-36 Physical component summary score determined quality of life in observational studies, in response to Modafinil

(various doses) in adult patients with unspecified narcolepsy


duration



Comparator


Pre-treatment

Post treatment

Becker 2004


6 weeks 151 123 44.5 ± 6.6 46.8 ± 11.2 N/A N/A 2.30 [0.06, 4.54]

Mitler 2000


40 weeks 432 473 45.5 ± 10.39 46.8 ± 10.87 N/A N/A 1.30 [-0.09, 2.69]

v. June 15, 2020

Table S21. SF-36 Mental component summary score determined quality of life in observational studies, in response to Modafinil

(various doses) in adult patients with unspecified narcolepsy


duration



Comparator


Pre-treatment

Post treatment

Becker 2004


6 weeks 151 123 41.4 ± 11.8 45.8 ± 12.3 N/A N/A 4.40 [1.52, 7.28]

Mitler 2000


40 weeks 432 473 42.4 ± 12.47 45.4 ± 10.87 N/A N/A 3.00 [1.47, 4.53]

Outcome: FATIGUE

Figure S11. SF-36 (Vitality scores) determined fatigue, in response to Modafinil (various doses) vs. placebo in adult patients with


Table S22. SF-36 Vitality score determined Fatigue in observational studies, in response to Modafinil (various doses) in adult



duration



Comparator


Pre-treatment

Post treatment

Becker 2002


6 weeks 151 123 27.9 ± 20.4 47.4 ± 24.9 N/A N/A 19.50 [14.03, 24.97]

Mitler 2000


40 weeks 447 473 32.6 ± 23.26 45.6 ± 23.92 N/A N/A 13.00 [9.95, 16.05]

Table S23. Summary of Findings table for Modafinil for the treatment of Hypersomnia secondary to narcolepsy in adults.

References: Joo 2010 (A); Lavault 2011(B); US Modafinil in Narcolepsy Multicenter Study 2000 (C); Billiard 1994(D); Broughton 1997(E); Dauvilliers 2013 (F) US Modafinil in Narcolepsy Multicenter Study 1998(G); Moldofski 2000(H); Saletu 2009(I); Mitler 2000 (J);Schwartz 2003 (K); Thorpy 2003 (L); Black 2006(M); Beusterien 1999(N);Becker 2002(O);Fry 1998(P); Dauvilliers 2017 (Q)


(GRADE)

Absolute Difference

Modafinil vs Placebo or Pre- Post difference

No of Participants

(studies)

Excessive daytime sleepiness *


⊕⊕⊕◯

MODERATE A,B

The mean ESS score in NT1 patients on Modafinil was 10.30 points lower1 [7.95 to

12.65 points lower] compared to placebo

19

(1 RCT)A

⊕◯◯◯

VERY LOW B

The mean ESS score pre-post difference in NT1 patients was 2.201 points lower1 [0.85 to

3.5 points lower]

68

(1 non-RCT) B

⊕⊕⊕⊕

HIGH

The mean ESS score in patients with unspecified narcolepsy on Modafinil was 2.77

points lower1 [1.73 to 3.80 points lower] compared to placebo

861

7 RCTs)C,E,F,G,H,I, M

⊕◯◯◯

VERY LOW C

The mean ESS score pre-post difference in patients with unspecified narcolepsy ranged

from 0.92 to 4.10 points lower1.

594

2 non-RCTs)J,K


[Maintenance of Wakefulness Test]

⊕⊕⊕⊕

HIGH

The mean MWT score in the Modafinil group was 4.14 minutes higher1 [3.44 min to 4.84

min higher] compared to placebo

858 patients

(7 RCTs)C, E,F,G,H,I,M

v. June 15, 2020

⊕⊕⊕◯

MODERATEB

The estimated mean MWT score in the Modafinil group was 2.09 minutes higher1 [0.42

min lower to 4.60 min higher] compared to placebo

43

(1 RCT)D


[Multiple Sleep Latency Test]

⊕⊕⊕◯

MODERATE A

The mean MSLT score in unspecified narcolepsy patients on Modafinil was 1.58 minutes

lower1 [0.92 min to 2.24 mins lower] compared to placebo

526 patients

(2 RCT)C,G

Cataplexy*

[# daily episodes]

⊕⊕⊕◯

MODERATE B

The mean number of daily cataplexy episodes in NT1 patients on Modafinil was 0.10

episodes lower [0.34 episodes lower to 0.14 episodes higher] compared to placebo.

46 patients

(1 RCTs)C

Cataplexy*

[[# daily episodes]

⊕⊕⊕◯

MODERATE B

The mean daily cataplexy frequency in unspecified narcolepsy patients on Modafinil was

0.13 points lower [0.40 points lower to 0.14 points higher] compared to placebo

63 patients

(1 RCT)E

Disease severity*

[Clinical Global Index (CGI)]

⊕⊕⊕◯

MODERATE A,B

The disease severity in NT 1 patients was 0.29 points lower2 [3.40 points lower to 2.82

points higher] compared to placebo

45 patients

(1 RCT)C

⊕⊕⊕◯

MODERATE C

The percentage of patients with unspecified narcolepsy reporting reduction in disease

severity ranged from 19% to 72%1

464 patients

(3 RCTs)E,M, P

Quality of life *

[Short Form Health Survey (SF-36) - Physical

component score]

⊕⊕⊕⊕

HIGH

The physical health summary component in unspecified narcolepsy patients was 0.5

points higher2 (95% CI: 2.23 points higher to 1.23 points lower) compared to placebo

481 patients

(1 RCT)N

⊕⊕◯◯

LOW

The mean SF-36 physical health summary component pre-post difference ranged from

1.3 to 2.3 points higher.

596 patients

(2 non RCTs)J, O

Quality of life *

[Short Form Health Survey (SF-36) - Mental

component score]

⊕⊕⊕◯

MODERATE A

The mental health summary component demonstrated mean difference of 3.49 points1

higher (95% CI: 1.76 points to 5.22 points higher) compared to placebo

481 patients

(1 RCT)N

⊕⊕◯◯

LOW

The mean SF-36 mental health summary component pre-post difference ranged from

3.0 to 4.40 points higher.

596 patients

(2 non RCTs)J, O

Fatigue

[Short Form Health Survey (SF-36) - Energy

and vitality component]

⊕⊕⊕⊕

HIGH

The mean SF-36- energy and vitality component in the modafinil group demonstrated

7.98 points higher1 (4.31 to 11.65 points higher) compared to placebo

481 patients

(1 RCT)N

⊕⊕◯◯

LOW

The mean pre-post difference on the SF-36 vitality score ranged from 13.0 to 19.50

points higher

* Critical Outcome 1 Meets the clinical significance threshold 2 Does not meet the clinical significance threshold A 95% CI crosses clinical significance threshold B Small sample size C Inconsistent results; Nonoverlapping confidence intervals

Intervention: NAPS


Table S24. MWT determined excessive daytime sleepiness, in response to nap therapy in adult patients with unspecified narcolepsy




Comparator


Pre-treatment

Post treatment

Rogers 1993

Observational

1 month

16

16 7.4 ± 6.0 10.0 ± 5.8

NA NA 2.60 [-1.49, 6.69]

v. June 15, 2020

Table S25. Summary of Findings table for Naps for the treatment of Narcolepsy in adults.

References: Rogers 1993 (A)


evidence

(GRADE)

Absolute Difference

Naps Pre- Post difference

No of

Participants

(studies)



⊕◯◯◯

VERY LOW A,B

The mean MWT pre-post difference in the Naps group was 2.60 minutes higher1 [1.49

minutes lower to 6.69 minutes higher]. 16 patients

(1 non-RCT) A


Intervention: PITOLISANT

Outcome: EXCESSIVE DAYTIME SLEEPINESS Figure S12. ESS determined excessive daytime sleepiness, in response to Pitolisant in adult patients with NT1.

Szakacs 2017 data obtained from personal communications. Lin 2008 is a cross over single blind study

Figure S13. ESS determined excessive daytime sleepiness, in response to Pitolisant in adult patients with unspecified narcolepsy

Figure S14. MWT determined excessive daytime sleepiness, in response to Pitolisant vs. placebo in adult patients with unspecified

narcolepsy

Figure S15. MWT determined excessive daytime sleepiness, in response to Pitolisant vs. placebo in adult patients with NT1

Szakacs 2017 data obtained from personal communications

v. June 15, 2020

Outcome: CATAPLEXY (FREQUENCY AND SEVERITY)

Table S26. Sleep diary determined daily cataplexy rate, in response to Pitolisant vs. placebo in adult patients with unspecified

narcolepsy.

Study Study Design

Study duration



Intervention

Placebo

Pts. on pitolisant

Pts on placebo



Dauvielliers 2013

RCT 4 weeks 23 14 0·52 ± 0·6 0·18 ± 0·4 (65.38 %)*

0·43 ± 0·7 0.39 ± 0.6 (9.3%)*

56.06%

*[(post-treatment mean/pre-treatment mean) -1 x 100] Dauvilliers 2013 post-hoc analysis data used

Table S27. Sleep diary determined weekly cataplexy rate, in response to Pitolisant vs. placebo in adult patients with NT1.

Study Study Design

Study duration



Intervention

Placebo

Pts. on pitolisant

Pts on placebo

Baseline** Post treatment** (% mean

reduction)

Baseline Post treatment (% mean

reduction)

Szakacs 2017 RCT 7 weeks 54 51 9.15 2.27 (75.19%) 7.31 4.52 (38.16%) 37.03%

*[(post-treatment mean/pre-treatment mean) -1 x 100] **Study provided mean values only


Figure S16. CGI- c; targeting cataplexy determined disease severity in an RCT, in response to Pitolisant (various doses) in adult


Dauvilliers 2013- Data obtained from personal communication

Figure S17. CGI- C determined disease severity in an RCT, in response to Pitolisant (various doses) in adult patients with NT1.

Szakacs 2017- Data obtained from personal communication

Table S28. Summary of Findings table for Pitolisant for the treatment of Narcolepsy in adults.

