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, m) H3 receptor inverse agonist (Pitolisant) Valproic acid) n) Macrolide (Clarithromycin) b) Antimanic Agent (Lithium Carbonate) o) Monoamine oxidase inhibitors/B (Selegiline) c) Anti-Parkinson Agent (Amantadine) p) Norepinephrine Reuptake Inhibitor (Atomoxetine) d) Antipsychotic (Risperidone) q) Selective dopamine and norepinephrine reuptake e) Benzodiazepine receptor agonists (Eszopiclone, inhibitor (Solriamfetol [JZP-110]) Zaleplon, Zolpidem) r) Selective serotonin reuptake inhibitors (Citalopram, f) Benzodiazepine receptor antagonist (Flumazenil) Escitalopram, Fluoxetine, Paroxetine, Sertraline) g) Benzodiazepines (Temazepam, Triazolam) s) Serotonin/Norepinephrine Reuptake Inhibitor h) Central Nervous System Depressant (Sodium (Venlafaxine) oxybate) t) Skeletal Muscle Relaxant (R-baclofen/ baclofen) i) Central Nervous System Stimulant (Amphetamines u) Thyroid Product (Levothyroxine) and related preparations, Armodafinil, v) Tricyclic antidepressants (Amitriptyline, Amoxapine, Methylphenidate and related preparations, Clomipramine, Doxepin, Imipramine, Maprotiline, Modafinil) Nortriptyline, Trimipramine) j) Combination therapy k) Dietary Supplement (L-carnitine) l) Dietary Supplement (L-carnitine)
Behavioral therapy a) Exercise d) Supportive care b) Scheduled naps/sleep extension e) Trigger avoidance c) Sleep hygiene
Immunotherapy
a) Intravenous immunoglobulin c) Steroids b) Plasmapheresis
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. No. of subjects Data (mean, SD) Intervention Comparator Study Study Study Design Pre- Post Difference, [CI] duration Pre Post Pre-treatment Post Pre- Post treatment treatment treatment Schwartz Open-label, 12 months 49 28 16.3 (3.5) Not provided N/A N/A -4.7 (−7.41, −1.93)* 2010 flexible-dose study *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 No. of subjects Data (mean, SD) Armodafinil Placebo Study Pre-Post Study Study Design Armodafinil Placebo Pre-treatment Change Pre- Change duration difference (CI) (pooled) from treatment from baseline baseline Harsh Multicenter 12 weeks 118 58 11.22 ± 6.52 1.75 ± 5.43 12.5 ± 6.6 -1.56 ± 7.62 3.31 (1.12- 2006 double-blind study 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. No. of subjects Data (mean, SD) Study Intervention Placebo Study Study Design Mean Difference duration Post intervention Pre-Rx % improvement Pre-Rx % improvement Harsh 2006 RCT 12 weeks Armodafinil- 132 N/A 71% N/A 33% 38% Placebo- 64
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. No. of subjects Data (mean, SD) Study Intervention Placebo Mean Difference Study Study Design duration (reduction) Post intervention Pre-Rx Post Rx Pre-Rx Post Rx Harsh 2006 RCT 12 weeks Armodafinil- 132 N/A 36.5% N/A 10% 26.5% Placebo- 64
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 No. of subjects Data (mean, SD) Intervention Placebo Mean difference Study Study Study Design (% difference in duration Post intervention Pre-Rx Post Rx (% Pre-Rx Post Rx (% improvement (%) improvement) (%) improvement) Harsh 2006 RCT 12 weeks Armodafinil- 131 81.3 ± 83.4 ±12.3 81.3 80.9 ± 12.7 2.50 [-1.28, 6.28] Placebo- 63 12.8 (2.1%) ±12.8 (-0.4%) 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 Absolute Difference No of (GRADE) Participants Armodafinil vs Placebo or Pre- Post difference (studies) Excessive daytime sleepiness* ⊕◯◯◯ The mean ESS score pre-post difference was 4.70 points lower1 [1.93 to 7.41 points 28 [Epworth Sleepiness Score] VERY LOW B lower]. (1 non-RCT) B Excessive daytime sleepiness* ⊕⊕⊕◯ The mean change from baseline in the MWT score in the Armodafinil group was an 176 [Maintenance of Wakefulness Test] MODERATE A estimated 3.31 minutes higher1 [1.12 min to 5.50 min higher] compared to placebo. (1 RCT) A Disease severity* ⊕⊕⊕⊕ The mean in % improvement in CGI-c scores in the armodafinil group was 38%.when 196 (CGI-C scores) HIGH compared to placebo. (1 RCT) A ⊕⊕⊕⊕ The mean reduction in number of patients reporting mistakes/accidents was 26.5% in 118 Accident risk HIGH the armodafinil group.1 (1 RCT) A Fatigue ⊕⊕⊕◯ The mean BFI score in the Armodafinil group was 1.10 points lower1 [1.72 points to 0.48 176 [Brief Fatigue Inventory] MODERATE A points lower] compared to placebo. (1 RCT) A Sleep Quality ⊕⊕⊕⊕ The % improvement in sleep efficiency in the armodafinil group was 2.5 % when 194 [Sleep efficiency] HIGH compared to placebo. (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 No. of subjects Data (mean, SD) Intervention Comparator Study Study Study Design Pre- Post Difference, [CI] duration Pre Post Pre-treatment Post Pre- Post treatment treatment treatment v. June 15, 2020
Chen Observational 16 16 18.9±3.7 15.7± 5.2 N/A N/A -3.20 [-6.33, -0.07] 1995
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 Absolute Difference No of (GRADE) Participants Armodafinil vs Placebo or Pre- Post difference (studies) Excessive daytime sleepiness* ⊕◯◯◯ The mean ESS score pre-post difference was 3.2 points lower1 [0.07 to 6.33 points 16 [Epworth Sleepiness Scale] VERY LOW B lower]. (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 No. of subjects Data (mean, SD) Intervention Comparator Study Study Study Design Pre- Post Difference, [CI] duration Pre Post Pre-treatment Post Pre- Post treatment treatment treatment Chen Observational Unspecified 60 60 20.1 ± 2.7 15.1 ± 5.6 N/A N/A -5.00 [-6.57, -3.43] 1995
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 No. of subjects Data (mean, SD) Intervention Comparator Study Study Study Design Pre- Post Difference, [CI] duration Pre Post Pre-treatment Post Pre- Post treatment treatment treatment Shindler1 Observational 4 weeks 20 20 2.1 ± 2.68 1.4 ± 4.2 N/A N/A 0.70 [-1.48, 2.88] 985
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 Absolute Difference No of evidence Participants (GRADE) Dexamphetamine vs Placebo or Pre- Post difference (studies) Excessive Daytime Sleepiness* ⊕◯◯◯ The mean pre-post difference in ESS in adult patients on dextroamphetamine was 5.0 60 patients [Epworth Sleepiness Scale] VERY LOW A points lower1 [ 3.43 points to 6.57 points lower] (1 non-RCT) B Cataplexy* ⊕ ◯◯◯ The mean pre-post % difference in the daily cataplexy rate was 33%1 20 patients [Episodes per day] VERY LOW A (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 Absolute Difference No of evidence Participants (GRADE) L-Carnitine vs Placebo or Pre- Post difference (studies) Excessive Daytime Sleepiness* ⊕⊕⊕ ◯ The mean ESS score in the L-Carnitine group was 0.00 points higher2 [1.96 lower to 28 patients [Epworth Sleepiness Scale] MODERATE A 1.96 points higher] compared to placebo (1 RCT) A Quality of life * ⊕⊕⊕◯ The mean SF-36 Mental health scores in Narcolepsy Type 1 patients in the L-carnitine 28 patients [Short Form Health Survey (SF-36) - mental MODERATE A group was 0.50 points higher [3.46 points lower to 4.46 points higher] compared to (1 RCT) A component score] placebo2 Fatigue [Short ⊕⊕⊕◯ The mean SF-36 energy/vitality component score in the L-Carnitine group was 2.00 28 patients Form Health Survey (SF-36) - Energy and vitality MODERATE A points higher [3.50 points lower to 7.50 points higher] compared to placebo2 (1 RCT) A component] * 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 No. of subjects Intervention Placebo duration Study Study Design Improvement Pre Post Pre- Post Pre-treatment Post treatment treatment treatment
