Evidence tables

Advice

Table 4 Dauvilliers et al. 2013

Study reference	Dauvilliers Y, Bassetti C, Lammers GJ et al. for the HARMONY I study group (2013) Pitolisant versus placebo or modafinil in patients with narcolepsy: a double-blind, randomised trial. Lancet Neurology 12:1068–75
Unique identifier	NCT01067222
Study type	RCT
Aim of the study	To evaluate the efficacy and safety of pitolisant compared with placebo or modafinil in people with narcolepsy (with or without cataplexy)
Study dates	May 2009 to June 2010
Setting	32 centres in France, Germany, Netherlands, Hungary and Switzerland
Number of participants	n=95 randomised (94 in the ITT analysis^a)
Population	Adults aged 18 years or older with narcolepsy with or without cataplexy. Participants could not take psychostimulants for at least 14 days before baseline but could remain on sodium oxybate or non-tricyclic antidepressants at stable doses for treating cataplexy. Median age 33 to 40 years, 54% male, 81% had cataplexy, 45% had taken psychostimulants previously (mostly modafinil or methylphenidate), 35% were using sodium oxybate (n=8) or non-tricyclic antidepressants (n=25) throughout the trial. Mean baseline Epworth Sleepiness Scale (ESS) score was about 18.
Inclusion criteria	Participants had to meet the International Classification of Sleep Disorders‑2 criteria for narcolepsy (with or without cataplexy); have self-reported excessive daytime sleepiness for more than 3 months; have narcolepsy confirmed by polysomogram, a multiple sleep latency test within the previous 5 years showing a mean sleep latency of 8 minutes or less with 2 or more sleep onset rapid eye movement periods, and an ESS score of 14 or more.
Exclusion criteria	Other disorder which could be the main cause of excessive daytime sleepiness in people without cataplexy (such as sleep apnoea), history of substance abuse, serious cardiovascular disorder, hepatic or renal abnormalities, psychiatric disorder. Use of tricyclic antidepressants. Women of child-bearing potential had to use effective contraception.
Intervention(s)	Pitolisant (n=32 randomised, n=31 in the ITT population) 3 weeks of flexible dosing 10 mg, 20 mg or 40 mg per day^b 5 weeks of stable dosing
Comparator(s)	Modafinil (n=33) 3 weeks of flexible dosing 100 mg, 200 mg or 400 mg per day^b 5 weeks of stable dosing Placebo (n=30)
Length of follow-up	8‑week treatment phase plus 1‑week withdrawal phase (all participants received placebo)
Outcomes	Primary outcome: Difference in change in ESS score between pitolisant and placebo after 8 weeks (to demonstrate superiority)^c Difference in change in ESS score between pitolisant and modafinil after 8 weeks (to demonstrate non-inferiority^d if superiority of pitolisant over placebo was demonstrated)
	Secondary outcomes: Maintenance of wakefulness test (MWT) administered in 4 sessions Sustained attention to response task (SART) administered in 4 sessions Modified clinical global impression of change (CGI‑C) targeting excessive daytime sleepiness and cataplexy European quality of life questionnaire (EQ‑5D) Patients global opinion of their treatment Symptoms of cataplexy assessed by patients' sleep diaries
	Safety outcomes: Any adverse events Haematology and blood chemistry tests, vital signs, electrocardiograms, and physical examination. Occurrence of withdrawal syndrome (as defined in DSM‑4) after treatment ended
Source of funding	Bioprojet, France
Overall risk of bias/quality assessment (CASP RCT checklist)	Did the trial address a clearly focused issue?	Yes
	Was the assignment of patients to treatments randomised?	Yes^e
	Were patients, health workers and study personnel blinded?	Yes^f
	Were the groups similar at the start of the trial?	Yes
	Aside from the experimental intervention, were the groups treated equally?	Yes
	Were all of the patients who entered the trial properly accounted for at its conclusion?	Yes
	How large was the treatment effect?	See table 1
	How precise was the estimate of the treatment effect?	See table 1
	Can the results be applied in your context? (or to the local population)	Unclear^g
	Were all clinically important outcomes considered?	Yes
	Are the benefits worth the harms and costs?	See key points
Study limitations	Small numbers of participants in the trial Short duration of the trial Flexible dosage and multiple visits could have affected efficacy Limited generalisability to excluded populations and people not taking any other treatments for narcolepsy People taking modafinil could have been aware of this because of its effects
Comments	^a The intention to treat population included all participants who had at least 1 dose of study medication and at least 1 post-baseline assessment. One person withdrew consent after randomisation in the pitolisant group. ^b For the first 7 days all participants took a low dose (10 mg pitolisant, 100 mg modafinil or placebo). For the next 7 days all participants took a medium dose (20 mg pitolisant, 200 mg modafinil or placebo). At day 14, doses were adjusted based on individual clinical efficacy and safety assessed by investigators. Participants could take 10 mg, 20 mg or 40 mg of pitolisant; 100 mg, 200 mg or 400 mg modafinil; or placebo. At day 21 the dose could only be decreased for tolerance. Participants then continued on their assigned stable dose for 5 weeks. Treatment was stopped on day 56 and all participants received 1 week of placebo. Pitolisant was given once daily in the morning; modafinil was given twice daily in the morning and at lunchtime. (masked using double-dummy medication in sealed capsules). Pitolisant was given as pitolisant hydrochloride 10 mg, 20 mg or 40 mg which is equivalent to 9 mg, 18 mg or 36 mg of pitolisant. ^c Baseline ESS values were the mean of values at day −7 and day 0. Final ESS values were the mean of values at day 49 and day 56. Missing data were imputed using last observation carried forward. ^d If superiority of pitolisant over placebo was shown, non-inferiority of pitolisant versus modafinil could be tested based on a non-inferiority margin of 2 points on the ESS score. ^e The method of randomisation suggests allocation was concealed. Participants were randomised to each treatment group (1:1:1) via an interactive web response system with a computer generated randomisation sequence. The investigator at each site interacted confidentially with the system to communicate dosage strength allocation. ^f Treatment allocation was masked using double-dummy medication in sealed capsules. Double-blinding was maintained by all participants taking 4 capsules per day (2 before breakfast and 2 before lunch) whatever the treatment or dose. However, because of its effects, people taking modafinil may have become aware of their treatment allocation. ^g There is limited generalisability to excluded populations (children, severely ill people, those with unstable comorbidities, and those who declined to participate because they didn't want to receive placebo) and people who were not taking any other medicines for narcolepsy or cataplexy (35% continued sodium oxybate or non-tricyclic antidepressants).
Abbreviations: CGI‑C, clinical global impression of change; DSM‑4, Diagnostic and Statistical Manual of Mental Disorders, 4^th edition; EQ‑5D, European quality of life questionnaire; ESS, Epworth Sleepiness Scale; ITT, intention to treat analysis; MWT, maintenance of wakefulness test; RCT, randomised controlled trial; SART, sustained attention to response task.