References: Dauvilliers 2013 (A); Lin 2008 (B); Szakacs 2017 (C)


(GRADE)

Absolute Difference

Pitolisant vs Placebo

No of Participants

(studies)

Excessive daytime sleepiness* [Epworth

Sleepiness Scale]

⊕⊕⊕◯

MODERATE A

The mean ESS score in the Pitolisant group in patients with unspecified narcolepsy was

3.6 points lower1 [6.27 to 0.93 points lower] compared to placebo.

61

(1 RCT) A

v. June 15, 2020

⊕⊕⊕⊕

HIGH

The mean ESS score in the Pitolisant group in patients with NT1 was 3.75 points lower1

[5.46 to 2.04 points lower] compared to placebo.

126

(2 RCTs) B ,C



⊕⊕⊕◯

MODERATE A, B

The mean MWT score in the Pitolisant group was 2.10 minutes higher1 [0.64 to 3.65

minutes lower] compared to placebo.

61

(1 RCT) A

⊕⊕⊕◯

MODERATE A

The mean MWT score in the Pitolisant group in patients with NT1 was 4.3 minutes

higher1 [9.05 minutes higher to 0.45 minutes lower] compared to placebo.

108

(1 RCT) C

Cataplexy*

[Daily Cataplexy rate]

⊕⊕⊕◯

MODERATE B

The mean reduction in daily cataplexy rates in the pitolisant group was 65.38%

compared to 9.3% in the placebo group. There was a reduction of 56.06%.1

37

(1 RCT) A

Cataplexy*

[Weekly Cataplexy rate]

⊕⊕⊕⊕

HIGH

The mean reduction in weekly cataplexy rates in the pitolisant group was 75% compared

to 38% in the placebo group. There was a % difference in weekly cataplexy reduction of

37.03%.1

105

(1 RCT) C

Disease severity*

CGI-Cataplexy

⊕⊕⊕◯

MODERATE A

The mean CGI-C score in the pitolisant group in patients with unspecified narcolepsy

was 0.5 points lower1 [1.3 points lower to 0.3 points higher] when compared to placebo.

51

(1 RCT) A

⊕⊕⊕⊕

HIGH

The mean CGI-C score in the pitolisant group in patients with NT 1 was 0.9 points

lower1 [1.33 to 0.47 points lower ] when compared to placebo.

100

(1 RCT) C

* Critical Outcome 1 Meets the clinical significance threshold 2 Does not meet the clinical significance threshold A 95% CI crosses clinical significance threshold on 1 side B Small sample size

Intervention: SELEGILINE


Figure S18: MSLT determined excessive daytime sleepiness, in response to Selegiline (various doses) vs. placebo in adult patients

with unspecified narcolepsy.

Mayer 1995- Data of 2 doses for last day of intervention combined and seconds converted to minutes.

Table S29. Summary of Findings table for Selegiline for the treatment of Narcolepsy in adults.

Reference: Mayer 1995 (A)


(GRADE)

Absolute Difference

Selegiline vs Placebo or Post-treatment values

No of

Participants

(studies)

Excessive daytime sleepiness* [Mean Sleep Latency Test]

⊕⊕⊕◯

MODERATE A

The mean MSLT score in the Selegiline group was 1.42 minutes higher1 [2.95 minutes

higher to 0.11 minutes lower] compared to placebo

30

(1 RCT) B


v. June 15, 2020

Intervention: SODIUM OXYBATE


Figure S19. ESS determined excessive daytime sleepiness, in response to sodium oxybate vs. placebo in adult patients with


Data obtained from personal communication with JAZZ

Figure S20. ESS determined excessive daytime sleepiness, in response to sodium oxybate (various doses) in adult patients with

NT1.

Sodium oxybate data is pooled doses data in both studies. Results are a change from baseline. Data obtained by personal communication.

Table S30. ESS determined excessive daytime sleepiness in an observational study, in response to sodium oxybate in adult patients



duration



Comparator

Pre Post Pre-treatment

Post treatment Pre-treatment

Post treatment

US Xyrem Study 2003


12 months 74 74 17.35 ± 3.22 11.5 ± 5.03 N/A N/A -5.85 [-7.21, -4.49]

Post treatment data is pooled data of all doses

Table S31. ESS determined excessive daytime sleepiness in observational studies, in response to sodium oxybate in adult patients

with NT1.


duration



Comparator



Post treatment

Leu-Semenescu 2016

Observational N/A 39 22 17.7 ± 3.7 13.9 ± 5.0 N/A N/A -3.8[-6.19.-1.41]

Poryazova 2011

Observational N/A 13 13 17.8 ± 1 13.9 ± 1.2 N/A N/A -3.90[-4.69, -3.09]

Mamelak 2004

Observational 10 weeks 20 20 20 14 - - -6.0 [unknown]

Mamelak 2004- Mean estimated from graph. No SD values provided

v. June 15, 2020

Figure S21. MSLT determined excessive daytime sleepiness, in response to sodium oxybate in adult patients with NT1.

Scrima 1990 is a double-blind, counterbalanced crossover design.

Table S32. MSLT determined excessive daytime sleepiness in an observational study, in response to sodium oxybate in adult

patients with NT1.


duration



Comparator



Post treatment

Poryazova 2011

Observational N/A 13 13 2 ± 1.5 2.4 ± 2.6 N/A N/A 0.30 [-1.31, 1.91]

Table S33. MSLT determined excessive daytime sleepiness, in an observational study in response to sodium oxybate in adult patients





Comparator


Pre-treatment

Post treatment

Scharf 1985

Observational cohort 4 weeks 30 30 3.7 ± 2.91 5.22 ± 4.24 N/A N/A 1.52 [3.36, -0.32]

Figure S22. MWT determined excessive daytime sleepiness, in response to sodium oxybate vs. placebo in adult patients with NT1.

Figure S23. MWT determined excessive daytime sleepiness, in response to sodium oxybate vs. placebo in adult patients with


Table S34. MWT determined excessive daytime sleepiness in an observational study, in response to sodium oxybate in adult

patients with NT1.


duration



Comparator

v. June 15, 2020



Post treatment

Poryazova 2011

Observational N/A 13 13 5.5 ± 4.5 17.4 ± 8.9 N/A N/A 11.90 [6.48, 17.32]

Mamelak 2004

Observational 10 weeks 20 20 4.5 10.6 N/A N/A 6.1[3.12, 9.08]

Mamelak 2004- No SD values for pre and post Sodium oxybate Rx provided. Pre-Post 95% CI derived from change from baseline values.

Outcome: CATAPLEXY

Table S35. Weekly number of cataplexy attacks in an RCT, in response to sodium oxybate (various doses) in adult patients with NT1.

Study Study Design

Study duration



Intervention

Placebo

Pts. on SO

Pts on placebo


Baseline Post treatment (% mean

reduction)

US Xyrem 2002 (SLEEP)

RCT 4 weeks 97 ( all doses)

33 32.67± 36.68 19.39 ± 36.0 (40.64 %)*

35.1± 47.1 24.0 ± 28.4 (31.6%)*

9.04%

Xyrem International 2005(Sleep Medicine)

RCT 8 weeks 169 58 36.66 ± 61.60 18.35 ± 53.21 (49.9%)

35.01 ± 51.80

20.75 ± 19.63 (40.73%)

9.17%

Xyrem International 2005(Sleep Medicine) and US Xyrem 2002- SO data is pooled dose data

Table S36. Change in weekly cataplexy episodes determined cataplexy frequency in an open label study, in response to sodium

oxybate in adult patients with NT1.


duration


Pre- Post Difference, [CI] (% difference in cataplexy

reduction)

Intervention

Comparator



Post treatment

US Xyrem Study 2003 (SLEEP)


12 months 75 75 41.08 ± 46.81

5.6 ± 8.86 N/A N/A -35.48 [-46.26, -24.70] (86.36%)

Table S37. Change in weekly cataplexy episodes determined cataplexy frequency in a double-blind withdrawal study, in response to

sodium oxybate in adult patients with NT1.


duration


Pre- Post Difference, [CI] (% difference in cataplexy

increase)

On Sodium oxybate

Off Sodium oxybate

Placebo SO Pre-withdrawal

Post withdrawal (% mean increase)

Pre-withdrawal

Post-withdrawal (% mean increase)

US Xyrem Multicenter Study group 2004

Double-blind withdrawal Study

2 weeks 29 26 9.9 ± 21.4 12.8 ± 33.5 (29.29%)

15.8 ± 39.9 46.4 ± 73.8 (193.67%)

SO: 2.90 [-12.38, 18.18] Placebo: 30.60 [0.07, 61.13] 164%


Table S38. CGI determined disease severity in response to sodium oxybate (various doses) in an RCT in adult patients with


Study Study Design

Study duration


Improvement Intervention Placebo Pre-

treatment Post

treatment Pre-treatment Post treatment

The U.S. Xyrem Multicenter Study Group 2002{SLEEP}

RCT 4 weeks 102 34 - - - - Average of 58% in the SO (all doses)

group

v. June 15, 2020

Black 2006 RCT 8 weeks 50 55 - - - - 48%


Figure S24. SF-36 (Physical health summary scores) determined quality of life, in response to sodium oxybate (various doses) vs.

placebo in adult patients with NT1.

Bogan 2016- values are for Sodium oxybate; 9 g and are the change from baseline values

Table S39. SF-36 (Mental health summary scores) determined quality of life, in response to sodium oxybate (various doses) vs.

placebo in adult patients with NT1.


duration


Mean Difference, [CI] Intervention

Placebo

Pre Post Pre-Rx Change from baseline

Pre-Rx Change from baseline

Bogan 2016 RCT 8 weeks 58 58 0 3.8 ± *13.71

0 1.0 ± *9.14 2.80 [-1.44, 7.04]

Bogan 2016- *SD values for Sodium oxybate (6 gm) calculated using SE estimated from graph. Per study- this dose resulted in a significant change from baseline.

Outcome: FATIGUE

Table S40. SF-36 (Vitality domain) determined fatigue, in response to sodium oxybate (various doses) vs. placebo in adult patients

with NT1.


duration



Placebo

Post intervention Pre-Rx Change from baseline


Bogan 2016 RCT 8 weeks Placebo- 58 4.5g- 64 6.0 g-58 9.0g-47

4.5 g- 5.4± 1.0 6.0 g- 6.7 ± 1.2 9.0 g-9.8 ± 1.8

2.2 ± 1.0 5.88 [3.73, 8.03]

Bogan 2016- *SD values for Sodium oxybate (6 gm) calculated using SE estimated from graph. Then mean and SD of 6 and 9 gm pooled. Per study, all SXB doses showed significant differences relative to placebo

Table S41. Summary of Findings table for sodium oxybate for the treatment of Hypersomnia secondary to narcolepsy in adults.