Reinish 1994 Observational- 4-300 wks 11 11 N/A N/A N/A N/A 89.7% prospective cohort
*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 Absolute Difference No of evidence Participants (GRADE) Methylphenidate vs Placebo or Pre- Post difference (studies) Disease Severity* ⊕◯◯◯ A marked improvement on the GIR was noted in 89.7% of the patients in response 11 patients [Treatment rating scale] VERY LOW A to methylphenidate. (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. No. of subjects Data (mean, SD) Intervention Comparator Study Study Study Design Pre- Post Difference, [CI] duration Pre Post Pre-treatment Post Pre- Post treatment treatment treatment Lavault Cross-sectional N/A 68 110 17.1 ± 4.2 14.9 ± 4.9 N/A N/A -2.20[-3.55, -0.85] 2011 study
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 No. of subjects Data (mean, SD) Intervention Comparator Study Study Study Design Pre- Post Difference, [CI] duration Pre Post Pre-treatment Post Pre- Post treatment treatment treatment Mitler 2000 Observational; 40 weeks 471 471 16.5 ± 4.34 12.4 ± 4.34 N/A N/A -4.10 [-4.65, -3.55] open label
Schwartz Observational; 6 weeks 123 123 12.7 ± 5.5 11.8 ± 5.5 N/A N/A -0.90 [-2.27, 0.47] 2003 open label
Thorpy Observational; 5 weeks 40 38 Not provided 9.79 ± 4.94 N/A N/A - 2003 open label
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. No. of subjects Data (mean, SD ) Intervention Placebo Study Pre- Post Study Study Design duration Difference, [CI] Intervention Placebo Pre- Post Pre-treatment Post treatment treatment treatment Billiard Double-blind cross- 12 weeks 43 43 - 9.05 ± 6.56 - 6.96 ± 5.25 2.09 [-0.42, 1994 over design 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 No. of subjects Data (mean, SD)
Intervention Placebo % difference in Study Study Study Design cataplexy duration Pts. Pts on Baseline Post treatment (% Baseline Post treatment (% reduction on place mean reduction) mean reduction) modaf bo inil Dauvilliers RCT 4 weeks 23 14 0.4 ± 0.6 0.26 ± 0.5 0·43 ± 0·7 0.39 ± 0.6 25% 2013 (35%)* (10%)*
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 No. of subjects Intervention Placebo Study Study Study duratio Improvement Design n Intervention Placebo Pre- Post Pre-treatment Post treatment treatment treatment US Modafinil in RCT 9 weeks 191 92 - - - - 72 % Narcolepsy Multicenter Study Group 1998 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 No. of subjects Data (mean, SD) Intervention Comparator Study Study Study Design Pre- Post Difference, [CI] duration Pre Post Pre-treatment Post Pre- Post treatment treatment treatment Becker Observational; open 6 weeks 151 123 44.5 ± 6.6 46.8 ± 11.2 N/A N/A 2.30 [0.06, 4.54] 2004 label
Mitler Observational; open 40 weeks 432 473 45.5 ± 10.39 46.8 ± 10.87 N/A N/A 1.30 [-0.09, 2.69] 2000 label
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 No. of subjects Data (mean, SD) Intervention Comparator Study Study Study Design Pre- Post Difference, [CI] duration Pre Post Pre-treatment Post Pre- Post treatment treatment treatment Becker Observational; open 6 weeks 151 123 41.4 ± 11.8 45.8 ± 12.3 N/A N/A 4.40 [1.52, 7.28] 2004 label
Mitler Observational; open 40 weeks 432 473 42.4 ± 12.47 45.4 ± 10.87 N/A N/A 3.00 [1.47, 4.53] 2000 label
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 No. of subjects Data (mean, SD) Intervention Comparator Study Study Study Design Pre- Post Difference, [CI] duration Pre Post Pre-treatment Post Pre- Post treatment treatment treatment Becker Observational; open 6 weeks 151 123 27.9 ± 20.4 47.4 ± 24.9 N/A N/A 19.50 [14.03, 24.97] 2002 label
Mitler Observational; open 40 weeks 447 473 32.6 ± 23.26 45.6 ± 23.92 N/A N/A 13.00 [9.95, 16.05] 2000 label
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 Absolute Difference No of Participants (GRADE) (studies) Modafinil vs Placebo or Pre- Post difference ⊕⊕⊕◯ The mean ESS score in NT1 patients on Modafinil was 10.30 points lower1 [7.95 to 19 MODERATE A,B 12.65 points lower] compared to placebo (1 RCT)A ⊕◯◯◯ The mean ESS score pre-post difference in NT1 patients was 2.201 points lower1 [0.85 to 68 Excessive daytime sleepiness * VERY LOW B 3.5 points lower] (1 non-RCT) B [Epworth Sleepiness Scale] ⊕⊕⊕⊕ The mean ESS score in patients with unspecified narcolepsy on Modafinil was 2.77 861 HIGH points lower1 [1.73 to 3.80 points lower] compared to placebo 7 RCTs)C,E,F,G,H,I, M ⊕◯◯◯ The mean ESS score pre-post difference in patients with unspecified narcolepsy ranged 594 VERY LOW C from 0.92 to 4.10 points lower1. 2 non-RCTs)J,K Excessive daytime sleepiness * ⊕⊕⊕⊕ The mean MWT score in the Modafinil group was 4.14 minutes higher1 [3.44 min to 4.84 858 patients [Maintenance of Wakefulness Test] HIGH min higher] compared to placebo (7 RCTs)C, E,F,G,H,I,M v. June 15, 2020
⊕⊕⊕◯ The estimated mean MWT score in the Modafinil group was 2.09 minutes higher1 [0.42 43 MODERATEB min lower to 4.60 min higher] compared to placebo (1 RCT)D Excessive daytime sleepiness * ⊕⊕⊕◯ The mean MSLT score in unspecified narcolepsy patients on Modafinil was 1.58 minutes 526 patients [Multiple Sleep Latency Test] MODERATE A lower1 [0.92 min to 2.24 mins lower] compared to placebo (2 RCT)C,G Cataplexy* ⊕⊕⊕◯ The mean number of daily cataplexy episodes in NT1 patients on Modafinil was 0.10 46 patients [# daily episodes] MODERATE B episodes lower [0.34 episodes lower to 0.14 episodes higher] compared to placebo. (1 RCTs)C Cataplexy* ⊕⊕⊕◯ The mean daily cataplexy frequency in unspecified narcolepsy patients on Modafinil was 63 patients [[# daily episodes] MODERATE B 0.13 points lower [0.40 points lower to 0.14 points higher] compared to placebo (1 RCT)E ⊕⊕⊕◯ The disease severity in NT 1 patients was 0.29 points lower2 [3.40 points lower to 2.82 45 patients Disease severity* MODERATE A,B points higher] compared to placebo (1 RCT)C [Clinical Global Index (CGI)] ⊕⊕⊕◯ The percentage of patients with unspecified narcolepsy reporting reduction in disease 464 patients MODERATE C severity ranged from 19% to 72%1 (3 RCTs)E,M, P ⊕⊕⊕⊕ The physical health summary component in unspecified narcolepsy patients was 0.5 481 patients HIGH points higher2 (95% CI: 2.23 points higher to 1.23 points lower) compared to placebo (1 RCT)N Quality of life * [Short Form Health Survey (SF-36) - Physical component score] ⊕⊕◯◯ The mean SF-36 physical health summary component pre-post difference ranged from 596 patients LOW 1.3 to 2.3 points higher. (2 non RCTs)J, O
⊕⊕⊕◯ The mental health summary component demonstrated mean difference of 3.49 points1 481 patients N Quality of life * MODERATE A higher (95% CI: 1.76 points to 5.22 points higher) compared to placebo (1 RCT) [Short Form Health Survey (SF-36) - Mental component score] ⊕⊕◯◯ The mean SF-36 mental health summary component pre-post difference ranged from 596 patients LOW 3.0 to 4.40 points higher. (2 non RCTs)J, O
