all literature search terms · us modafinil (1998)- mean (sd) is pooled data of modafinil 200mg and...
TRANSCRIPT
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
v. June 15, 2020
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.
v. June 15, 2020
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
v. June 15, 2020
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
Study Study Design Study duration
No. of subjects Data (mean, SD)
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
No. of subjects Data (mean, SD)
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.
Study Study Design Study
duration
No. of subjects Data (mean, SD)
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
Study Study Design Study
duration
No. of subjects Data (mean, SD)
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
Outcome: EXCESSIVE DAYTIME SLEEPINESS
Table S7. ESS determined excessive daytime sleepiness, in response to Clomipramine in adult patients with 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
v. June 15, 2020
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)
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 Scale]
⊕◯◯◯
VERY LOW B
The mean ESS score pre-post difference was 3.2 points lower1 [0.07 to 6.33 points
lower].
16
(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 B Small sample size
Intervention: DEXTROAMPHETAMINE
Outcome: EXCESSIVE DAYTIME SLEEPINESS
Table S9. ESS determined excessive daytime sleepiness, in response to dextroamphetamine in adult patients with 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
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
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
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
v. June 15, 2020
1 Meets the clinical significance threshold 2 Does not meet the clinical significance threshold A Small sample size
Intervention: L-CARNITINE
Outcome: EXCESSIVE DAYTIME SLEEPINESS
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)
Outcomes [Tool] Quality of the
evidence
(GRADE)
Absolute Difference
L-Carnitine vs Placebo or Pre- Post difference
No of
Participants
(studies)
Excessive Daytime Sleepiness*
[Epworth Sleepiness Scale]
⊕⊕⊕◯
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
Outcome: DISEASE SEVERITY
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)
Outcomes [Tool] Quality of the
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
* Critical Outcome 1 Meets the clinical significance threshold 2 Does not meet the clinical significance threshold A Small sample size
Intervention: MODAFINIL
Outcome: EXCESSIVE DAYTIME SLEEPINESS
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.
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
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
unspecified narcolepsy.
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
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
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
Observational; open label
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.
Study Study Design Study
duration
No. of subjects Data (mean, SD )
Pre- Post Difference, [CI]
Intervention
Placebo
Intervention Placebo Pre-treatment
Post treatment
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
unspecified narcolepsy
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
unspecified narcolepsy
Study Study Design Study duration
No. of subjects Data (mean, SD)
% difference in cataplexy reduction
Intervention
Placebo
Pts. on
modafinil
Pts on place
bo
Baseline Post treatment (% mean reduction)
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
Outcome: DISEASE SEVERITY
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
No. of subjects Intervention Placebo
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
Outcome: QUALITY OF LIFE
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
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
Becker 2004
Observational; open label
6 weeks 151 123 44.5 ± 6.6 46.8 ± 11.2 N/A N/A 2.30 [0.06, 4.54]
Mitler 2000
Observational; open label
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
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
Becker 2004
Observational; open label
6 weeks 151 123 41.4 ± 11.8 45.8 ± 12.3 N/A N/A 4.40 [1.52, 7.28]
Mitler 2000
Observational; open label
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
unspecified narcolepsy
Table S22. SF-36 Vitality score determined Fatigue in observational studies, in response to Modafinil (various doses) in adult
patients with 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
Becker 2002
Observational; open label
6 weeks 151 123 27.9 ± 20.4 47.4 ± 24.9 N/A N/A 19.50 [14.03, 24.97]
Mitler 2000
Observational; open label
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)
Outcomes [Tool] Quality of the evidence
(GRADE)
Absolute Difference
Modafinil vs Placebo or Pre- Post difference
No of Participants
(studies)
Excessive daytime sleepiness *
[Epworth Sleepiness Scale]
⊕⊕⊕◯
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
Excessive daytime sleepiness *
[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
Excessive daytime sleepiness *
[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
Outcome: EXCESSIVE DAYTIME SLEEPINESS
Table S24. MWT determined excessive daytime sleepiness, in response to nap therapy in adult patients with 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
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)
Outcomes [Tool] Quality of the
evidence
(GRADE)
Absolute Difference
Naps Pre- Post difference
No of
Participants
(studies)
Excessive Daytime Sleepiness*
[Maintenance of Wakefulness Test]
⊕◯◯◯
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
* 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: 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
No. of subjects Data (mean, SD)
% difference in cataplexy reduction
Intervention
Placebo
Pts. on pitolisant
Pts on placebo
Baseline Post treatment (% mean reduction)
Baseline Post treatment (% mean reduction)
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
No. of subjects Data (mean, SD)
% difference in cataplexy reduction
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
Outcome: DISEASE SEVERITY
Figure S16. CGI- c; targeting cataplexy determined disease severity in an RCT, in response to Pitolisant (various doses) in adult
patients with unspecified narcolepsy
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)
Outcomes [Tool] Quality of the evidence
(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
Excessive daytime sleepiness*
[Maintenance of Wakefulness Test]
⊕⊕⊕◯
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
Outcome: EXCESSIVE DAYTIME SLEEPINESS
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)
Outcomes [Tool] Quality of the evidence
(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
* 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: SODIUM OXYBATE
Outcome: EXCESSIVE DAYTIME SLEEPINESS
Figure S19. ESS determined excessive daytime sleepiness, in response to sodium oxybate vs. placebo in adult patients with
unspecified narcolepsy.