References: Leu-Semenescu 2016(A); Poryazova 2011(B);Scrima1990(C);Scharf 1985(D); Mamelak 2004(E);Black 2006 (F); US Xyrem multicenter study group 2003 (G); Bogan 2016(H); Xyrem International 2005-Sleep Medicine (I); Xyrem International 2005-JCSM (J); US Xyrem 2002 (K) US Xyrem Multicenter Study group 2004 (L) Dauvilliers 2017 (M); Roth 2017 (N)

Outcomes

[Tool]

Quality of the evidence

(GRADE)

Absolute Difference

Sodium oxybate vs Placebo or Pre- Post difference

No of

Participants

(studies)

Excessive daytime sleepiness * [Epworth

Sleepiness Scale]

⊕◯◯◯

VERY LOW B

The mean ESS score range of pre-post differences in NT 1 patients on SO was 3.8 to

3.9 points lower1.

35 patients

(2 non-RCT)A,B

⊕◯◯◯

VERY LOW B

The mean ESS score range of pre-post differences in patients with unspecified

narcolepsy on SO was 5.85 points lower1 [4.49 to 7.21 points lower].

74 patients

(1 non-RCT)G

⊕⊕⊕◯

MODERATE

The mean ESS score in unspecified Narcolepsy patients on SO was 3.30 points lower

[1.16 points to 5.44 points lower]

102 patients

(1 RCT)F

⊕⊕⊕⊕

HIGH

The mean ESS score in NT 1 patients on SO was 1.47 points lower2 [2.38 points to 0.56

points lower]

339 patients

(2 RCT)J, K

v. June 15, 2020



⊕⊕⊕◯

MODERATE B

The mean MSLT score in patients with unspecified narcolepsy on SO was 0.70 minutes

lower2 [1.81 min lower to 0.41 mins higher] compared to placebo

10 patients

(1 RCT)C

⊕◯◯◯

VERY LOW B

The mean MSLT score pre-post difference in NT1 patients was 0.40 points lower2 [0.39

to 2.01 points lower]

13 patients

(1 non-RCT)B

⊕◯◯◯

VERY LOW B

The mean MSLT score pre-post difference in patients with unspecified narcolepsy was

1.52 points lower1 [0.32 points lower] to 3.36 points higher]

30 patients

(1 non-RCT)D



⊕⊕⊕⊕

HIGH

The mean MWT score in unspecified narcolepsy patients on SO was 5.10 points higher1

[2.47 to 7.73 points higher]

102 patients

(1 RCT)F

⊕⊕⊕⊕

HIGH

The mean MWT score in NT1 patients on SO was 3.80 points higher1 [1.16 to 6.44

points higher]

213 patients

(1 RCT)J

⊕◯◯◯

VERY LOW B

The mean MWT score pre-post difference ranged from 6.1 to 11.9 minutes higher1 in

NT1 patients.

33 patients

(2 non-RCTs)D,E

Cataplexy*

[# Weekly episodes]

⊕⊕⊕⊕

HIGH

The percentage difference in weekly cataplexy episodes ranged from 9.04% to 9.17% in

patients with narcolepsy when compared with placebo.

357 patients

(2 RCTs)J, K

⊕⊕⊕◯

MODERATE B

The percentage difference in weekly cataplexy episodes in the withdrawn group showed

a 164.38% increase in weekly cataplexy rate of when compared with patients who

continued on SXB.

55 patients

(1 RCT) L

⊕◯◯◯

VERY LOW B

The pre-post percentage reduction in weekly cataplexy episodes was 86.36% 75 patients

(1 non-RCT)G

Disease severity*

[Clinical Global Index (CGI)]

⊕⊕⊕⊕

HIGH

The percentage of patients reporting (much and very much) improvement in CGI scores

ranged from 48% to 58%.

241 patients

(2 RCTs)F,G

Quality of life *

[Short Form Health Survey (SF-36) -

Physical component score]

⊕⊕⊕◯

MODERATE A

The mean change from baseline SF-36 Physical Summary Scores in NT1 patients on

SO was 4.80 points higher [1.76 points to 7.84 points higher] compared to placebo1

106 patients

(1 RCT)H

Quality of life *


component score]

⊕⊕⊕◯

MODERATE A

The mean change from baseline SF-36 Mental Summary Scores in NT1 patients on SO

was 2.8 points higher [1.44 points lower to 7.04 points higher] compared to placebo2

116 patients

(1 RCT)H

Fatigue

[SF-36 Vitality domain]

⊕⊕⊕⊕

HIGH

The mean SF-36 Vitality domain score pre-post difference in NT1 patients was 5.88

points higher [3.73 points to 8.03 points higher]

163 patients

(1 RCT)H


Intervention: Solriamfetol (JZP-110)


Figure S25. ESS determined excessive daytime sleepiness, in response to solriamfetol in adult patients with unspecified narcolepsy.

Both studies-Change from baseline depicted

Table S42. ESS determined excessive daytime sleepiness, in response to solriamfetol in adult patients with unspecified narcolepsy.


duration


Mean Difference, [CI] Intervention

Placebo

Post intervention Pre-Rx Change from baseline


Ruoff 2016 RCT 12 weeks JZP-110- 40 Placebo- 45

N/A -8.7 ± 6.32 N/A -2.5 ± 3.35 -6.20 [-8.39, -4.01]

Ruoff 2016- Data (mean; SE) was estimated from a graph, then converted to Mean (SD)

v. June 15, 2020

Figure S26. MWT determined excessive daytime sleepiness, in response to solriamfetol (various doses) in adult patients with unspecified narcolepsy.

Ruoff 2016- Mean (SD) calculated from mean (SE) Bogan 2015 - a crossover study All studies- Change from baseline depicted.


Table S43. CGI-C determined disease severity in RCTs, in response to solriamfetol (various doses) in adult patients with unspecified

narcolepsy.


duration



Placebo


Bogan 2015 RCT 2 weeks JZP-110- 33 Placebo- 33 (cross over study)

N/A 75.8% N/A 39.4% 36.4%


N/A 86.0% N/A 38.3% 47.7%

Thorpy 2019 RCT 12 weeks JZP- 118 Placebo- 59

N/A 83.35% N/A 41.4% 41.95%

Numbers are indicative of % patients achieving at least a minimal improvement subjectively assessed.

Table S44. PGI-C determined disease severity in an RCT, in response to solriamfetol (various doses) in adult patients with unspecified

narcolepsy.


duration



Placebo



N/A 93.0% N/A 38.3% 54.7%

Thorpy 2019 RCT 12 weeks JZP- 118 Placebo- 59

N/A *81.45% N/A 39.7% 41.75%

*Thorpy 2019- Data of 300 and 150 mg combined

v. June 15, 2020

Table S45. Summary of Findings table for Solriamfetol for the treatment of Narcolepsy in adults.

References: Bogan 2015 (A); Ruoff 2016 (B); Thorpy 2019 (C)


evidence

(GRADE)

Absolute Difference

Methylphenidate vs Placebo or Pre- Post difference

No of

Participants

(studies)



⊕⊕⊕◯

MODERATE A

The mean change from baseline in the ESS score in the solriamfetol group was 4.3

points lower1 [6.78 points to 1.82 points lower] compared to placebo.

210 patients

(2 RCTs) A,C

⊕⊕⊕◯

MODERATE A

The mean difference in the ESS post-treatment score was 6.2 minutes lower1 [8.39

to 4.01 minutes lower]

85

(1 RCT) B



⊕⊕⊕⊕

HIGH

The mean change from baseline in the ESS score in the solriamfetol group was 10.4

points higher1 [8.29 points to 12.50 points higher] compared to placebo.

295 patients

(3 RCTs) A,B,C

Disease severity*

[Clinical Global Impression of change(CGI- C)]

⊕⊕⊕⊕

HIGH

The improvement in the Clinical Global Impression of change(CGI- C) in the

solriamfetol group ranged from 36.4% to 47.7% when compared to placebo

295 patients

(3 RCTs) A,B,C

Disease severity*

[Patient Global Impression of change(PGI- C)]

⊕⊕⊕⊕

HIGH

The improvement in Patient Global Impression of change(PGI- C) in the solriamfetol

group ranged from 41.75% to 54.7% when compared to placebo.

262 patients

(2 RCTs) B, C


Intervention: TRIAZOLAM


Figure S27. MWT determined excessive daytime sleepiness, in response to Triazolam in adult patients with NT1.

Thorpy 1992 is a single-blind within-subject crossover-designed study. Data is the pooled values of 2 nights.

Figure S28. MSLT determined excessive daytime sleepiness, in response to Triazolam in adult patients with NT1.

Thorpy 1992 is a single-blind within-subject crossover-designed study. Data is the pooled values of 2 nights.

Outcome: SLEEP QUALITY Figure S29: Sleep efficiency (assessed by polysomnography) determined sleep quality in an RCT, in response to Triazolam in adult

patients with unspecified narcolepsy.

Table S46– Summary of Findings table for Triazolam for the treatment of Narcolepsy in adults.

Reference: Thorpy 1992 (A)

v. June 15, 2020


evidence

(GRADE)

Absolute Difference

Triazolam vs Placebo or Pre- Post difference

No of

Participants

(studies)



⊕⊕⊕◯

MODERATE A,B

The mean MSLT score in the Triazolam group was 0.22 minutes lower2 [1.35 minutes

lower to 0.91 minutes higher] compared to placebo

10 patients

(1 RCT) A



⊕⊕◯◯

LOW C

The mean MWT score in the Triazolam group was 0.29 minutes higher2 [2.94 min

lower to 3.52 min higher] compared to placebo.