Fatigue ⊕⊕⊕⊕ The mean SF-36- energy and vitality component in the modafinil group demonstrated 481 patients [Short Form Health Survey (SF-36) - Energy HIGH 7.98 points higher1 (4.31 to 11.65 points higher) compared to placebo (1 RCT)N and vitality component] ⊕⊕◯◯ The mean pre-post difference on the SF-36 vitality score ranged from 13.0 to 19.50 LOW 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 No. of subjects Data (mean, SD) Intervention Comparator Study Study Study Design Pre- Post Difference, [CI] duration Pre Post Pre-treatment Post Pre- Post treatment treatment treatment Rogers Observational 1 month 16 16 7.4 ± 6.0 10.0 ± 5.8 NA NA 2.60 [-1.49, 6.69] 1993
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 Absolute Difference No of evidence Participants (GRADE) Naps Pre- Post difference (studies) Excessive Daytime Sleepiness* ⊕ ◯◯◯ The mean MWT pre-post difference in the Naps group was 2.60 minutes higher1 [1.49 16 patients [Maintenance of Wakefulness Test] VERY LOW A,B minutes lower to 6.69 minutes higher]. (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. No. of subjects Data (mean, SD) Intervention Placebo Study Study % difference in Study Design duration Pts. on Pts on Baseline Post treatment Baseline Post treatment cataplexy reduction pitolisant placebo (% mean (% mean reduction) reduction) Dauvielliers RCT 4 weeks 23 14 0·52 ± 0·6 0·18 ± 0·4 0·43 ± 0·7 0.39 ± 0.6 56.06% 2013 (65.38 %)* (9.3%)*
*[(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. No. of subjects Data (mean, SD) Intervention Placebo Study Study % difference in Study Design duration Pts. on Pts on Baseline** Post treatment** Baseline Post treatment cataplexy reduction pitolisant placebo (% mean (% mean reduction) 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 Absolute Difference No of Participants (GRADE) (studies) Pitolisant vs Placebo Excessive daytime sleepiness* [Epworth ⊕⊕⊕◯ The mean ESS score in the Pitolisant group in patients with unspecified narcolepsy was 61 Sleepiness Scale] MODERATE A 3.6 points lower1 [6.27 to 0.93 points lower] compared to placebo. (1 RCT) A v. June 15, 2020
⊕⊕⊕⊕ The mean ESS score in the Pitolisant group in patients with NT1 was 3.75 points lower1 126 HIGH [5.46 to 2.04 points lower] compared to placebo. (2 RCTs) B ,C ⊕⊕⊕◯ The mean MWT score in the Pitolisant group was 2.10 minutes higher1 [0.64 to 3.65 61 Excessive daytime sleepiness* MODERATE A, B minutes lower] compared to placebo. (1 RCT) A [Maintenance of Wakefulness Test] ⊕⊕⊕◯ The mean MWT score in the Pitolisant group in patients with NT1 was 4.3 minutes 108 MODERATE A higher1 [9.05 minutes higher to 0.45 minutes lower] compared to placebo. (1 RCT) C Cataplexy* ⊕⊕⊕◯ The mean reduction in daily cataplexy rates in the pitolisant group was 65.38% 37 [Daily Cataplexy rate] MODERATE B compared to 9.3% in the placebo group. There was a reduction of 56.06%.1 (1 RCT) A Cataplexy* ⊕⊕⊕⊕ The mean reduction in weekly cataplexy rates in the pitolisant group was 75% compared 105 [Weekly Cataplexy rate] HIGH to 38% in the placebo group. There was a % difference in weekly cataplexy reduction of (1 RCT) C 37.03%.1 ⊕⊕⊕◯ The mean CGI-C score in the pitolisant group in patients with unspecified narcolepsy 51 Disease severity* MODERATE A was 0.5 points lower1 [1.3 points lower to 0.3 points higher] when compared to placebo. (1 RCT) A CGI-Cataplexy ⊕⊕⊕⊕ The mean CGI-C score in the pitolisant group in patients with NT 1 was 0.9 points 100 HIGH lower1 [1.33 to 0.47 points lower ] when compared to placebo. (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 Absolute Difference No of (GRADE) Participants Selegiline vs Placebo or Post-treatment values (studies) Excessive daytime sleepiness* ⊕⊕⊕◯ The mean MSLT score in the Selegiline group was 1.42 minutes higher1 [2.95 minutes 30 [Mean Sleep Latency Test] MODERATE A higher to 0.11 minutes lower] compared to placebo (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. No. of subjects Data (mean, SD) Intervention Comparator Study Study Study Design Pre- Post Difference, [CI] duration Pre Post Pre- Post treatment Pre- Post treatment treatment treatment US Xyrem Observational; 12 months 74 74 17.35 ± 3.22 11.5 ± 5.03 N/A N/A -5.85 [-7.21, -4.49] Study 2003 open label 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. No. of subjects Data (mean, SD) Intervention Comparator Study Study Study Design Pre- Post Difference, [CI] duration Pre Post Pre- Post treatment Pre- Post treatment treatment treatment Leu- Observational N/A 39 22 17.7 ± 3.7 13.9 ± 5.0 N/A N/A -3.8[-6.19.-1.41] Semenescu 2016 Poryazova Observational N/A 13 13 17.8 ± 1 13.9 ± 1.2 N/A N/A -3.90[-4.69, -3.09] 2011
Mamelak Observational 10 weeks 20 20 20 14 - - -6.0 [unknown] 2004
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. No. of subjects Data (mean, SD) Intervention Comparator Study Study Study Design Pre- Post Difference, [CI] duration Pre Post Pre- Post treatment Pre- Post treatment treatment treatment Poryazova Observational N/A 13 13 2 ± 1.5 2.4 ± 2.6 N/A N/A 2011 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. No. of subjects Data (mean, SD) Intervention Comparator Study Study Study Design Pre- Post Difference, [CI] duration Pre Post Pre-treatment Post Pre- Post treatment treatment treatment Scharf Observational cohort 4 weeks 30 30 3.7 ± 2.91 5.22 ± 4.24 N/A N/A 1.52 [3.36, -0.32] 1985
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. No. of subjects Data (mean, SD) Study Study Study Design Intervention Comparator Pre- Post Difference, [CI] duration
v. June 15, 2020
Pre Post Pre- Post treatment Pre- Post treatment treatment treatment Poryazova Observational N/A 13 13 5.5 ± 4.5 17.4 ± 8.9 N/A N/A 11.90 [6.48, 17.32] 2011 Mamelak Observational 10 weeks 20 20 4.5 10.6 N/A N/A 6.1[3.12, 9.08] 2004 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. No. of subjects Data (mean, SD) Intervention Placebo Study Study % difference in Study Design duration Pts. on Pts on Baseline Post treatment (% Baseline Post treatment cataplexy reduction SO placebo mean reduction) (% mean reduction) US Xyrem 2002 RCT 4 weeks 97 33 32.67± 36.68 19.39 ± 36.0 (40.64 35.1± 47.1 24.0 ± 28.4 9.04% (SLEEP) ( all %)* (31.6%)* doses) Xyrem RCT 8 weeks 169 58 36.66 ± 61.60 18.35 ± 53.21 35.01 ± 20.75 ± 19.63 9.17% International (49.9%) 51.80 (40.73%) 2005(Sleep Medicine) 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. No. of subjects Data (mean, SD) Intervention Comparator Pre- Post Difference, [CI] Study Study Study Design (% difference in cataplexy duration Pre Post Pre- Post treatment Pre- Post reduction) treatment treatment treatment US Xyrem Observational; 12 months 75 75 41.08 ± 5.6 ± 8.86 N/A N/A -35.48 [-46.26, -24.70] Study 2003 open label 46.81 (86.36%) (SLEEP)
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. No. of subjects Data (mean, SD) On Sodium oxybate Off Sodium oxybate Study Pre- Post Difference, [CI] Study Study Design duratio Placebo SO Pre- Post Pre- Post- (% difference in cataplexy n withdrawal withdrawal withdrawal withdrawal increase) (% mean (% mean increase) increase) US Xyrem Double-blind 2 weeks 29 26 9.9 ± 21.4 12.8 ± 33.5 15.8 ± 39.9 46.4 ± 73.8 SO: 2.90 [-12.38, 18.18] Multicenter withdrawal (29.29%) (193.67%) Placebo: 30.60 [0.07, 61.13] Study group Study 164% 2004