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
with 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
US Xyrem Study 2003
Observational; open label
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.
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
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.
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
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
with 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
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
unspecified narcolepsy.
Table S34. MWT determined excessive daytime sleepiness in an observational study, in response to sodium oxybate in adult
patients with NT1.
Study Study Design Study
duration
No. of subjects Data (mean, SD)
Pre- Post Difference, [CI] Intervention
Comparator
v. June 15, 2020
Pre Post Pre-treatment
Post treatment Pre-treatment
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
No. of subjects Data (mean, SD)
% difference in cataplexy reduction
Intervention
Placebo
Pts. on SO
Pts on placebo
Baseline Post treatment (% mean reduction)
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.
Study Study Design Study
duration
No. of subjects Data (mean, SD)
Pre- Post Difference, [CI] (% difference in cataplexy
reduction)
Intervention
Comparator
Pre Post Pre-treatment
Post treatment Pre-treatment
Post treatment
US Xyrem Study 2003 (SLEEP)
Observational; open label
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.
Study Study Design Study
duration
No. of subjects Data (mean, SD)
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%
Outcome: DISEASE SEVERITY
Table S38. CGI determined disease severity in response to sodium oxybate (various doses) in an RCT in adult patients with
unspecified narcolepsy.
Study Study Design
Study duration
No. of subjects Intervention Placebo
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%
Outcome: QUALITY OF LIFE
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.
Study Study Design Study
duration
No. of subjects Data (mean, SD)
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.
Study Study Design Study
duration
No. of subjects Data (mean, SD)
Pre- Post Difference, [CI] Intervention
Placebo
Post intervention Pre-Rx Change from baseline
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
Excessive daytime sleepiness *
[Multiple Sleep Latency Test]
⊕⊕⊕◯
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
Excessive daytime sleepiness *
[Maintenance of Wakefulness Test]
⊕⊕⊕⊕
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 *
[Short Form Health Survey (SF-36) - Mental
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
* 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: Solriamfetol (JZP-110)
Outcome: EXCESSIVE DAYTIME SLEEPINESS
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.
Study Study Design Study
duration
No. of subjects Data (mean, SD)
Mean Difference, [CI] Intervention
Placebo
Post intervention Pre-Rx Change from baseline
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.
Outcome: DISEASE SEVERITY
Table S43. CGI-C determined disease severity in RCTs, in response to solriamfetol (various doses) in adult patients with unspecified
narcolepsy.
Study Study Design Study
duration
No. of subjects Data (mean, SD)
Mean Difference Intervention
Placebo
Post intervention Pre-Rx % improvement Pre-Rx % improvement
Bogan 2015 RCT 2 weeks JZP-110- 33 Placebo- 33 (cross over study)
N/A 75.8% N/A 39.4% 36.4%
Ruoff 2016 RCT 12 weeks JZP-110- 40 Placebo- 45
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.