10 patients

(1 RCT) A

Sleep Quality

[Sleep Efficiency %]

⊕⊕⊕◯

MODERATE A

The mean difference in sleep efficiency in the triazolam group was 9.90 % higher (

95% CI: 3.01 to 16.79 percent higher) when compared to placebo.2

10 patients

(1 RCT) A

* Critical Outcome 1 Meets the clinical significance threshold 2 Does not meet the clinical significance threshold A 95% CI crosses clinical significance threshold B Small sample size C 95% CI crosses clinical significance threshold on both sides (high/ serious imprecision)

PICO 2: Idiopathic Hypersomnia Intervention: CLARITHROMYCIN

Outcome: EXCESSIVE DAYTIME SLEEPINESS Figure S30. ESS determined excessive daytime sleepiness in an RCT, in response to Clarithromycin vs. placebo in adult patients with Idiopathic Hypersomnia.

Trotti 2015 is a randomized, placebo-controlled, double-blind, crossover trial. Measures were calculated for the average of week 1 and week 2 results. Data obtained by personal communication.

Figure S31. SSS determined excessive daytime sleepiness in an RCT, in response to Clarithromycin vs. placebo in adult patients with

Idiopathic Hypersomnia.

Trotti 2015-Randomised double blind cross-over trial. Measures were calculated for the average of week 1 and week 2 results. Data obtained by personal communication.


Table S47. Treatment response scale determined disease severity in an observational study, in response to Clarithromycin (various

doses) in adult patients with Idiopathic Hypersomnia.


duration

No. of subjects Response Scale


Pre-treatment

Post treatment n (%)

Pre Post Improved Ineffective Stopped (due to side

effects)

Trotti 2014 Observational; retrospective

2 weeks 24 24 Not recorded 17 (71%) 5 (21%) 2 (8%) N/A

v. June 15, 2020


Figure S32. SF-36 Total score determined Quality of Life in an RCT, in response to Clarithromycin vs. placebo in adult patients with



Figure S33. FOSQ determined Quality of Life in an RCT, in response to Clarithromycin vs. placebo in adult patients with Idiopathic

Hypersomnia.

Trotti 2015- Randomized, placebo-controlled, double-blind, crossover trial. Measures were calculated for the average of week 1 and week 2 results. Data obtained by personal communication.

Outcome: COGNITIVE PERFORMANCE

Figure S34. RRT on the Psychomotor vigilance test (PVT) determined cognitive performance in an RCT, in response to Clarithromycin

vs. placebo in adult patients with Idiopathic Hypersomnia.

Trotti 2015 is a randomized, placebo-controlled, double-blind, crossover trial. Data obtained by personal communication.

Outcome: FATIGUE

Figure S35. SF-36; Energy/Vitality subsection determined Fatigue in an RCT, in response to Clarithromycin vs. placebo in adult

patients with Idiopathic Hypersomnia.


Table S48. Summary of Findings table for Clarithromycin for the treatment of Idiopathic Hypersomnia in adults.

References: Trotti 2014 (A); Trotti 2015 (B)

v. June 15, 2020


(GRADE)

Absolute Difference

Clarithromycin vs Placebo or Pre- Post difference

No of

Participants

(studies)



⊕⊕⊕◯

MODERATE A,B

The mean ESS score in the Clarithromycin group was 3.30 points lower1 [1.01 points

higher to 7.61 points lower] compared to placebo.

10

(1 RCT) B


[Stanford Sleepiness Scale]

⊕⊕⊕◯

MODERATE A,B

The mean SSS score in the Clarithromycin group was 0.80 points lower2 [2.17 points

lower to 0.57 points higher] compared to placebo.

10

(1 RCT) B

Disease severity*

[Treatment response scale]

⊕◯◯◯

VERY LOW B

71% of patients reported an improvement following treatment. 1 24

(1 non-RCT) A

Quality of Life*

[Functional Outcomes of Sleep

Questionnaire]

⊕⊕⊕◯

MODERATE A,B

The mean FOSQ score in the Clarithromycin group was 1.91 points higher1 [0.52 points


10

(1 RCT) B

Quality of Life*

[SF-36 Total score]

⊕⊕⊕◯

MODERATE A,B

The mean SF-36 total score in the Clarithromycin group was 9.70 points higher1 [1.63

points lower to 21.03 points higher] compared to placebo.

10

(1 RCT) B

Cognitive Performance

[Reciprocal Reaction Time]

⊕⊕⊕◯

MODERATE A,B

The mean improvement in RRT with clarithromycin over placebo was 0.34 millisec-1 (

0.37 lower to 1.05 higher).

10

(1 RCT) B

Fatigue

[Short Form Health Survey (SF-36)

Energy/Vitality scale]

⊕⊕⊕◯

MODERATE A, B

The mean SF-26 Energy/Vitality scale score in the Clarithromycin group was 14.1 points

higher1 [36.1 points higher to 7.9 points lower] compared to placebo.

10

(1 RCT) B


Intervention: FLUMAZENIL


Table S49. Treatment response (benefit) scale determined disease severity in an observational study, in response to flumazenil

(various doses) in adult patients with Idiopathic Hypersomnia.


duration


Pre- Post Difference, [CI] Pre-

treatment Post treatment symptomatic benefit n (%)

Pre Post Yes No

Trotti 2016 Observational;

retrospective

2 yrs. 36 36 Not recorded 23 (64%) 13 (36%) N/A

Data obtained by personal communication

Table S50. Summary of Findings table for Flumazenil for the treatment of Idiopathic Hypersomnia in adults.

References: Trotti 2016 (A)


(GRADE)

Absolute Difference

Clarithromycin vs Placebo or Pre- Post difference

No of

Participants

(studies)

Disease severity*

[Treatment response scale]

⊕◯◯◯

VERY LOW A

64% of patients reported an improvement following treatment. 1 36

(1 non-RCT) A

Intervention: METHYLPHENIDATE


Table S51. Treatment response scale determined disease severity in an observational study, in response to methylphenidate

(various doses) in adult patients with Idiopathic Hypersomnia.


duration


Pre- Post Difference, [CI] Post treatment n (%)

v. June 15, 2020

Pre-

treatment

Pre Post Complete

response

Partial

response

Poor

response

Ali 2009 Observational;

retrospective

2 weeks 61 Not recorded 25 (41%) 13 (21%) 2 (3%) N/A

Table S52. Summary of Findings table for Methylphenidate for the treatment of Idiopathic Hypersomnia in adults.

Reference: Ali 2009 (A)


(GRADE)

Absolute Difference

Pre- Post differences

No of Participants

(studies)

Disease severity

(Treatment response scale) ⊕◯◯◯ Very Low B

41% of patients reported a complete response following treatment. 1 61

(1 non-RCT) A




Figure S36. ESS determined excessive daytime sleepiness in an RCT, in response to Modafinil (various doses) in adult patients with


Mayer 2016 is a randomized, placebo-controlled, double-blind trial. Data obtained by personal communication.

Table S53. ESS determined excessive daytime sleepiness in an observational study, in response to Modafinil (various doses) in adult

patients with Idiopathic Hypersomnia.


duration



Comparator


Post treatment

Pre-treatment

Post treatment

Lavault 2011 Cross-sectional study

N/A *n=77 *n=88 16.3 ± 4

13.3 ± 5.2

N/A N/A -3.00 [1.59, 4.41]

Anderson 2007

Retrospective observational

3.8 years (mean)

54 39 - N/A N/A -6.0 ± 5.4 (mean reduction, SD)

*n = number of patients for which the information was found.

v. June 15, 2020

Figure S37. MWT determined excessive daytime sleepiness in an RCT, in response to Modafinil (various doses) in adult patients with




Figure S38. CGI determined disease severity in an RCT, in response to Modafinil (various doses) in adult patients with Idiopathic

Hypersomnia.


Table S54. Treatment response scale determined disease severity in an observational study, in response to Modafinil (various



duration


Pre- Post Difference, [CI] Pre-

treatment Post treatment (%)

Pre Post Improved Not followed

Stopped for side effect

Bastuji 1988 Observational 2 months 18 18 Not recorded 83 11 6 N/A

Table S55. Treatment response scale determined disease severity in an observational study, in response to Modafinil (various



duration



Pre-treatment

Post treatment n (%)

Pre Post Complete Partial Poor

Ali 2009 Observational 11 yrs. 50 25 Not recorded 18 (36%) 4 (8%) 3(6%) N/A

Table S56. Summary of Findings table for Modafinil for the treatment of Idiopathic Hypersomnia in adults.

Reference: Anderson 2007 (A); Lavault 2011 (B); Mayer 2015 (C); Bastuji 1988 (D); Ali 2009(E)


evidence

(GRADE)

Absolute Difference


No of

Participants

(studies)



⊕⊕⊕◯

MODERATE A,B

The mean ESS score in the Modafinil group was 4.00 points lower1 [0.71 points to

7.29 points lower] compared to placebo.

31

(1 RCT) C

⊕⊕◯◯

LOW

The mean ESS score pre-post differences ranged from 3.0 to 6.0 points lower1. 127

(2 non-RCTs) A,B

v. June 15, 2020

Excessive daytime sleepiness* [Maintenance of Wakefulness Test]

⊕⊕◯◯

LOW B,C

The mean MWT score in the Modafinil group was 3.00 points higher1 [5.78 points


29

(1 RCT) C

Disease Severity*

[Clinical Global Impression Scale]

⊕⊕⊕◯

MODERATE A,B

The mean CGI score in the Modafinil group was 1.00 points lower1 [0.14 points to

1.86 points lower] compared to placebo.

30

(1 RCT) C

Disease severity*

[Treatment response scales; various]

⊕◯◯◯

VERY LOW B

% of patients who reported an improvement following treatment ranged from 36%-

83%. 1

43

(2 non-RCT) D, E

* Critical Outcome 1 Meets the clinical significance threshold 2 Does not meet the clinical significance threshold A 95% CI crosses clinical significance threshold on 1 side (imprecision) B Small sample size C 95% CI crosses clinical significance threshold on both sides (high/ serious imprecision)

Intervention: PITOLISANT


Table S57. ESS determined excessive daytime sleepiness in an observational study, in response to Pitolisant in adult patients with



duration



Comparator


Pre-treatment

Post treatment

Leu-Semenescu 2014

Observational; chart review

N/A 65 65 17 ± 2.2 14.35 ± 3.79

N/A N/A -2.65 [-3.72, -1.58]

Mean (SD) converted from median (interquartile range) provided.

Table S58. Summary of Findings table for Pitolisant for the treatment of Idiopathic Hypersomnia in adults.