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. No. of subjects Intervention Placebo Study Study Study Improvement Design duration Intervention Placebo Pre- Post Pre-treatment Post treatment treatment treatment The U.S. Xyrem RCT 4 weeks 102 34 - - - - Average of 58% in Multicenter Study the SO (all doses) Group group 2002{SLEEP} 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. No. of subjects Data (mean, SD) Intervention Placebo Study Study Study Design Mean Difference, [CI] duration Pre Post Pre-Rx Change from Pre-Rx Change from baseline 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. No. of subjects Data (mean, SD) Intervention Placebo Study Study Study Design Pre- Post Difference, [CI] duration Post intervention Pre-Rx Change from Pre-Rx Change from baseline baseline Bogan 2016 RCT 8 weeks Placebo- 58 4.5 g- 5.4± 1.0 2.2 ± 1.0 5.88 [3.73, 8.03] 4.5g- 64 6.0 g- 6.7 ± 1.2 6.0 g-58 9.0 g-9.8 ± 1.8 9.0g-47 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 Quality of the evidence Absolute Difference No of [Tool] (GRADE) Participants Sodium oxybate vs Placebo or Pre- Post difference (studies) ⊕◯◯◯ The mean ESS score range of pre-post differences in NT 1 patients on SO was 3.8 to 35 patients VERY LOW B 3.9 points lower1. (2 non-RCT)A,B ⊕◯◯◯ The mean ESS score range of pre-post differences in patients with unspecified 74 patients Excessive daytime sleepiness * [Epworth VERY LOW B narcolepsy on SO was 5.85 points lower1 [4.49 to 7.21 points lower]. (1 non-RCT)G Sleepiness Scale] ⊕⊕⊕◯ The mean ESS score in unspecified Narcolepsy patients on SO was 3.30 points lower 102 patients MODERATE [1.16 points to 5.44 points lower] (1 RCT)F ⊕⊕⊕⊕ The mean ESS score in NT 1 patients on SO was 1.47 points lower2 [2.38 points to 0.56 339 patients HIGH points lower] (2 RCT)J, K v. June 15, 2020
⊕⊕⊕◯ The mean MSLT score in patients with unspecified narcolepsy on SO was 0.70 minutes 10 patients MODERATE B lower2 [1.81 min lower to 0.41 mins higher] compared to placebo (1 RCT)C Excessive daytime sleepiness * ⊕◯◯◯ The mean MSLT score pre-post difference in NT1 patients was 0.40 points lower2 [0.39 13 patients [Multiple Sleep Latency Test] VERY LOW B to 2.01 points lower] (1 non-RCT)B ⊕◯◯◯ The mean MSLT score pre-post difference in patients with unspecified narcolepsy was 30 patients VERY LOW B 1.52 points lower1 [0.32 points lower] to 3.36 points higher] (1 non-RCT)D ⊕⊕⊕⊕ The mean MWT score in unspecified narcolepsy patients on SO was 5.10 points higher1 102 patients HIGH [2.47 to 7.73 points higher] (1 RCT)F Excessive daytime sleepiness * ⊕⊕⊕⊕ The mean MWT score in NT1 patients on SO was 3.80 points higher1 [1.16 to 6.44 213 patients [Maintenance of Wakefulness Test] HIGH points higher] (1 RCT)J ⊕◯◯◯ The mean MWT score pre-post difference ranged from 6.1 to 11.9 minutes higher1 in 33 patients VERY LOW B NT1 patients. (2 non-RCTs)D,E ⊕⊕⊕⊕ The percentage difference in weekly cataplexy episodes ranged from 9.04% to 9.17% in 357 patients HIGH patients with narcolepsy when compared with placebo. (2 RCTs)J, K ⊕⊕⊕ The percentage difference in weekly cataplexy episodes in the withdrawn group showed 55 patients Cataplexy* ◯ B a 164.38% increase in weekly cataplexy rate of when compared with patients who (1 RCT) L [# Weekly episodes] MODERATE continued on SXB. ⊕◯◯◯ The pre-post percentage reduction in weekly cataplexy episodes was 86.36% 75 patients VERY LOW B (1 non-RCT)G Disease severity* ⊕⊕⊕⊕ The percentage of patients reporting (much and very much) improvement in CGI scores 241 patients [Clinical Global Index (CGI)] HIGH ranged from 48% to 58%. (2 RCTs)F,G Quality of life * ⊕⊕⊕◯ The mean change from baseline SF-36 Physical Summary Scores in NT1 patients on 106 patients [Short Form Health Survey (SF-36) - MODERATE A SO was 4.80 points higher [1.76 points to 7.84 points higher] compared to placebo1 (1 RCT)H Physical component score] Quality of life * ⊕⊕⊕◯ The mean change from baseline SF-36 Mental Summary Scores in NT1 patients on SO 116 patients [Short Form Health Survey (SF-36) - Mental MODERATE A was 2.8 points higher [1.44 points lower to 7.04 points higher] compared to placebo2 (1 RCT)H component score] Fatigue ⊕⊕⊕⊕ The mean SF-36 Vitality domain score pre-post difference in NT1 patients was 5.88 163 patients [SF-36 Vitality domain] HIGH points higher [3.73 points to 8.03 points higher] (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. No. of subjects Data (mean, SD) Intervention Placebo Study Study Study Design Mean Difference, [CI] duration Post intervention Pre-Rx Change from Pre-Rx Change from baseline baseline Ruoff 2016 RCT 12 weeks JZP-110- 40 N/A -8.7 ± 6.32 N/A -2.5 ± 3.35 -6.20 [-8.39, -4.01] Placebo- 45
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. No. of subjects Data (mean, SD) Study Intervention Placebo Study Study Design Mean Difference duration Post intervention Pre-Rx % improvement Pre-Rx % improvement Bogan 2015 RCT 2 weeks JZP-110- 33 N/A 75.8% N/A 39.4% 36.4% Placebo- 33 (cross over study)
Ruoff 2016 RCT 12 weeks JZP-110- 40 N/A 86.0% N/A 38.3% 47.7% Placebo- 45
Thorpy 2019 RCT 12 weeks JZP- 118 N/A 83.35% N/A 41.4% 41.95% Placebo- 59
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. No. of subjects Data (mean, SD) Study Intervention Placebo Study Study Design Mean Difference duration Post intervention Pre-Rx % improvement Pre-Rx % improvement Ruoff 2016 RCT 12 weeks JZP-110- 40 N/A 93.0% N/A 38.3% 54.7% Placebo- 45
Thorpy 2019 RCT 12 weeks JZP- 118 N/A *81.45% N/A 39.7% 41.75% Placebo- 59
*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 Absolute Difference No of evidence Participants (GRADE) Methylphenidate vs Placebo or Pre- Post difference (studies) ⊕⊕⊕◯ The mean change from baseline in the ESS score in the solriamfetol group was 4.3 210 patients Excessive Daytime Sleepiness* MODERATE A points lower1 [6.78 points to 1.82 points lower] compared to placebo. (2 RCTs) A,C [Epworth Sleepiness Scale] ⊕⊕⊕◯ The mean difference in the ESS post-treatment score was 6.2 minutes lower1 [8.39 85 MODERATE A to 4.01 minutes lower] (1 RCT) B Excessive Daytime Sleepiness* ⊕⊕⊕⊕ The mean change from baseline in the ESS score in the solriamfetol group was 10.4 295 patients [Maintenance of Wakefulness Test] HIGH points higher1 [8.29 points to 12.50 points higher] compared to placebo. (3 RCTs) A,B,C Disease severity* ⊕⊕⊕⊕ The improvement in the Clinical Global Impression of change(CGI- C) in the 295 patients [Clinical Global Impression of change(CGI- C)] HIGH solriamfetol group ranged from 36.4% to 47.7% when compared to placebo (3 RCTs) A,B,C Disease severity* ⊕⊕⊕⊕ The improvement in Patient Global Impression of change(PGI- C) in the solriamfetol 262 patients [Patient Global Impression of change(PGI- C)] HIGH group ranged from 41.75% to 54.7% when compared to placebo. (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 Absolute Difference No of evidence Participants (GRADE) Triazolam vs Placebo or Pre- Post difference (studies) Excessive Daytime Sleepiness* ⊕⊕⊕ ◯ The mean MSLT score in the Triazolam group was 0.22 minutes lower2 [1.35 minutes 10 patients [Multiple Sleep Latency Test] MODERATE A,B lower to 0.91 minutes higher] compared to placebo (1 RCT) A Excessive Daytime Sleepiness* ⊕⊕ ◯ ◯ The mean MWT score in the Triazolam group was 0.29 minutes higher2 [2.94 min 10 patients [Maintenance of Wakefulness Test] LOW C lower to 3.52 min higher] compared to placebo. (1 RCT) A Sleep Quality ⊕⊕⊕◯ The mean difference in sleep efficiency in the triazolam group was 9.90 % higher ( 10 patients [Sleep Efficiency %] MODERATE A 95% CI: 3.01 to 16.79 percent higher) when compared to placebo.2 (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. No. of subjects Response Scale