Study Study Design Study
duration
No. of subjects Data (mean, SD)
Mean Difference Intervention
Placebo
Post intervention Pre-Rx % improvement Pre-Rx % improvement
Ruoff 2016 RCT 12 weeks JZP-110- 40 Placebo- 45
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)
Outcomes [Tool] Quality of the
evidence
(GRADE)
Absolute Difference
Methylphenidate vs Placebo or Pre- Post difference
No of
Participants
(studies)
Excessive Daytime Sleepiness*
[Epworth Sleepiness Scale]
⊕⊕⊕◯
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
Excessive Daytime Sleepiness*
[Maintenance of Wakefulness Test]
⊕⊕⊕⊕
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
* Critical Outcome 1 Meets the clinical significance threshold 2 Does not meet the clinical significance threshold A Small sample size
Intervention: TRIAZOLAM
Outcome: EXCESSIVE DAYTIME SLEEPINESS
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
Outcomes [Tool] Quality of the
evidence
(GRADE)
Absolute Difference
Triazolam vs Placebo or Pre- Post difference
No of
Participants
(studies)
Excessive Daytime Sleepiness*
[Multiple Sleep Latency Test]
⊕⊕⊕◯
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
Excessive Daytime Sleepiness*
[Maintenance of Wakefulness Test]
⊕⊕◯◯
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.
Outcome: DISEASE SEVERITY
Table S47. Treatment response scale determined disease severity in an observational study, in response to Clarithromycin (various
doses) in adult patients with Idiopathic Hypersomnia.
Study Study Design Study
duration
No. of subjects Response Scale
Pre- Post Difference, [CI]
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
Outcome: QUALITY OF LIFE
Figure S32. SF-36 Total score determined Quality of Life 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 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.
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.
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
Outcomes [Tool] Quality of the evidence
(GRADE)
Absolute Difference
Clarithromycin vs Placebo or Pre- Post difference
No of
Participants
(studies)
Excessive daytime sleepiness*
[Epworth Sleepiness Scale]
⊕⊕⊕◯
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
Excessive daytime sleepiness*
[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
lower to 4.34 points higher] compared to placebo.
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
* 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: FLUMAZENIL
Outcome: DISEASE SEVERITY
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.
Study Study Design Study
duration
No. of subjects Response Scale
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)
Outcomes [Tool] Quality of the evidence
(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
Outcome: DISEASE SEVERITY
Table S51. Treatment response scale determined disease severity in an observational study, in response to methylphenidate
(various doses) in adult patients with Idiopathic Hypersomnia.
Study Study Design Study
duration
No. of subjects Response Scale
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)
Outcomes [Tool] Quality of the evidence
(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
* 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: MODAFINIL
Outcome: EXCESSIVE DAYTIME SLEEPINESS
Figure S36. ESS determined excessive daytime sleepiness in an RCT, in response to Modafinil (various doses) in adult patients with
Idiopathic Hypersomnia.
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.
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
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
Idiopathic Hypersomnia.
Mayer 2016 is a randomized, placebo-controlled, double-blind trial. Data obtained by personal communication.
Outcome: DISEASE SEVERITY
Figure S38. CGI determined disease severity in an RCT, in response to Modafinil (various doses) in adult patients with Idiopathic
Hypersomnia.
Mayer 2016 is a randomized, placebo-controlled, double-blind trial. Data obtained by personal communication.
Table S54. Treatment response scale determined disease severity in an observational study, in response to Modafinil (various
doses) in adult patients with Idiopathic Hypersomnia.
Study Study Design Study
duration
No. of subjects Response Scale
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
doses) in adult patients with Idiopathic Hypersomnia.
Study Study Design Study
duration
No. of subjects Response Scale
Pre- Post Difference, [CI]
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)
Outcomes [Tool] Quality of the
evidence
(GRADE)
Absolute Difference
Pre- Post differences
No of
Participants
(studies)
Excessive daytime sleepiness*
[Epworth Sleepiness Scale]
⊕⊕⊕◯
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
lower to 11.78 points higher] compared to placebo.
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
Outcome: EXCESSIVE DAYTIME SLEEPINESS
Table S57. ESS determined excessive daytime sleepiness in an observational study, in response to Pitolisant in adult patients with
Idiopathic Hypersomnia.
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
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)
Outcomes [Tool] Quality of the evidence
(GRADE)
Absolute Difference
Pre- Post differences
No of Participants
(studies)
Excessive Daytime Sleepiness*
[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
* 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: SODIUM OXYBATE
Outcome: EXCESSIVE DAYTIME SLEEPINESS
Table S59. ESS determined excessive daytime sleepiness in an observational study, in response to Sodium oxybate in adult patients
with Idiopathic Hypersomnia.