Reference: Leu-Semenescu 2014(A)


(GRADE)

Absolute Difference


No of Participants

(studies)


[Epworth Sleepiness Scale] ⊕◯◯◯ Very Low A,B

The mean ESS score pre-post difference was 2.65 points lower [ 3.72 points to 1.58

points lower] 1

65 patients

( 1 non-RCT)A




Table S59. ESS determined excessive daytime sleepiness in an observational study, in response to Sodium oxybate in adult patients

with Idiopathic Hypersomnia.


duration



Intervention

Comparator


Post treatment

Pre-treatment

Post treatment

Leu-Semenescu 2016

Observational N/A 42 25 15.7 ± 4 13 ± 4.9 N/A N/A -2.70 [-4.97, -0.43]

v. June 15, 2020

Table S60. Summary of Findings table for Sodium oxybate for the treatment of Idiopathic Hypersomnia in adults.

Reference: Leu-Semenescu 2016 (A)

Outcomes

[Tool]

Quality of the

evidence

(GRADE)

Absolute Difference


No of

Participants

(studies)

Excessive daytime sleepiness* [Epworth

Sleepiness Scale]

⊕◯◯◯

VERY LOW A


lower].

25

(1 non-RCT) A

* Critical Outcome 1 Meets the clinical significance threshold 2 Does not meet the clinical significance threshold 3 four-point scale: 0 = complete lack of benefit; 3 = major benefit A 95% CI crosses clinical significance threshold B Small sample size

PICO 3: KLS Intervention: LITHIUM


Table S61. Total no. of episodes within the observation period in an observational study, in response to Lithium in patients (mixed

population) with Kleine-Levin Syndrome.


duration


Pre- Post Difference, [CI] % reduction

(means only)

Intervention

Comparator


Pre-treatment

Post treatment

Leu-Semenescu 2015

Prospective, open label

21.5 6 17.8 months

71 71 13.2 ± 11 (Duration of observation=54.5 ± 70.5

2.7 ± 5.1 (Duration of observation = 22.4± 16.7

N/A N/A -10.50 [-13.32, -7.68] 20.45%

Note: Duration of observation differs in the 2 groups

Table S62. Episode frequency/year change in an observational study, in response to Lithium in patients (mixed population) with

Kleine-Levin Syndrome.


duration

No. of subjects Data (mean, SD) Pre- Post

Difference, [CI] % reduction (means only)

Intervention

Comparator


Post treatment

Pre-treatment

Post treatment

Leu-Semenescu 2015

Prospective, open-label

21.5 6 17.8 months

71 71 3.8 ± 2.9 1.3 ± 1.8 N/A N/A -2.50 [-3.29, -1.71] 34.21%

Table S63. Mean episode duration in an observational study, in response to Lithium in patients (mixed population) with Kleine-Levin

Syndrome.


duration


Pre- Post Difference, [CI] % reduction (means only)

Intervention

Comparator


Post treatment

Pre-treatment

Post treatment

Leu-Semenescu 2015

Prospective, open-label

21.5 ±17.8 months

71 71 17.3 ± 16.8 10 ± 12.3 N/A N/A -7.30 [-12.05, -2.55] 57.8%

Table S64. Summary of Findings table for Lithium for the treatment of Kleine-Levin Syndrome in adults and children.

Reference: Leu-Semenescu 2015 (A)

v. June 15, 2020


evidence

(GRADE)

Absolute Difference

Lithium vs Placebo or Pre- Post difference

No of

Participants

(studies)

Disease severity*

[Total no. of episodes within the observation period]

⊕◯◯◯

VERY LOW A

The mean number of episodes pre-post difference was 20.45% (10.50 episodes) lower

[7.68 to 13.32 episodes lower].

71 patients

(1 non-RCT) A

Disease severity*

[Episode frequency per year]

⊕◯◯◯

VERY LOW A

The mean episode frequency pre-post difference was 34.21% (2.50 episodes) lower

per year lower [1.71 to 3.29 episodes lower].

71 patients

(1 non-RCT) A

Disease severity*

[Mean episode duration]

⊕◯◯◯

VERY LOW A

The mean episode duration pre-post difference was 57.8% (7.30 days) lower [2.46 to

12.14 episodes lower].

71 patients

(1 non-RCT) A


Intervention: METHYL-PREDNISOLONE


Table S65. Mean episode duration change in an observational study, in response to IV Methyl prednisolone (IV-MP) in patients with

Kleine-Levin Syndrome.


duration

No. of subjects Data (mean, SD) Pre- Post

Difference, [CI] % reduction (means

only)

Treated

Untreated

Treated Un-treated

Baseline Post Rx Baseline Post Rx

Leotard 2018 Observational; open label retrospective

3y 26 48 48.2 ± 54.1 26.58 ± 28.23 N/A N/A -21.62 [-45.09, 1.85] 55.14%

Leotard 2018-Data presented as median (IQR) in days. Mean and SD calculated

Table S66. Episode shortening in an observational study, in response to IV Methyl prednisolone (IV-MP) in patients with Kleine-Levin

Syndrome.


duration



Intervention

Comparator

Treated Un-treated

Treated Un-treated Pre-treatment

Post treatment

Leotard 2018 Observational; open label retrospective

3y 26 48 -12 (-68 to -3) 0 (-0.8 to 2) N/A N/A 21.62 [-45.09, 1.85]

Leotard 2018-Data presented as median (IQR) in days. Mean and SD calculated.

Table S67. Summary of Findings table for Methylprednisolone for the treatment of Kleine-Levin Syndrome in adults and adolescents.

Reference: Leotard 2018 (A)


evidence

(GRADE)

Absolute Difference

Methyl-Prednisolone vs Placebo or Pre- Post difference

No of

Participants

(studies)

Disease severity*

[Episode Duration change]

⊕◯◯◯

VERY LOW A

The mean episode duration pre-post difference was 55.14%(11 days) lower [6 days

higher to 56 days lower].

26 patients

(1 non-RCT) A

Disease severity*

[Episode shortening]

⊕◯◯◯

VERY LOW A

The mean episode shortening pre-post difference was 12 episodes lower [3 episodes

higher to 68 episodes lower].

26 patients

(1 non-RCT) A


v. June 15, 2020

PICO 4a: Hypersomnia secondary to medical (including neurological) disorders

Hypersomnia secondary to Alpha-synucleinopathies

Intervention: ARMODAFINIL


Table S68. ESS determined excessive daytime sleepiness in an observational study, in response to Armodafinil in adult patients with

Hypersomnia secondary to Dementia with Lewy bodies (DLB).


duration



Intervention

Comparator


Pre-treatment

Post treatment

Lapid 2017

Single-arm, open-label, pilot

study

12 weeks 20 17 14 ± 4.34 8 ± 4.92 N/A N/A -6.0[-9.01, -2.99]

Lapid 2017- Mean (SD)values are calculated from median (range) provided in paper.

Table S69. MWT determined excessive daytime sleepiness in an observational study, in response to Armodafinil in adult patients with

Hypersomnia secondary to DLB.


duration



Intervention

Comparator


Pre-treatment

Post treatmen

t

Lapid 2017

Single-arm, open-label, pilot

study

12 weeks 20 17 9.6 ± 6.65 20 ± 10.97 N/A N/A 10.40 [4.43, 16.37]

Lapid 2017- Values are derived from median (range) provided in paper.

Table S70. Summary of Findings table for Armodafinil for the treatment of Hypersomnia secondary to DLB in adults.

References: Lapid 2017(A)


(GRADE)

Absolute Difference


No of

Participants

(studies)



⊕◯◯◯

VERY LOW B


lower]

17 patients

(1 non-RCT) A



⊕◯◯◯

VERY LOW ,B

The mean MWT score pre-post difference was 10.40 minutes higher1 [4.43 minutes to

16.37 higher]

17 patients

(1 non-RCT) A

* Critical Outcome 1 Meets the clinical significance threshold 2 Does not meet the clinical significance threshold A 95% CI crosses clinical significance threshold (imprecision) B Small sample size C 95% CI crosses clinical significance threshold on both sides (high/ serious imprecision)

v. June 15, 2020

Intervention: LIGHT THERAPY


Figure S39. ESS determined excessive daytime sleepiness in an RCT, in response to Light therapy in adult patients with Hypersomnia

secondary to Parkinson disease.

Outcome B2: FATIGUE Figure S40. FSS determined fatigue in an RCT, in response to Light therapy in adult patients with Hypersomnia associated with Parkinson disease.

Table S71. Summary of Findings table for Light therapy for the treatment of Hypersomnia secondary to Parkinson disease in adults.

Reference: Videnovic 2017 (A)


(GRADE)

Absolute Difference


No of

Participants

(studies)


[Epworth Sleepiness Scale] ⊕⊕⊕◯ MODERATEA, B

The mean ESS score in the Light therapy group was 1.77 points lower2 [1.14 points

higher to 4.68 points lower] compared to dim light.

31 patients

(1 RCT)B

Fatigue

[Fatigue Severity Scale] ⊕⊕◯◯ LOWB, C

The mean FSS score in the light therapy group was 1.39 points higher2 [7.49 points

lower to 10.27 points higher] compared to dim light.

31 patients

(1 RCT)B

* Critical Outcome 1 Meets the clinical significance threshold 2 Does not meet the clinical significance threshold A 95% CI crosses clinical significance threshold on one side (imprecision) B Small sample size C 95% CI crosses clinical significance threshold on both sides (serious Imprecision)



Figure S41. ESS determined excessive daytime sleepiness in RCTs, in response to Modafinil (various doses) vs. placebo in adult

patients with Hypersomnia secondary to Parkinson disease.

v. June 15, 2020

Hogl 2002- Change score (mean, SD)

Table S72. ESS determined excessive daytime sleepiness in an observational study, in response to Modafinil (various doses) vs.

placebo in adult patients with Hypersomnia secondary to Parkinson disease.


duration



Comparator


Pre-treatment

Post treatment

Nieves 2002

Observational, open label

4 weeks 10 9 14.22 ± 3.03 6.0 ± 4.87 N/A N/A -8.22[-11.97, -4.47]

Figure S42. MWT determined excessive daytime sleepiness in RCTs, in response to Modafinil (various doses) vs. placebo in adult

patients with Hypersomnia secondary Parkinson disease.