Pre- Post treatment n (%) Study Study Study Design treatment Pre- Post Difference, [CI] duration Pre Post Improved Ineffective Stopped (due to side effects) Trotti 2014 Observational; 2 weeks 24 24 Not recorded 17 (71%) 5 (21%) 2 (8%) N/A retrospective
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 Absolute Difference No of (GRADE) Participants Clarithromycin vs Placebo or Pre- Post difference (studies) Excessive daytime sleepiness* ⊕⊕⊕◯ The mean ESS score in the Clarithromycin group was 3.30 points lower1 [1.01 points 10 [Epworth Sleepiness Scale] MODERATE A,B higher to 7.61 points lower] compared to placebo. (1 RCT) B Excessive daytime sleepiness* ⊕⊕⊕◯ The mean SSS score in the Clarithromycin group was 0.80 points lower2 [2.17 points 10 [Stanford Sleepiness Scale] MODERATE A,B lower to 0.57 points higher] compared to placebo. (1 RCT) B Disease severity* ⊕◯◯◯ 71% of patients reported an improvement following treatment. 1 24 [Treatment response scale] VERY LOW B (1 non-RCT) A Quality of Life* ⊕⊕⊕◯ The mean FOSQ score in the Clarithromycin group was 1.91 points higher1 [0.52 points 10 [Functional Outcomes of Sleep MODERATE A,B lower to 4.34 points higher] compared to placebo. (1 RCT) B Questionnaire] Quality of Life* ⊕⊕⊕◯ The mean SF-36 total score in the Clarithromycin group was 9.70 points higher1 [1.63 10 [SF-36 Total score] MODERATE A,B points lower to 21.03 points higher] compared to placebo. (1 RCT) B Cognitive Performance ⊕⊕⊕◯ The mean improvement in RRT with clarithromycin over placebo was 0.34 millisec-1 ( 10 [Reciprocal Reaction Time] MODERATE A,B 0.37 lower to 1.05 higher). (1 RCT) B Fatigue ⊕⊕⊕◯ The mean SF-26 Energy/Vitality scale score in the Clarithromycin group was 14.1 points 10 [Short Form Health Survey (SF-36) MODERATE A, B higher1 [36.1 points higher to 7.9 points lower] compared to placebo. (1 RCT) B Energy/Vitality scale] * 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. No. of subjects Response Scale Study Study Study Design Pre- Post treatment symptomatic benefit n (%) Pre- Post Difference, [CI] duration treatment Pre Post Yes No
Trotti 2016 Observational; 2 yrs. 36 36 Not recorded 23 (64%) 13 (36%) N/A retrospective
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 Absolute Difference No of (GRADE) Participants Clarithromycin vs Placebo or Pre- Post difference (studies) Disease severity* ⊕◯◯◯ 64% of patients reported an improvement following treatment. 1 36 [Treatment response scale] VERY LOW A (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. No. of subjects Response Scale Study Study Study Design Pre- Post Difference, [CI] duration Post treatment n (%) v. June 15, 2020
Pre- treatment Pre Post Complete Partial Poor response response response
Ali 2009 Observational; 2 weeks 61 Not recorded 25 (41%) 13 (21%) 2 (3%) N/A retrospective
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 Absolute Difference No of Participants (GRADE) (studies) Pre- Post differences Disease severity ⊕◯◯◯ 41% of patients reported a complete response following treatment. 1 61 (Treatment response scale) Very Low B (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. No. of subjects Data (mean, SD) Intervention Comparator Study Study Study Design Pre- Post Difference, [CI] duration Pre Post Pre- Post Pre- Post treatment treatment treatment treatment Lavault 2011 Cross-sectional N/A *n=77 *n=88 16.3 ± 4 13.3 ± 5.2 N/A N/A -3.00 [1.59, 4.41] study
Anderson Retrospective 3.8 years 54 39 - N/A N/A -6.0 ± 5.4 2007 observational (mean) (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. No. of subjects Response Scale
Study Pre- Post treatment (%) Study Study Design Pre- Post Difference, [CI] duration treatment Pre Post Improved Not Stopped for followed 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. No. of subjects Response Scale
Pre- Study treatment Post treatment n (%) Study Study Design Pre- Post Difference, [CI] duration 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 Absolute Difference No of evidence Participants (GRADE) Pre- Post differences (studies) ⊕⊕⊕◯ The mean ESS score in the Modafinil group was 4.00 points lower1 [0.71 points to 31 Excessive daytime sleepiness* MODERATE A,B 7.29 points lower] compared to placebo. (1 RCT) C [Epworth Sleepiness Scale] ⊕⊕◯◯ The mean ESS score pre-post differences ranged from 3.0 to 6.0 points lower1. 127 LOW (2 non-RCTs) A,B v. June 15, 2020
Excessive daytime sleepiness* ⊕⊕◯◯ The mean MWT score in the Modafinil group was 3.00 points higher1 [5.78 points 29 [Maintenance of Wakefulness Test] LOW B,C lower to 11.78 points higher] compared to placebo. (1 RCT) C Disease Severity* ⊕⊕⊕◯ The mean CGI score in the Modafinil group was 1.00 points lower1 [0.14 points to 30 [Clinical Global Impression Scale] MODERATE A,B 1.86 points lower] compared to placebo. (1 RCT) C Disease severity* ⊕◯◯◯ % of patients who reported an improvement following treatment ranged from 36%- 43 [Treatment response scales; various] VERY LOW B 83%. 1 (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. No. of subjects Data (mean, SD) Intervention Comparator Study Study Study Design Pre- Post Difference, [CI] duration Pre Post Pre-treatment Post Pre- Post treatment treatment treatment Leu- Observational; N/A 65 65 17 ± 2.2 14.35 ± N/A N/A -2.65 [-3.72, -1.58] Semenescu chart review 3.79 2014
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 Absolute Difference No of Participants (GRADE) (studies) Pre- Post differences Excessive Daytime Sleepiness* ⊕◯◯◯ The mean ESS score pre-post difference was 2.65 points lower [ 3.72 points to 1.58 65 patients [Epworth Sleepiness Scale] Very Low A,B points lower] 1 ( 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. No. of subjects Data (mean, SD) Intervention Comparator Study Pre- Post Difference, Study Study Design duration [CI] Pre Post Pre- Post Pre- Post treatment treatment treatment treatment Leu- Observational N/A 42 25 15.7 ± 4 13 ± 4.9 N/A N/A -2.70 [-4.97, -0.43] Semenescu 2016
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 Quality of the Absolute Difference No of [Tool] evidence Participants (GRADE) Sodium oxybate vs Placebo or Pre- Post difference (studies) Excessive daytime sleepiness* [Epworth ⊕◯◯◯ The mean ESS score pre-post difference was 2.70 points lower1 [0.43 to 4.97 points 25 Sleepiness Scale] VERY LOW A lower]. (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. No. of subjects Data (mean, SD) Intervention Comparator Pre- Post Difference, Study Study Study Design [CI] % reduction duration Pre Post Pre-treatment Post Pre- Post treatment (means only) treatment treatment Leu- Prospective, 21.5 6 17.8 71 71 13.2 ± 11 2.7 ± 5.1 N/A N/A -10.50 [-13.32, -7.68] Semenescu open label months (Duration of (Duration of 20.45% 2015 observation=5 observation = 4.5 ± 70.5 22.4± 16.7 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. No. of subjects Data (mean, SD) Pre- Post Intervention Comparator Study Difference, [CI] Study Study Design duration % reduction Pre Post Pre- Post Pre- Post treatment (means only) treatment treatment treatment Leu- Prospective, 21.5 6 17.8 71 71 3.8 ± 2.9 1.3 ± 1.8 N/A N/A -2.50 [-3.29, -1.71] Semenescu open-label months 34.21% 2015