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
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
Sodium oxybate vs Placebo or Pre- Post difference
No of
Participants
(studies)
Excessive daytime sleepiness* [Epworth
Sleepiness Scale]
⊕◯◯◯
VERY LOW A
The mean ESS score pre-post difference was 2.70 points lower1 [0.43 to 4.97 points
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
Outcome: DISEASE SEVERITY
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.
Study Study Design Study
duration
No. of subjects Data (mean, SD)
Pre- Post Difference, [CI] % reduction
(means only)
Intervention
Comparator
Pre Post Pre-treatment Post treatment
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.
Study Study Design Study
duration
No. of subjects Data (mean, SD) Pre- Post
Difference, [CI] % reduction (means only)
Intervention
Comparator
Pre Post Pre-treatment
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.
Study Study Design Study
duration
No. of subjects Data (mean, SD)
Pre- Post Difference, [CI] % reduction (means only)
Intervention
Comparator
Pre Post Pre-treatment
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
Outcomes [Tool] Quality of the
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
* Critical Outcome 1 Meets the clinical significance threshold 2 Does not meet the clinical significance threshold A Small sample size
Intervention: METHYL-PREDNISOLONE
Outcome: DISEASE SEVERITY
Table S65. Mean episode duration change in an observational study, in response to IV Methyl prednisolone (IV-MP) in patients with
Kleine-Levin Syndrome.
Study Study Design Study
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.
Study Study Design Study
duration
No. of subjects Data (mean, SD)
Pre- Post Difference, [CI]
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)
Outcomes [Tool] Quality of the
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
* Critical Outcome 1 Meets the clinical significance threshold 2 Does not meet the clinical significance threshold A Small sample size
v. June 15, 2020
PICO 4a: Hypersomnia secondary to medical (including neurological) disorders
Hypersomnia secondary to Alpha-synucleinopathies
Intervention: ARMODAFINIL
Outcome: EXCESSIVE DAYTIME SLEEPINESS
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).
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
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.
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 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)
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 Scale]
⊕◯◯◯
VERY LOW B
The mean ESS score pre-post difference was 6.00 points lower1 [2.99 to 9.01 points
lower]
17 patients
(1 non-RCT) A
Excessive daytime sleepiness *
[Maintenance of Wakefulness Test]
⊕◯◯◯
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
Outcome: EXCESSIVE DAYTIME SLEEPINESS
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)
Outcomes [Tool] Quality of the evidence
(GRADE)
Absolute Difference
Pre- Post differences
No of
Participants
(studies)
Excessive Daytime Sleepiness*
[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)
Intervention: MODAFINIL
Outcome: EXCESSIVE DAYTIME SLEEPINESS
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.
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
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
Outcome: QUALITY OF LIFE
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)
Outcomes [Tool] Quality of the evidence
(GRADE)
Absolute Difference
Modafinil vs Placebo or Pre- Post difference
No of
Participants
(studies)
Excessive daytime sleepiness *
[Epworth Sleepiness Scale]
⊕⊕⊕◯
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
Excessive daytime sleepiness *
[Maintenance of Wakefulness Test]
⊕⊕⊕◯
MODERATE A, B
The mean MWT score in the Modafinil group was 1.77 minutes higher2 [ 10.24 minutes
higher to 6.70 minutes lower] compared to placebo
24 patients
(1 RCT) B
Excessive daytime sleepiness *
[Multiple Sleep Latency Test]
⊕⊕⊕◯
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)
Intervention: SODIUM OXYBATE
Outcome: EXCESSIVE DAYTIME SLEEPINESS
Figure S46. ESS determined excessive daytime sleepiness in an RCT, in response to sodium oxybate vs. placebo in adult patients
with Hypersomnia secondary to Parkinson disease.
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
with Hypersomnia secondary to Parkinson disease.
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)
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]
⊕⊕⊕◯
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
Excessive daytime sleepiness *
[Multiple Sleep Latency Test]
⊕⊕⊕◯
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
[Fatigue Severity Scale]
⊕⊕⊕◯
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
* 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)
Posttraumatic hypersomnia
Intervention: ARMODAFINIL
Outcome: EXCESSIVE DAYTIME SLEEPINESS
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)
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 Scale]
⊕⊕⊕◯
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
Excessive daytime sleepiness *
[Multiple Sleep Latency Test]
⊕⊕⊕◯
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
* 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)
Intervention: MODAFINIL
Outcome: EXCESSIVE DAYTIME SLEEPINESS
Figure S51. ESS determined excessive daytime sleepiness in an RCT, in response to Modafinil (various doses) vs. placebo in adult
patients with Hypersomnia associated with traumatic brain injury.