Figure S43. MSLT determined excessive daytime sleepiness in RCTs, in response to Modafinil (various doses) vs. placebo in adult

patients with Hypersomnia secondary to Parkinson disease.

Ondo 2005- data presented is the visit 2 data for Modafinil and placebo


Figure S44. SF-36- Total score determined quality of life in RCTs, in response to Modafinil (various doses) vs. placebo in adult patients

with Hypersomnia secondary to Parkinson disease.

Outcome: FATIGUE

Figure S45. FSS determined fatigue severity in RCTs, in response to Modafinil (various doses) in adult patients with Hypersomnia

secondary to Parkinson disease.

v. June 15, 2020

Table S73. Summary of Findings table for Modafinil for the treatment of Hypersomnia secondary to Parkinson disease in adults.

References: Adler 2003 (A); Hogl 2002 (B); Lou 2009 (C); Ondo 2005(D); Nieves 2002 (E)


(GRADE)

Absolute Difference


No of

Participants

(studies)



⊕⊕⊕◯

MODERATE A

The mean ESS score in the Modafinil group was 2.25 points lower1 [0.69 to 3.80 points

lower] compared to placebo

122

(4 RCT) A, B, C,D

⊕◯◯◯

VERY LOW B

The mean ESS score pre-post difference was 8.22 points lower 1 (11.97 points lower to

4.47 points higher).

10

(1 non-RCT) E



⊕⊕⊕◯

MODERATE A, B

The mean MWT score in the Modafinil group was 1.77 minutes higher2 [ 10.24 minutes


24 patients

(1 RCT) B



⊕⊕⊕◯

MODERATE A, B

The mean MSLT score in the Modafinil group was 0.80 minutes higher 2 (3.06 minutes

higher to1.46 minutes lower ] compared to placebo

37 patients

(1 RCT) D

Quality of life*

[Short Form Health Survey (SF-36) - Total

score]

⊕⊕◯◯

LOW B,C

The mean SF-36 Total score in the Modafinil group was 0.20 points lower 2 (95% CI:

8.32 points higher to 7.92 points lower] compared to placebo

37 patients

(1 RCT) D

Fatigue

[Fatigue Severity Scale]

⊕⊕⊕◯

MODERATE A, B

The mean FSS score in the Modafinil group 0.22 points lower (95% CI: 1.26 points lower

and 0.83 points higher] compared to placebo

77 patients

(2 RCTs) A, D

* Critical Outcome 1 Meets the clinical significance threshold 2 Does not meet the clinical significance threshold A 95% CI crosses clinical significance threshold on one side (imprecision) B Small sample size C 95% CI crosses clinical significance threshold on both sides (high/ serious imprecision)



Figure S46. ESS determined excessive daytime sleepiness in an RCT, in response to sodium oxybate vs. placebo in adult patients


Values are the change from baseline in ESS scores while receiving Sodium oxybate or placebo

Figure S47. MSLT determined excessive daytime sleepiness in an RCT, in response to sodium oxybate vs. placebo in adult patients


Values are the change from baseline in MSLT scores while receiving Sodium oxybate or placebo

v. June 15, 2020

Outcome: FATIGUE

Figure S48. FSS determined fatigue severity in an RCT, in response to sodium oxybate in adult patients with Hypersomnia secondary

to Parkinson disease.

Values are the change from baseline in FSS scores while receiving Sodium oxybate or placebo.

Table S74. Summary of Findings table for sodium oxybate for the treatment of Hypersomnia secondary to Parkinson disease in adults.

Reference: Buchelle 2018(A)


(GRADE)

Absolute Difference


No of Participants

(studies)



⊕⊕⊕◯

MODERATE A,B

The mean ESS score in the Sodium oxybate group was 4.20 points lower1 [1.99 to 6.41

points lower] compared to placebo

12 patients

(1 RCT) A



⊕⊕⊕◯

MODERATE A,B

The mean MSLT score in the Sodium oxybate group was 2.90 minutes higher2 [1.30 to

4.50 minutes higher] compared to placebo

12 patients

(1 RCT) A

Fatigue


⊕⊕⊕◯

MODERATE B

The mean FSS score was 0.10 points lower2 [0.66 lower to 0.86 higher] compared to

placebo

12 patients

(1 RCT) A


Posttraumatic hypersomnia



Figure S49. ESS determined excessive daytime sleepiness in an RCT, in response to Armodafinil (various doses) vs. placebo in adult

patients with Hypersomnia associated with traumatic brain injury.

Menn 2014- Values are the change from baseline in ESS scores while receiving Armodafinil (pooled doses) or placebo.

Figure S50. MSLT determined excessive daytime sleepiness in an RCT, in response to Armodafinil (various doses) vs. placebo in

adult patients with Hypersomnia associated with traumatic brain injury.

Menn 2014- Values are the change from baseline in MSLT scores while receiving Armodafinil (pooled doses) or placebo

v. June 15, 2020

Table S75. Summary of Findings table for Armodafinil for the treatment of Hypersomnia associated with traumatic brain injury in adults.

Reference: Menn 2014(A)


(GRADE)

Absolute Difference


No of

Participants

(studies)



⊕⊕⊕◯

MODERATE A

The mean ESS score in the Armodafinil group was 0.68 points lower2 [3.19 points lower

to 1.83 points higher] compared to placebo

104 patients

(1 RCT) A



⊕⊕⊕◯

MODERATE A

The mean MSLT score in the Armodafinil group was 2.29 minutes higher1 [0.43 to 4.15

minutes higher] compared to placebo

105 patients

(1 RCTs) A




Figure S51. ESS determined excessive daytime sleepiness in an RCT, in response to Modafinil (various doses) vs. placebo in adult


Figure S52. MWT determined excessive daytime sleepiness in an RCT, in response to Modafinil (various doses) vs. placebo in adult


Outcome: FATIGUE

Figure S53. FSS determined fatigue severity in an RCT, in response to Modafinil (various doses) in adult patients with Hypersomnia

associated with traumatic brain injury.

Table S76. Summary of Findings table for Modafinil for the treatment of Hypersomnia secondary to traumatic brain injury (TBI) in

adults.

Reference: Kaiser 2010 (A)


(GRADE)

Absolute Difference


No of Participants

(studies)



⊕⊕⊕◯

MODERATE A



20

(1 RCT) A

v. June 15, 2020



⊕⊕⊕◯

MODERATE A, B

The mean MWT score in the Modafinil group was 8.00 minutes higher1 [15.08 minutes


20

(1 RCT) A

Fatigue


⊕⊕⊕◯

MODERATE A, B

The mean FSS score in the Modafinil group was 0.80 points lower 1 [ 0.08 to 1.52 points


20

(1 RCT) A


Genetic disorders associated with primary central nervous system somnolence

Intervention: METHYLPHENYDATE


Figure S54. ESS determined excessive daytime sleepiness in an RCT, in response to Methylphenidate vs. placebo in adult patients

with Hypersomnia secondary to myotonic dystrophy.

Puymirat 2012- a crossover study. Values are the change from baseline in ESS scores while receiving Methylphenidate or placebo. Mean (SD) calculated from median (IQR) provided in study.

Table S77. Summary of Findings table for Methylphenidate for the treatment of Hypersomnia secondary to a myotonic dystrophy in

adults.

Reference: Puymirat 2012 (A)


(GRADE)

Absolute Difference


No of

Participants

(studies)



⊕⊕⊕◯

MODERATE A, B

The mean ESS score in the Methylphenidate group was 1.36 points lower2 [4.28 points

lower to 1.56 points higher] compared to placebo

17

(1 RCT) A




Figure S55. ESS determined excessive daytime sleepiness in an RCT, in response to Modafinil vs. placebo in adult patients with

Hypersomnia secondary to myotonic dystrophy.

v. June 15, 2020

Figure S56. MWT determined excessive daytime sleepiness in an RCT, in response to Modafinil (various doses) vs. placebo in adult

patients with Hypersomnia secondary to myotonic dystrophy.

Figure S57. MSLT determined excessive daytime sleepiness in an RCT, in response to modafinil vs. placebo in adult patients with


Outcome: QUALITY OF LIFE Figure S58. Short Form Health Survey (SF-36- Total score) determined quality of life in RCTs, in response to Modafinil (various doses)

vs. placebo in adult patients with Hypersomnia secondary to Parkinson disease.

Figure S59. Short Form Health Survey (SF-36- Mental component) determined quality of life in an RCT, in response to Modafinil

(various doses) vs. placebo in adult patients with Hypersomnia secondary to myotonic dystrophy.

Talbot 2003- A crossover study. Mean and SD derived from the sample size, median & 5th/95th percentile range

Figure S60. Short Form Health Survey (SF-36- Physical component) determined quality of life in an RCT, in response to Modafinil

(various doses) vs. placebo in adult patients with Hypersomnia secondary to a myotonic dystrophy.

Talbot 2003- A crossover study. Mean and SD derived from the sample size, median & 5th/95th percentile range.

v. June 15, 2020

Outcome: FATIGUE

Figure S61. Short Form Health Survey (SF-36- Energy and vitality component) determined Fatigue in an RCT, in response to Modafinil

(various doses) vs. placebo in adult patients with Hypersomnia secondary to myotonic dystrophy.

Talbot 2003-A crossover study. Mean and SD derived from the sample size, median & 5th/95th percentile range

Table S78. Summary of Findings table for Modafinil for the treatment of Hypersomnia secondary to myotonic dystrophy in adults.

References: Orlikowski 2009 (A); Talbot 2003 (B)


(GRADE)

Absolute Difference


No of Participants

(studies)



⊕⊕⊕◯

MODERATE A


lower] compared to placebo.