Table S63. Mean episode duration in an observational study, in response to Lithium in patients (mixed population) with Kleine-Levin Syndrome. No. of subjects Data (mean, SD) Intervention Comparator Study Pre- Post Difference, [CI] Study Study Design duration % reduction (means only) Pre Post Pre- Post Pre- Post treatment treatment treatment treatment Leu- Prospective, 21.5 ±17.8 71 71 17.3 ± 16.8 10 ± 12.3 N/A N/A -7.30 [-12.05, -2.55] Semenescu open-label months 57.8% 2015
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 Absolute Difference No of evidence Participants (GRADE) Lithium vs Placebo or Pre- Post difference (studies) Disease severity* ⊕◯◯◯ The mean number of episodes pre-post difference was 20.45% (10.50 episodes) lower 71 patients [Total no. of episodes within the observation period] VERY LOW A [7.68 to 13.32 episodes lower]. (1 non-RCT) A Disease severity* ⊕◯◯◯ The mean episode frequency pre-post difference was 34.21% (2.50 episodes) lower 71 patients [Episode frequency per year] VERY LOW A per year lower [1.71 to 3.29 episodes lower]. (1 non-RCT) A Disease severity* ⊕◯◯◯ The mean episode duration pre-post difference was 57.8% (7.30 days) lower [2.46 to 71 patients [Mean episode duration] VERY LOW A 12.14 episodes lower]. (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. No. of subjects Data (mean, SD) Pre- Post Treated Untreated Study Difference, [CI] % Study Study Design duration reduction (means Treated Un- Baseline Post Rx Baseline Post Rx only) treated Leotard 2018 Observational; 3y 26 48 48.2 ± 54.1 26.58 ± 28.23 N/A N/A -21.62 [-45.09, 1.85] open label 55.14% retrospective
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. No. of subjects Data (mean, SD) Intervention Comparator Study Pre- Post Study Study Design duration Difference, [CI] Treated Un- Treated Un-treated Pre- Post treated treatment treatment Leotard 2018 Observational; 3y 26 48 -12 (-68 to -3) 0 (-0.8 to 2) N/A N/A 21.62 [-45.09, 1.85] open label retrospective
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 Absolute Difference No of evidence Participants (GRADE) Methyl-Prednisolone vs Placebo or Pre- Post difference (studies) Disease severity* ⊕◯◯◯ The mean episode duration pre-post difference was 55.14%(11 days) lower [6 days 26 patients [Episode Duration change] VERY LOW A higher to 56 days lower]. (1 non-RCT) A Disease severity* ⊕◯◯◯ The mean episode shortening pre-post difference was 12 episodes lower [3 episodes 26 patients [Episode shortening] VERY LOW A higher to 68 episodes lower]. (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). No. of subjects Data (mean, SD) Intervention Comparator Study Study Study Design Pre- Post Difference, [CI] duration Pre Post Pre-treatment Post Pre- Post treatment treatment treatment Lapid Single-arm, 12 weeks 20 17 14 ± 4.34 8 ± 4.92 N/A N/A -6.0[-9.01, -2.99] 2017 open-label, pilot study
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. No. of subjects Data (mean, SD) Intervention Comparator Study Study Study Design Pre- Post Difference, [CI] duration Pre Post Pre-treatment Post Pre- Post treatment treatment treatmen t Lapid Single-arm, 12 weeks 20 17 9.6 ± 6.65 20 ± 10.97 N/A N/A 10.40 [4.43, 16.37] 2017 open-label, pilot study
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 Absolute Difference No of (GRADE) Participants Armodafinil vs Placebo or Pre- Post difference (studies) Excessive daytime sleepiness * ⊕◯◯◯ The mean ESS score pre-post difference was 6.00 points lower1 [2.99 to 9.01 points 17 patients [Epworth Sleepiness Scale] VERY LOW B lower] (1 non-RCT) A Excessive daytime sleepiness * ⊕◯◯◯ The mean MWT score pre-post difference was 10.40 minutes higher1 [4.43 minutes to 17 patients [Maintenance of Wakefulness Test] VERY LOW ,B 16.37 higher] (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 Absolute Difference No of (GRADE) Participants Pre- Post differences (studies) Excessive Daytime Sleepiness* ⊕⊕⊕◯ The mean ESS score in the Light therapy group was 1.77 points lower2 [1.14 points 31 patients [Epworth Sleepiness Scale] MODERATEA, B higher to 4.68 points lower] compared to dim light. (1 RCT)B Fatigue ⊕⊕◯◯ The mean FSS score in the light therapy group was 1.39 points higher2 [7.49 points 31 patients [Fatigue Severity Scale] LOWB, C lower to 10.27 points higher] compared to dim light. (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. No. of subjects Data (mean, SD) Intervention Comparator Study Study Study Design Pre- Post Difference, [CI] duration Pre Post Pre-treatment Post Pre- Post treatment treatment treatment Nieves Observational, 4 weeks 10 9 14.22 ± 3.03 6.0 ± 4.87 N/A N/A -8.22[-11.97, -4.47] 2002 open label
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 Absolute Difference No of (GRADE) Participants Modafinil vs Placebo or Pre- Post difference (studies) ⊕⊕⊕◯ The mean ESS score in the Modafinil group was 2.25 points lower1 [0.69 to 3.80 points 122 Excessive daytime sleepiness * MODERATE A lower] compared to placebo (4 RCT) A, B, C,D [Epworth Sleepiness Scale] ⊕◯◯◯ The mean ESS score pre-post difference was 8.22 points lower 1 (11.97 points lower to 10 VERY LOW B 4.47 points higher). (1 non-RCT) E Excessive daytime sleepiness * ⊕⊕⊕◯ The mean MWT score in the Modafinil group was 1.77 minutes higher2 [ 10.24 minutes 24 patients [Maintenance of Wakefulness Test] MODERATE A, B higher to 6.70 minutes lower] compared to placebo (1 RCT) B Excessive daytime sleepiness * ⊕⊕⊕◯ The mean MSLT score in the Modafinil group was 0.80 minutes higher 2 (3.06 minutes 37 patients [Multiple Sleep Latency Test] MODERATE A, B higher to1.46 minutes lower ] compared to placebo (1 RCT) D Quality of life* ⊕⊕◯◯ The mean SF-36 Total score in the Modafinil group was 0.20 points lower 2 (95% CI: 37 patients [Short Form Health Survey (SF-36) - Total LOW B,C 8.32 points higher to 7.92 points lower] compared to placebo (1 RCT) D score] Fatigue ⊕⊕⊕◯ The mean FSS score in the Modafinil group 0.22 points lower (95% CI: 1.26 points lower 77 patients [Fatigue Severity Scale] MODERATE A, B and 0.83 points higher] compared to placebo (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 Absolute Difference No of Participants (GRADE) (studies) Sodium oxybate vs Placebo or Pre- Post difference Excessive daytime sleepiness * ⊕⊕⊕◯ The mean ESS score in the Sodium oxybate group was 4.20 points lower1 [1.99 to 6.41 12 patients [Epworth Sleepiness Scale] MODERATE A,B points lower] compared to placebo (1 RCT) A Excessive daytime sleepiness * ⊕⊕⊕◯ The mean MSLT score in the Sodium oxybate group was 2.90 minutes higher2 [1.30 to 12 patients [Multiple Sleep Latency Test] MODERATE A,B 4.50 minutes higher] compared to placebo (1 RCT) A Fatigue ⊕⊕⊕◯ The mean FSS score was 0.10 points lower2 [0.66 lower to 0.86 higher] compared to 12 patients [Fatigue Severity Scale] MODERATE B placebo (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 Absolute Difference No of (GRADE) Participants Armodafinil vs Placebo or Pre- Post difference (studies) Excessive daytime sleepiness * ⊕⊕⊕◯ The mean ESS score in the Armodafinil group was 0.68 points lower2 [3.19 points lower 104 patients [Epworth Sleepiness Scale] MODERATE A to 1.83 points higher] compared to placebo (1 RCT) A Excessive daytime sleepiness * ⊕⊕⊕◯ The mean MSLT score in the Armodafinil group was 2.29 minutes higher1 [0.43 to 4.15 105 patients [Multiple Sleep Latency Test] MODERATE A minutes higher] compared to placebo (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 Absolute Difference No of Participants (GRADE) (studies) Modafinil vs Placebo or Pre- Post difference Excessive daytime sleepiness * ⊕⊕⊕◯ The mean ESS score in the Modafinil group was 3.00 points lower1 [1.19 to 4.81 points 20 [Epworth Sleepiness Scale] MODERATE A lower] compared to placebo (1 RCT) A v. June 15, 2020