Figure S52. MWT determined excessive daytime sleepiness in an RCT, in response to Modafinil (various doses) vs. placebo in adult
patients with Hypersomnia associated with traumatic brain injury.
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)
Outcomes [Tool] Quality of the evidence
(GRADE)
Absolute Difference
Modafinil vs Placebo or Pre- Post difference
No of Participants
(studies)
Excessive daytime sleepiness *
[Epworth Sleepiness Scale]
⊕⊕⊕◯
MODERATE A
The mean ESS score in the Modafinil group was 3.00 points lower1 [1.19 to 4.81 points
lower] compared to placebo
20
(1 RCT) A
v. June 15, 2020
Excessive daytime sleepiness *
[Maintenance of Wakefulness Test]
⊕⊕⊕◯
MODERATE A, B
The mean MWT score in the Modafinil group was 8.00 minutes higher1 [15.08 minutes
higher to 0.92 minutes lower] compared to placebo
20
(1 RCT) A
Fatigue
[Fatigue Severity Scale]
⊕⊕⊕◯
MODERATE A, B
The mean FSS score in the Modafinil group was 0.80 points lower 1 [ 0.08 to 1.52 points
lower] compared to placebo
20
(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 one side (imprecision) B Small sample size C 95% CI crosses clinical significance threshold on both sides (high/ serious imprecision)
Genetic disorders associated with primary central nervous system somnolence
Intervention: METHYLPHENYDATE
Outcome: EXCESSIVE DAYTIME SLEEPINESS
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)
Outcomes [Tool] Quality of the evidence
(GRADE)
Absolute Difference
Modafinil vs Placebo or Pre- Post difference
No of
Participants
(studies)
Excessive daytime sleepiness *
[Epworth Sleepiness Scale]
⊕⊕⊕◯
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
* 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)
Intervention: MODAFINIL
Outcome: EXCESSIVE DAYTIME SLEEPINESS
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
Hypersomnia secondary to myotonic dystrophy.
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)
Outcomes [Tool] Quality of the evidence
(GRADE)
Absolute Difference
Modafinil vs Placebo or Pre- Post difference
No of Participants
(studies)
Excessive daytime sleepiness *
[Epworth Sleepiness Scale]
⊕⊕⊕◯
MODERATE A
The mean ESS score in the Modafinil group was 3.60 points lower1 [1.52 to 5.67 points
lower] compared to placebo.
66
(2 RCTs) A, B
Excessive daytime sleepiness *
[Maintenance of Wakefulness Test]
⊕⊕⊕◯
MODERATE A, B
The mean MWT score in the Modafinil group was 5.79 minutes higher 1 [16.23 minutes
higher to 4.64 minutes lower] compared to placebo
66
(2 RCTs) A, B
Excessive daytime sleepiness *
[Multiple Sleep Latency Test]
⊕⊕⊕◯
MODERATE A, B
The mean MSLT score in the Modafinil group was 0.26 minutes lower 2 [3.77 minutes
higher to 4.29 minutes lower] compared to placebo
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 *
[Short Form Health Survey (SF-36) - Mental
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
* 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)
Intervention: SELEGILINE
Outcome: EXCESSIVE DAYTIME SLEEPINESS
Figure S62. MSLT determined excessive daytime sleepiness in an RCT, in response to Selegiline vs. placebo in adult patients with
Hypersomnia secondary to myotonic dystrophy.
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
Outcomes [Tool] Quality of the evidence
(GRADE)
Absolute Difference
Modafinil vs Placebo or Pre- Post difference
No of Participants
(studies)
Excessive daytime sleepiness *
[Multiple Sleep Latency Test]
⊕⊕◯◯
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
* 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)
Hypersomnia secondary to brain tumors, infections, or other central nervous system lesions
Intervention: MODAFINIL
Outcome: EXCESSIVE DAYTIME SLEEPINESS
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.
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
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.
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
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)
Outcomes [Tool] Quality of the evidence
(GRADE)
Absolute Difference
Modafinil vs Placebo or Pre- Post difference
No of Participants
(studies)
Excessive daytime sleepiness *
[Epworth Sleepiness Scale]
⊕◯◯◯
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
[Fatigue Severity Scale]
⊕◯◯◯
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
* 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)
Hypersomnia secondary to endocrine disorder
Intervention: LIRAGLUTIDE
Outcome: EXCESSIVE DAYTIME SLEEPINESS
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.