66

(2 RCTs) A, B



⊕⊕⊕◯

MODERATE A, B

The mean MWT score in the Modafinil group was 5.79 minutes higher 1 [16.23 minutes


66

(2 RCTs) A, B



⊕⊕⊕◯

MODERATE A, B

The mean MSLT score in the Modafinil group was 0.26 minutes lower 2 [3.77 minutes


66

(2 RCTs) A, B

Quality of life*

[Short Form Health Survey (SF-36) - Total

score]

⊕⊕◯◯

LOW B,C

The mean SF-36 Total score in the Modafinil group was 1.81 points lower [ 3.31 points

higher to 5.41 lower] compared to placebo

66

(2 RCTs) A, B

Quality of life *

Short Form Health Survey (SF-36) - Physical

component score]

⊕⊕◯◯

LOW B,C

The mean SF-36 Physical Summary Score in the Modafinil group was 2.44 points

higher1 [8.04 points lower to 12.92 points higher] compared to placebo

37patients

(1 RCT) A

Quality of life *


component score]

⊕⊕◯◯

LOW B,C

The mean SF-36 Mental Summary Score in the Modafinil group was

0.32 points lower2 [8.47 points lower to 7.83 points higher] compared to placebo

37 patients

(1 RCT) A

Fatigue

[Short Form Health Survey (SF-36) - Energy

and vitality component]

⊕⊕⊕◯

MODERATE A, B

The mean SF-36- Energy and vitality component in the Modafinil group was 10.69 points

higher1 [1.07 points lower to 22.45 points higher] compared to placebo

38patients

(1 RCT) B


Intervention: SELEGILINE


Figure S62. MSLT determined excessive daytime sleepiness in an RCT, in response to Selegiline vs. placebo in adult patients with


Table S79. Summary of Findings table for Selegiline for the treatment of Hypersomnia secondary to a medical disorder in adults.

References: Antonini 1997 (A)

v. June 15, 2020


(GRADE)

Absolute Difference


No of Participants

(studies)



⊕⊕◯◯

LOW B, C

The mean MSLT score in the Selegiline group was 3.70 minutes lower1[ 8.83 minutes

lower to 1.43 min higher] compared to placebo

20

(1 RCT) A


Hypersomnia secondary to brain tumors, infections, or other central nervous system lesions



Table S80. ESS determined excessive daytime sleepiness in observational studies, in response to Modafinil (various doses) vs.

placebo in adult patients with Hypersomnia associated with multiple sclerosis.


duration



Comparator


Pre-treatment

Post treatment

Zifko 2002

Observational, open label

3 months 50 47 9.7 ±3.9 4.9 ±2.9 N/A N/A -4.80[-6.19, -3.41]

Outcome: FATIGUE

Table S81. FSS determined fatigue severity in an observational study, in response to Modafinil (various doses) in adult patients with

Hypersomnia secondary to multiple sclerosis.


duration



Comparator


Pre-treatment

Post treatment

Zifko 2002

Open label, observational

3 months 47 47 30.3± 8.5 25.4 ± 3.7 N/A N/A -4.90 [-7.55, -2.25]

78% of patients had FSS scores that improved by more than 2 points.

Table S82. Summary of Findings table for Modafinil for the treatment of Hypersomnia secondary to a multiple sclerosis in adults.

References: Zifko 2002 (A)


(GRADE)

Absolute Difference


No of Participants

(studies)



⊕◯◯◯

VERY LOW B

The mean ESS pre-post difference score in the modafinil group was 4.80 points lower1

(95% CI: 6.19 points lower to 3.41 points higher).

47

(1 non-RCT) A

Fatigue


⊕◯◯◯

VERY LOW B

The mean FSS pre-post difference score in the modafinil group was 4.9 points (95% CI:

2.25 to 7.55 points lower).

47

(1 non-RCT) A

v. June 15, 2020


Hypersomnia secondary to endocrine disorder

Intervention: LIRAGLUTIDE


Table S83. ESS determined excessive daytime sleepiness in an observational study, in response to Liraglutide in adult patients with

hypersomnia secondary to Type 2 DM.


duration



Intervention

Comparator


Pre-treatment

Post treatment

Gomez-Peralta 2015

Open label, retrospective

3 months 158 158 5.7 ± 4.4 4.2 ± 3.6 N/A N/A -1.50 [-2.39, -0.61]

Table S84. Summary of Findings table for Liraglutide for the treatment of Hypersomnia secondary to Type 2 DM in adults.

References: Gomez-Peralta 2015 (A)


(GRADE)

Absolute Difference


No of Participants

(studies)



⊕◯◯◯

VERY LOW A


lower]

158

(1 non-RCT) A


PICO 4b: Hypersomnia secondary to a psychiatric disorder Intervention: LIGHT THERAPY


Table S85. SSS determined subjective sleepiness in an RCT, in response to Light therapy (various doses) in adult patients with

hypersomnia secondary to winter seasonal affective disorder.


duration



Comparator


Pre-treatment

Post treatment

Partonen 1996

RCT 2 weeks 16 16 5.21± 0.81 4.32 ± 0.96 N/A N/A -0.89 [-1.51, -0.27]

Partonen 1996- Baseline data is pooled baseline data for early evening, late evening and morning data for patients’ subject to both the 1 hour and 15-minute light exposure. Post intervention data is pooled after- intervention data for early evening, late evening and morning data for patients’ subject to both the 1 hour and 15-minute light exposure.

v. June 15, 2020

Table S86. Summary of Findings table for Light therapy for the treatment of Hypersomnia secondary to winter seasonal affective

disorder in adults.

Reference: Partonen 1996 (A)


(GRADE)

Absolute Difference


No of Participants

(studies)


[Stanford Sleepiness Scale]

⊕⊕⊕◯ MODERATE A,B

The mean SSS score pre-post differences was 0.89 points lower2 [0.27 to 1.51 points

lower].

16 patients

(1 RCT)A

* Critical Outcome 1 Meets the clinical significance threshold 2 Does not meet the clinical significance threshold A 95% CI crosses clinical significance threshold on 1 side (imprecision) B Small sample size



Figure S63. ESS determined excessive daytime sleepiness in an RCT, in response to Modafinil (various doses) in adult patients with

hypersomnia with major depressive disorder.

Table S87. ESS determined excessive daytime sleepiness in an RCT, in response to Modafinil (various doses) in adult patients with

hypersomnia with major depressive disorder.

Study Study Design

Study duration

No. of subjects completing study

Data (mean, SD)

Post Difference, [CI] Intervention

Comparator

Modafinil Placebo Pre-treatment

Post treatment

Pre-treatment

Post treatment

De Battista 2003

RCT 6 weeks 69 67 9.5± 4.5

7.1 ± 3.3* 10.5± 4.9 8.8 ±3.3* -1.70 [-2.82, -0.58]

De Battista 2003- *Post treatment data for SD estimated from graph. SD data presented here was converted from SE data

Table S88. ESS determined excessive daytime sleepiness, in response to Modafinil in adult patients with hypersomnia with major

depressive disorder.


duration



Comparator


Pre-treatment

Post treatment

Ninan 2004

Open label observational

6 weeks 29 29 10.3 ± 4.9 4.8 ±6.3* N/A N/A -5.50 [-8.40, -2.60]

Ninan 2004- *Post treatment data estimated from graph

v. June 15, 2020

Outcome: FATIGUE

Figure S64. FSS determined fatigue, in response to Modafinil (various doses) in adult patients with hypersomnia with major depressive

disorder.

Table S89. FSS determined fatigue, in response to Modafinil (various doses) in adult patients with hypersomnia with major depressive

disorder.

Study Study Design

Study duration

No. of subjects completing study

Data (mean, SD)

Pre- Post Difference Intervention

Comparator

Modafinil Placebo Pre-treatment Post treatment

Pre-treatment

Post treatment

De Battista 2003

RCT 6 weeks 69 67 5.1 ± 1.3 *Change score: -0.55(SD)

5.0 ± 1.3 change score:

-0.25 (SD)

0.35

De Battista 2003-*Post Rx data from graph. SD data presented here was converted from SE data

Table S90. FSS determined fatigue, in response to Modafinil in adult patients with adult patients with hypersomnia with major

depressive disorder.


duration



Comparator


Pre-treatment

Post treatment

Ninan 2004

Open label observational

6 weeks 29 5.2 ± 0.8 3.0 ± 2.5*

N/A N/A -2.20 [-3.16, -1.24]

*Author noted that modafinil (combined with an SSRI) significantly reduces mean FSS scores at week 1- week 6 (graph)

Table S91. Summary of Findings table for Modafinil for the treatment of Hypersomnia secondary to major depressive disorder in adults.

References: Dunlop 2007(A); De Battista 2003 (B); Ninan 2004 (C)


(GRADE)

Absolute Difference


No of

Participants

(studies)



⊕⊕⊕◯

MODERATE A

The mean ESS score in the Modafinil group ranged from 0.8 points to 1.70 points lower

compared to placebo2

208

(2 RCTs) A, B

⊕◯◯◯

VERY LOW B

The mean ESS score pre-post differences was 5.5 points lower [ 2.6 to 8.40 points

lower] 1.

29

(1 non-RCTs) C

Fatigue


⊕⊕⊕◯

MODERATE A,B

The mean FSS score in the Modafinil group was 0.10 points lower [0.85 points lower to

0.65 points higher] compared to placebo2

72 patients

(1 RCT) A

⊕⊕⊕◯

MODERATE A,B

The estimated FSS change score in the Modafinil group was 0.35 points lower compared to placebo2

136 patients

(1 RCT) B

⊕◯◯◯

VERY LOW B

The mean FSS score pre-post differences was 2.20 points lower [1.24 to 3.16 points

lower]1.

29 patients

(1 non-RCT) C


v. June 15, 2020

SIDE EFFECT DATA IN ADULT POPULATIONS


Figure S65. Meta-analysis of data for the occurrence of headache in response to Armodafinil (various doses).


Figure S66. Meta-analysis of data for the occurrence of insomnia in response to Modafinil (various doses).

v. June 15, 2020

Figure S67. Meta-analysis of data for the occurrence of nausea in response to Modafinil (various doses).

v. June 15, 2020

Figure S68. Meta-analysis of data for the occurrence of diarrhea in response to Modafinil (various doses).

Figure S69. Meta-analysis of data for the occurrence of headache in response to Modafinil (various doses).

v. June 15, 2020

Figure S70. Meta-analysis of data for the occurrence of dry mouth in response to Modafinil (various doses).

v. June 15, 2020

Figure S71. Meta-analysis of data for the occurrence of anxiety or nervousness or panic attacks in response to Modafinil (various

doses).

v. June 15, 2020

Figure S72. Meta-analysis of data for the occurrence of flu or flu like symptoms in response to Modafinil (various doses).

v. June 15, 2020

Figure S73. Meta-analysis of data for the occurrence of loss of appetite in response to Modafinil (various doses).