Excessive daytime sleepiness * ⊕⊕⊕◯ The mean MWT score in the Modafinil group was 8.00 minutes higher1 [15.08 minutes 20 [Maintenance of Wakefulness Test] MODERATE A, B higher to 0.92 minutes lower] compared to placebo (1 RCT) A Fatigue ⊕⊕⊕◯ The mean FSS score in the Modafinil group was 0.80 points lower 1 [ 0.08 to 1.52 points 20 [Fatigue Severity Scale] MODERATE A, B lower] compared to placebo (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 Absolute Difference No of (GRADE) Participants Modafinil vs Placebo or Pre- Post difference (studies) Excessive daytime sleepiness * ⊕⊕⊕◯ The mean ESS score in the Methylphenidate group was 1.36 points lower2 [4.28 points 17 [Epworth Sleepiness Scale] MODERATE A, B lower to 1.56 points higher] compared to placebo (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 Absolute Difference No of Participants (GRADE) (studies) Modafinil vs Placebo or Pre- Post difference Excessive daytime sleepiness * ⊕⊕⊕◯ The mean ESS score in the Modafinil group was 3.60 points lower1 [1.52 to 5.67 points 66 [Epworth Sleepiness Scale] MODERATE A lower] compared to placebo. (2 RCTs) A, B Excessive daytime sleepiness * ⊕⊕⊕◯ The mean MWT score in the Modafinil group was 5.79 minutes higher 1 [16.23 minutes 66 [Maintenance of Wakefulness Test] MODERATE A, B higher to 4.64 minutes lower] compared to placebo (2 RCTs) A, B Excessive daytime sleepiness * ⊕⊕⊕◯ The mean MSLT score in the Modafinil group was 0.26 minutes lower 2 [3.77 minutes 66 [Multiple Sleep Latency Test] MODERATE A, B higher to 4.29 minutes lower] compared to placebo (2 RCTs) A, B Quality of life* ⊕⊕◯◯ The mean SF-36 Total score in the Modafinil group was 1.81 points lower [ 3.31 points 66 [Short Form Health Survey (SF-36) - Total LOW B,C higher to 5.41 lower] compared to placebo (2 RCTs) A, B score] Quality of life * ⊕⊕◯◯ The mean SF-36 Physical Summary Score in the Modafinil group was 2.44 points 37patients Short Form Health Survey (SF-36) - Physical LOW B,C higher1 [8.04 points lower to 12.92 points higher] compared to placebo (1 RCT) A component score] Quality of life * ⊕⊕◯◯ The mean SF-36 Mental Summary Score in the Modafinil group was 37 patients [Short Form Health Survey (SF-36) - Mental LOW B,C 0.32 points lower2 [8.47 points lower to 7.83 points higher] compared to placebo (1 RCT) A component score] Fatigue ⊕⊕⊕◯ The mean SF-36- Energy and vitality component in the Modafinil group was 10.69 points 38patients [Short Form Health Survey (SF-36) - Energy MODERATE A, B higher1 [1.07 points lower to 22.45 points higher] compared to placebo (1 RCT) B and vitality component] * 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 Absolute Difference No of Participants (GRADE) (studies) Modafinil vs Placebo or Pre- Post difference Excessive daytime sleepiness * ⊕⊕◯◯ The mean MSLT score in the Selegiline group was 3.70 minutes lower1[ 8.83 minutes 20 [Multiple Sleep Latency Test] LOW B, C lower to 1.43 min higher] compared to placebo (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. No. of subjects Data (mean, SD) Intervention Comparator Study Study Study Design Pre- Post Difference, [CI] duration Pre Post Pre-treatment Post Pre- Post treatment treatment treatment Zifko Observational, 3 months 50 47 9.7 ±3.9 4.9 ±2.9 N/A N/A -4.80[-6.19, -3.41] 2002 open label
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. No. of subjects Data (mean, SD) Intervention Comparator Study Study Study Design Pre- Post Difference, [CI] duration Pre Post Pre-treatment Post Pre- Post treatment treatment treatment Zifko Open label, 3 months 47 47 30.3± 8.5 25.4 ± 3.7 N/A N/A -4.90 [-7.55, -2.25] 2002 observational
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 Absolute Difference No of Participants (GRADE) (studies) Modafinil vs Placebo or Pre- Post difference Excessive daytime sleepiness * ⊕◯◯◯ The mean ESS pre-post difference score in the modafinil group was 4.80 points lower1 47 [Epworth Sleepiness Scale] VERY LOW B (95% CI: 6.19 points lower to 3.41 points higher). (1 non-RCT) A Fatigue ⊕◯◯◯ The mean FSS pre-post difference score in the modafinil group was 4.9 points (95% CI: 47 [Fatigue Severity Scale] VERY LOW B 2.25 to 7.55 points lower). (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. No. of subjects Data (mean, SD) Intervention Comparator Study Study Study Design Pre- Post Difference, [CI] duration Pre Post Pre-treatment Post Pre- Post treatment treatment treatment Gomez- Open label, 3 months 158 158 5.7 ± 4.4 4.2 ± 3.6 N/A N/A -1.50 [-2.39, -0.61] Peralta retrospective 2015
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 Absolute Difference No of Participants (GRADE) (studies) Modafinil vs Placebo or Pre- Post difference Excessive daytime sleepiness * ⊕◯◯◯ The mean ESS score pre-post difference was 1.50 points lower2 [0.61 to 2.39 points 158 [Epworth Sleepiness Scale] VERY LOW A lower] (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. No. of subjects Data (mean, SD) Intervention Comparator Study Study Study Design Pre- Post Difference, [CI] duration Pre Post Pre-treatment Post Pre- Post treatment treatment treatment Partonen RCT 2 weeks 16 16 5.21± 0.81 4.32 ± 0.96 N/A N/A -0.89 [-1.51, -0.27] 1996 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 Absolute Difference No of Participants (GRADE) (studies) Pre- Post differences
2 ⊕⊕⊕◯ The mean SSS score pre-post differences was 0.89 points lower [0.27 to 1.51 points 16 patients Excessive daytime sleepiness* A A,B lower]. (1 RCT) [Stanford Sleepiness Scale] MODERATE
* 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. No. of subjects Data (mean, SD) Study completing study Intervention Comparator duration Study Study Design Post Difference, [CI] Modafinil Placebo Pre- Post Pre- Post treatment treatment treatment treatment De 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] Battista 2003 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. No. of subjects Data (mean, SD) Intervention Comparator Study Study Study Design Pre- Post Difference, [CI] duration Pre Post Pre-treatment Post Pre- Post treatment treatment treatment Ninan Open label 6 weeks 29 29 10.3 ± 4.9 4.8 ±6.3* N/A N/A -5.50 [-8.40, -2.60] 2004 observational