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
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)
Outcomes [Tool] Quality of the evidence
(GRADE)
Absolute Difference
Modafinil vs Placebo or Pre- Post difference
No of Participants
(studies)
Excessive daytime sleepiness *
[Epworth Sleepiness Scale]
⊕◯◯◯
VERY LOW A
The mean ESS score pre-post difference was 1.50 points lower2 [0.61 to 2.39 points
lower]
158
(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)
PICO 4b: Hypersomnia secondary to a psychiatric disorder Intervention: LIGHT THERAPY
Outcome: EXCESSIVE DAYTIME SLEEPINESS
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.
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
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)
Outcomes [Tool] Quality of the evidence
(GRADE)
Absolute Difference
Pre- Post differences
No of Participants
(studies)
Excessive daytime sleepiness*
[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
Intervention: MODAFINIL
Outcome: EXCESSIVE DAYTIME SLEEPINESS
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.
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
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.
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
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)
Outcomes [Tool] Quality of the evidence
(GRADE)
Absolute Difference
Modafinil vs Placebo or Pre- Post difference
No of
Participants
(studies)
Excessive daytime sleepiness *
[Epworth Sleepiness Scale]
⊕⊕⊕◯
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
[Fatigue Severity Scale]
⊕⊕⊕◯
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
* 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
v. June 15, 2020
SIDE EFFECT DATA IN ADULT POPULATIONS
Intervention: ARMODAFINIL
Figure S65. Meta-analysis of data for the occurrence of headache in response to Armodafinil (various doses).
Intervention: MODAFINIL
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
Intervention: SODIUM OXYBATE
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
Outcome: EXCESSIVE DAYTIME SLEEPINESS
Table S92. ESS determined excessive daytime sleepiness in an observational study, in response to Modafinil (various doses) in
pediatric patients with Narcolepsy 1.
Study Study Design Study
duration
No. of subjects Data (mean, SD) Pre- Post Difference,
[CI] Intervention
Comparator
v. June 15, 2020
Pre Post Pre-treatment Post treatment
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
pediatric patients with Narcolepsy 1.
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
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]]
Outcome: DISEASE SEVERITY
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
No. of subjects Intervention Placebo
Improvement
(points) Pre Post Pre-
treatment
Post
treatment
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
Modafinil vs Placebo or Pre- Post difference
No of Participants
(studies)
Excessive daytime sleepiness *
[Epworth Sleepiness Scale]
⊕◯◯◯
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
Excessive daytime sleepiness *
[Multiple Sleep Latency Test]
⊕◯◯◯
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
* 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: SODIUM OXYBATE
Outcome: EXCESSIVE DAYTIME SLEEPINESS
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
pediatric patients with Narcolepsy 1.
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
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.
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
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.
Study Study Design Study duration
No. of subjects Data (mean, SD)
% difference in cataplexy reduction
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
pediatric patients with Narcolepsy 1.
Study Study Design Study
duration
No. of subjects Data (mean, SD) % difference in mean cataplexy reduction
Intervention
Comparator
v. June 15, 2020
Pre Post Pre-treatment
Post treatment Pre-treatment
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.
Study Study Design Study
duration
No. of subjects Data (mean, SD)
% difference in mean cataplexy reduction
Intervention
Comparator
Pre Post Pre-treatment
Post treatment Pre-treatment
Post treatment
Huang 2009 Observational 3 months 13 13 3.9 ± 1.3 0.2 ± 0.8 N/A N/A 94.8%
Outcome: DISEASE SEVERITY
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
Modafinil vs Placebo or Pre- Post 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
Excessive daytime sleepiness *
[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
Excessive daytime sleepiness *
[Multiple Sleep Latency Test]
⊕◯◯◯
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
* Critical Outcome 1 Meets the clinical significance threshold 2 Does not meet the clinical significance threshold A Small sample size
Intervention: IV IMMUNOGLOBULIN
Outcome: DISEASE SEVERITY
Table S102. CGI-S determined disease severity in an observational study, in response to IVIG in pediatric patients with Narcolepsy 1.
Study Study Design Study
duration
No. of subjects Data (mean, SD)
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)
Outcomes [Tool] Quality of the
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
* Critical Outcome 1 Meets the clinical significance threshold 2 Does not meet the clinical significance threshold A Small sample size