Figure S74. Meta-analysis of data for the occurrence of tachycardia/palpitations/atrial fibrillation in response to Modafinil (various

doses).

v. June 15, 2020


Figure S75. Meta-analysis of data for the occurrence of nausea in response to Sodium oxybate (various doses).

Figure S76. Meta-analysis of data for the occurrence of diarrhea in response to Sodium oxybate (various doses).

v. June 15, 2020

Figure S77. Meta-analysis of data for the occurrence of sleep disturbances* in response to Sodium oxybate (various doses).

*Includes somnolence, sleep walking, parasomnia, snoring, OSA, dream abnormality etc.

Figure S78. Meta-analysis of data for the occurrence of urinary/renal disturbances* in response to Sodium oxybate (various doses).

*Includes incontinence, nocturnal enuresis etc.

v. June 15, 2020

Figure S79. Meta-analysis of data for the occurrence of chest discomfort* in response to Sodium oxybate (various doses).

*Includes thoracic discomfort, dyspnea etc.

Figure S80. Meta-analysis of data for the occurrence of anxiety or nervousness in response to sodium oxybate (various doses).

v. June 15, 2020

Figure S81. Meta-analysis of data for the occurrence of headache in response to sodium oxybate (various doses).

Figure S82. Meta-analysis of data for the occurrence of dizziness in response to sodium oxybate (various doses).

PEDIATRIC POPULATION

PICO 1: Narcolepsy Intervention: MODAFINIL


Table S92. ESS determined excessive daytime sleepiness in an observational study, in response to Modafinil (various doses) in

pediatric patients with Narcolepsy 1.


duration

No. of subjects Data (mean, SD) Pre- Post Difference,

[CI] Intervention

Comparator

v. June 15, 2020


Pre-treatment

Post treatment

Yeh 2010 Observational, prospective

6- 12 months

10 10 20 ± 1.63 13.8 ± 3.26 N/A N/A -6.20 [-8.46 , -3.94]

Aran 2010- Mean SD calculated from Mean (SE provided)

Table S93. MSLT determined excessive daytime sleepiness in an observational study, in response to Modafinil (various doses) in



duration



Intervention

Comparator


Pre-treatment

Post treatment

Yeh 2010 Observational 6-12 months

10 10 1.72 ± 0.80 2.16 ± 0.96 N/A N/A 0.44 [-0.33, 1.21]]


Table S94. Seven-point rating scale determined disease severity in an observational study in response to modafinil in pediatric patients

with Narcolepsy 1.

Study Study Design

Study

duration


Improvement

(points) Pre Post Pre-

treatment

Post

treatment


Aran 2010 Observational;

retrospective

12 months 41 36 NA NA NA NA 1.9 (1.7, 2.1)

Aran 2010- 7-point scale: On a scale of -3 to 3, -3 was maximal negative effect, 0 was no effect, and 3 was maximal positive effect

Table S95. Summary of Findings table for Modafinil for the treatment of Hypersomnia secondary to narcolepsy in pediatric populations.

References: Yeh 2010 (A), Aran 2010 (B)

Outcomes

[Tool]

Quality of the

evidence

(GRADE)

Absolute Difference


No of Participants

(studies)



⊕◯◯◯

VERY LOW A

The pre-post ESS score in NT1 patients on Modafinil was 6.09 points lower1

[8.46 to 3.94 points lower]

36 patients

(1 non-RCT)A



⊕◯◯◯

VERY LOW A

The mean MSLT score pre-post difference in NT1 patients on Modafinil was

0.44 minutes higher2 [1.21 min higher to 0.33 mins lower]

10 patients

(1 non-RCT)A

Disease Severity

[7 – point rating scale]

⊕◯◯◯

VERY LOW A

There was an improvement of 1.9 points1 [1.7 points to 2.1 points higher] with

modafinil in NT1 patients.

36 patients

(1 non-RCT)B


v. June 15, 2020



Figure S83. ESS-CHAD determined excessive daytime sleepiness, in an RCT-withdrawal study

in response to sodium oxybate (various doses) in pediatric patients with Narcolepsy 1.

Plazzi 2018-Data converted from median (IQR) provided

Table S96. ESS-CHAD determined excessive daytime sleepiness in observational studies in response to Sodium oxybate in



duration



Intervention

Comparator



Post treatment

Filardi 2018 Observational 7 days 24 24 15.71± 2.56 10.29 ± 3.52 N/A N/A -5.42 [-7.16, -3.68]

Mansukhani 2012

Observational 3–90 months

10 10 18.4 ± 2.58 11.5 ± 3.8 N/A N/A -6.90 [-9.75, -4.05]

Mansukhani 2012- Mean SD calculated from Median and Range values provided.

Table S97. MSLT determined excessive daytime sleepiness in an observational trial, in response to sodium oxybate in pediatric

patients with Narcolepsy 1.


duration



Comparator



Post treatment

Huang 2009 Observational N/A 13 13 2.8 ± 3.1 4.6 ± 3.7 N/A N/A 1.80 [-0.82, 4.42]

Outcome: CATAPLEXY

Table S98. Change from baseline in the weekly number of cataplexy attacks in an RCT- withdrawal study, in

response to sodium oxybate in pediatric patients with Narcolepsy 1.




On Sodium oxybate

Off Sodium oxybate

Pts. on

SXB

Pts on place

bo

Baseline Post treatment (% mean change)

Baseline Post treatment (% mean change)

Plazzi 2018 RCT 4 weeks 31 32 6.37 ± 10.16

7.99 ± 12.2 (25.4%)

5.02 ± 7.23 22.73 ± 24.38 (352.7%)

327.3%

*[(post-treatment mean/pre-treatment mean) -1 x 100]

Table S99. Change in weekly cataplexy episodes determined cataplexy frequency, in response to sodium oxybate in



duration

No. of subjects Data (mean, SD) % difference in mean cataplexy reduction

Intervention

Comparator

v. June 15, 2020



Post treatment

Mansukhani 2012

Observational 3–90 months

15 14 149.46 ± 204.82

4.05 ± 6.14 N/A N/A -145.41 [38.07, 252.75] (97.2%)

Mansukhani 2012- Mean SD calculated from Median and Range values provided.

Table S100. Change in daily cataplexy episodes determined cataplexy frequency in an observational study, in

response to sodium oxybate in pediatric patients with Narcolepsy 1.


duration


% difference in mean cataplexy reduction

Intervention

Comparator



Post treatment

Huang 2009 Observational 3 months 13 13 3.9 ± 1.3 0.2 ± 0.8 N/A N/A 94.8%


Figure S84. CGI-C determined cataplexy severity in an RCT- withdrawal study, in response to sodium oxybate in pediatric

patients with Narcolepsy 1.

Plazzi 2018 Data represented is the mean change in CGI-C scores for each group

Table S101. Summary of Findings table for sodium oxybate for the treatment of hypersomnia secondary to narcolepsy in pediatric populations.

References: Plazzi 2018(A); Mansukhani 2012 (B); Huang 2009 (C); Aran 2010 (D); Filardi 2018 (E)

Outcomes

[Tool]

Quality of the

evidence

(GRADE)

Absolute Difference


No of Participants

(studies)

Cataplexy*

[# weekly episodes]

⊕⊕⊕◯

MODERATE A

The mean pre-post % difference in the weekly cataplexy rate in narcolepsy

patients on and off Sodium oxybate was 327%1.

61 patients

(1 RCT)A

⊕◯◯◯

VERY LOW A

The mean pre-post % difference in the weekly cataplexy rate in narcolepsy

patients on and off Sodium oxybate was 97.2%1.

14 patients 1 non-RCT)B

Cataplexy*

[[# daily episodes]

⊕◯◯◯

VERY LOW A

The mean pre-post % difference in the daily cataplexy rate in narcolepsy

patients on and off Sodium oxybate was 94.8%1.

13 patients

(1 non-RCT)C

v. June 15, 2020

Disease Severity

[CGI-C (cataplexy severity) score]

⊕⊕⊕◯

MODERATE A

The mean score in pediatric patients with narcolepsy was 1.10 points higher1

[0.53 to 1.67 points higher] compared to placebo

63 patients

(1 RCT)A


[Epworth Sleepiness Scale-CHAD]

⊕⊕⊕◯

MODERATE A

The mean ESS-CHAD score in pediatric patients on Sodium oxybate was 2.65

points lower 1 (95% CI: 1.3 to 4.0 points lower) compared to placebo.

61 patients

(1 RCT)A

⊕◯◯◯

VERY LOW A

There was a pre-post difference of 5.42 points to 6.9 points lower in the mean

ESS-CHAD.

34 patients (2 non-RCT) B, E



⊕◯◯◯

VERY LOW A

The mean MSLT score in pediatric patients on Sodium oxybate was 1.80

minutes higher1 (4.42 minutes higher to 0.82 minutes lower).

13 patients

(1 non-RCT)C


Intervention: IV IMMUNOGLOBULIN


Table S102. CGI-S determined disease severity in an observational study, in response to IVIG in pediatric patients with Narcolepsy 1.


duration


Pre- Post Difference,

[CI]

Intervention

Control

Intervention Control Pre-Rx *Change from baseline

Pre-Rx *Change from baseline

Lecendreux 2016

Open label, controlled, longitudinal observational Study

F/U length: 2.4 (1.1) y for IVIg gp;

3.9 (1.7) y in controls

22 30 1.63 ± 0.39

2.65± 0.6 1.64 ± 0.49

2.0 ±0.5 2.65 [0.562, 4.738]

Lecendreux 2016- Pre Rx-mean (SD) calculated from Median (Range) provided. Change from baseline estimated from graph for last time point (>24 months)

Table S103. Summary of Findings table for IV Immunoglobulin for the treatment of Narcolepsy 1 in pediatric populations.

Reference: Lecendreux 2016 (A)


evidence

(GRADE)

Absolute Difference

IVIg Immunoglobulin Pre- Post difference

No of

Participants

(studies)

Disease Severity*

[CGI-Sleepiness]

⊕◯◯◯

VERY LOW A

The mean CGI score pre-post difference in the IVIg group was 2.65 points higher1

[0.56 to 4.74 points higher]. 22 patients

(1 non-RCT) A


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