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. No. of subjects Data (mean, SD) completing study Intervention Comparator Study Study Study Pre- Post Difference Design duration Modafinil Placebo Pre-treatment Post Pre- Post treatment treatment treatment De RCT 6 weeks 69 67 5.1 ± 1.3 *Change 5.0 ± 1.3 change 0.35 Battista score: score: 2003 -0.55(SD) -0.25 (SD) 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. No. of subjects Data (mean, SD) Intervention Comparator Study Study Study Design Pre- Post Difference, [CI] duration Pre Post Pre-treatment Post Pre- Post treatment treatment treatment Ninan Open label 6 weeks 29 5.2 ± 0.8 3.0 ± 2.5* N/A N/A -2.20 [-3.16, -1.24] 2004 observational *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 Absolute Difference No of (GRADE) Participants Modafinil vs Placebo or Pre- Post difference (studies) ⊕⊕⊕◯ The mean ESS score in the Modafinil group ranged from 0.8 points to 1.70 points lower 208 Excessive daytime sleepiness * MODERATE A compared to placebo2 (2 RCTs) A, B [Epworth Sleepiness Scale] ⊕◯◯◯ The mean ESS score pre-post differences was 5.5 points lower [ 2.6 to 8.40 points 29 VERY LOW B lower] 1. (1 non-RCTs) C ⊕⊕⊕◯ The mean FSS score in the Modafinil group was 0.10 points lower [0.85 points lower to 72 patients MODERATE A,B 0.65 points higher] compared to placebo2 (1 RCT) A ⊕⊕⊕◯ The estimated FSS change score in the Modafinil group was 0.35 points lower 136 patients Fatigue MODERATE A,B compared to placebo2 (1 RCT) B [Fatigue Severity Scale] ⊕◯◯◯ The mean FSS score pre-post differences was 2.20 points lower [1.24 to 3.16 points 29 patients VERY LOW B lower]1. (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. No. of subjects Data (mean, SD) Study Pre- Post Difference, Study Study Design Intervention Comparator duration [CI] v. June 15, 2020
Pre Post Pre-treatment Post Pre- Post treatment treatment treatment Yeh 2010 Observational, 6- 12 10 10 20 ± 1.63 13.8 ± 3.26 N/A N/A -6.20 [-8.46 , -3.94] prospective months 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. No. of subjects Data (mean, SD) Intervention Comparator Study Pre- Post Difference, Study Study Design duration [CI] Pre Post Pre-treatment Post Pre- Post treatment treatment treatment Yeh 2010 Observational 6-12 10 10 1.72 ± 0.80 2.16 ± 0.96 N/A N/A 0.44 [-0.33, 1.21]] months
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 No. of subjects Intervention Placebo duration Improvement Study Study Design (points) Pre Post Pre- Post Pre-treatment Post treatment treatment treatment
Aran 2010 Observational; 12 months 41 36 NA NA NA NA 1.9 (1.7, 2.1) retrospective
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 Quality of the Absolute Difference No of Participants [Tool] evidence (studies) (GRADE) Modafinil vs Placebo or Pre- Post difference Excessive daytime sleepiness * ⊕◯◯◯ The pre-post ESS score in NT1 patients on Modafinil was 6.09 points lower1 36 patients [Epworth Sleepiness Scale] VERY LOW A [8.46 to 3.94 points lower] (1 non-RCT)A Excessive daytime sleepiness * ⊕◯◯◯ The mean MSLT score pre-post difference in NT1 patients on Modafinil was 10 patients [Multiple Sleep Latency Test] VERY LOW A 0.44 minutes higher2 [1.21 min higher to 0.33 mins lower] (1 non-RCT)A Disease Severity ⊕◯◯◯ There was an improvement of 1.9 points1 [1.7 points to 2.1 points higher] with 36 patients [7 – point rating scale] VERY LOW A modafinil in NT1 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. No. of subjects Data (mean, SD) Intervention Comparator Study Pre- Post Difference, Study Study Design duration [CI] Pre Post Pre- Post treatment Pre- Post treatment treatment 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 Observational 3–90 10 10 18.4 ± 2.58 11.5 ± 3.8 N/A N/A -6.90 [-9.75, -4.05] 2012 months
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. No. of subjects Data (mean, SD) Intervention Comparator Study Study Study Design Pre- Post Difference, [CI] duration Pre Post Pre- Post treatment Pre- Post treatment treatment 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. No. of subjects Data (mean, SD) On Sodium oxybate Off Sodium oxybate % difference in Study Study Study Design cataplexy duration Pts. Pts on Baseline Post treatment (% Baseline Post treatment (% reduction on place mean change) mean change) SXB bo Plazzi 2018 RCT 4 weeks 31 32 6.37 ± 7.99 ± 12.2 5.02 ± 7.23 22.73 ± 24.38 327.3% 10.16 (25.4%) (352.7%)
*[(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. No. of subjects Data (mean, SD) Study % difference in mean Study Study Design Intervention Comparator duration cataplexy reduction v. June 15, 2020
Pre Post Pre- Post treatment Pre- Post treatment treatment treatment Mansukhani Observational 3–90 15 14 149.46 ± 4.05 ± 6.14 N/A N/A -145.41 [38.07, 252.75] 2012 months 204.82 (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. No. of subjects Data (mean, SD) Intervention Comparator Study % difference in mean Study Study Design duration cataplexy reduction Pre Post Pre- Post treatment Pre- Post treatment treatment 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 Quality of the Absolute Difference No of Participants [Tool] evidence (studies) (GRADE) Modafinil vs Placebo or Pre- Post difference ⊕⊕⊕◯ The mean pre-post % difference in the weekly cataplexy rate in narcolepsy 61 patients Cataplexy* MODERATE A patients on and off Sodium oxybate was 327%1. (1 RCT)A [# weekly episodes] ⊕◯◯◯ The mean pre-post % difference in the weekly cataplexy rate in narcolepsy 14 patients VERY LOW A patients on and off Sodium oxybate was 97.2%1. 1 non-RCT)B Cataplexy* ⊕◯◯◯ The mean pre-post % difference in the daily cataplexy rate in narcolepsy 13 patients [[# daily episodes] VERY LOW A patients on and off Sodium oxybate was 94.8%1. (1 non-RCT)C
v. June 15, 2020
Disease Severity ⊕⊕⊕◯ The mean score in pediatric patients with narcolepsy was 1.10 points higher1 63 patients [CGI-C (cataplexy severity) score] MODERATE A [0.53 to 1.67 points higher] compared to placebo (1 RCT)A ⊕⊕⊕◯ The mean ESS-CHAD score in pediatric patients on Sodium oxybate was 2.65 61 patients Excessive daytime sleepiness * MODERATE A points lower 1 (95% CI: 1.3 to 4.0 points lower) compared to placebo. (1 RCT)A [Epworth Sleepiness Scale-CHAD] ⊕◯◯◯ There was a pre-post difference of 5.42 points to 6.9 points lower in the mean 34 patients VERY LOW A ESS-CHAD. (2 non-RCT) B, E Excessive daytime sleepiness * ⊕◯◯◯ The mean MSLT score in pediatric patients on Sodium oxybate was 1.80 13 patients [Multiple Sleep Latency Test] VERY LOW A minutes higher1 (4.42 minutes higher to 0.82 minutes lower). (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. No. of subjects Data (mean, SD) Intervention Control Pre- Post Study Study Study Design Difference, duration Intervention Control Pre-Rx *Change from Pre-Rx *Change from [CI] baseline baseline Lecendreux Open label, F/U length: 22 30 1.63 ± 2.65± 0.6 1.64 ± 2.0 ±0.5 2.65 [0.562, 2016 controlled, 2.4 (1.1) y 0.39 0.49 4.738] longitudinal for IVIg gp; observational 3.9 (1.7) y in Study controls 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 Absolute Difference No of evidence Participants (GRADE) IVIg Immunoglobulin Pre- Post difference (studies) Disease Severity* ⊕ ◯◯◯ The mean CGI score pre-post difference in the IVIg group was 2.65 points higher1 22 patients [CGI-Sleepiness] VERY LOW A [0.56 to 4.74 points higher]. (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