Table 5 Szakacs et al. 2017

Study reference	Szakacs Z, Dauvilliers Y, Mikhaylov V et al. for the HARMONY-CTP study group (2017) Safety and efficacy of pitolisant on cataplexy in patients with narcolepsy: a randomised, double-blind, placebo-controlled trial. Lancet Neurology; published 24 January, DOI: http://dx.doi.org/10.1016/S1474-4422(16)30333-7
Unique identifier	NCT01800045
Study type	RCT
Aim of the study	To evaluate the efficacy and safety of pitolisant on cataplexy compared with placebo in people with narcolepsy with cataplexy
Study dates	April 2013 to January 2015
Setting	16 centres in Bulgaria, Czech Republic, Hungary, Macedonia, Poland, Russia, Serbia, Turkey and Ukraine
Number of participants	n=106 randomised (105 in the ITT analysis^a)
Population	Adults aged 18 years or older with narcolepsy with cataplexy. Participants could not take psychostimulants or sedatives but could remain on sodium oxybate or antidepressants if doses were stable at least 1 month before randomisation and throughout the trial. Median age was 34 to 39 years and 50% were male. In the pitolisant group, the mean number of cataplexy episodes per week at baseline was 11, 41% of people had taken cataplexy medicines in the previous 3 months, and 7% continued these during the trial. In the placebo group, the mean number of cataplexy episodes per week at baseline was 9, 80% of people had taken cataplexy medicines in the previous 3 months, and 16% continued these during the trial. Mean baseline Epworth Sleepiness Scale (ESS) scores were about 17 in both groups.
Inclusion criteria	Participants had to meet the International Classification of Sleep Disorders‑2 criteria for narcolepsy with cataplexy (defined as excessive daytime sleepiness and a history of cataplexy). This was confirmed in most people by polysomogram and a multiple sleep latency test within the previous year showing 2 or more sleep onset rapid eye movement periods, 3 or more cataplexies per week and an ESS score of 12 or more. There was a 3‑week selection period before randomisation consisting of 1‑week washout period and 2‑week baseline period to collect baseline cataplexy data.
Exclusion criteria	Other disorder which could be the main cause of excessive daytime sleepiness (such as sleep apnoea), history of substance abuse, serious cardiovascular disorder, hepatic or renal abnormalities, psychiatric disorder. Women of child-bearing potential had to use effective contraception.
Intervention(s)	Pitolisant (n=54) 3 weeks of flexible dosing 5 mg, 10 mg or 20 mg per day^b 4 weeks of stable dosing 5 mg, 10 mg, 20 mg or 40 mg per day
Comparator(s)	Placebo (n=52 randomised, n=51 in the ITT population)
Length of follow-up	7‑week treatment phase plus 1‑week withdrawal phase (all participants received placebo)
Outcomes	Primary outcome: Change in the weekly cataplexy rate (average number of cataplexy attacks per week) between the 2 weeks of baseline and the 4 weeks of stable dosing^c
	Secondary outcomes: Weekly cataplexy rate changes in people maintained or not on anticataplectic medicines Mean change in ESS score Proportion of participants with a final ESS score of 10 or less Proportion of participants with a weekly cataplexy rate above 15 (a non-validated cut-off) Maintenance of wakefulness test (MWT) administered in 4 sessions Modified clinical global impression of change (CGI‑C) targeting excessive daytime sleepiness and cataplexy European quality of life questionnaire (EQ‑5D) Patients global opinion of their treatment Number of days with hallucinations (recorded in patients' diaries)
	Safety outcomes: Any adverse events Laboratory tests, vital signs, electrocardiograms, and physical examination. Beck Depression Inventory Occurrence of withdrawal syndrome (as defined in DSM‑4) after treatment ended
Source of funding	Bioprojet, France
Overall risk of bias/quality assessment (CASP RCT checklist)	Did the trial address a clearly focused issue?	Yes
	Was the assignment of patients to treatments randomised?	Yes^d
	Were patients, health workers and study personnel blinded?	Yes^e
	Were the groups similar at the start of the trial?	Unclear^f
	Aside from the experimental intervention, were the groups treated equally?	Yes
	Were all of the patients who entered the trial properly accounted for at its conclusion?	Yes
	How large was the treatment effect?	See table 1
	How precise was the estimate of the treatment effect?	See table 1
	Can the results be applied in your context (or to the local population)?	Unclear^g
	Were all clinically important outcomes considered?	Yes
	Are the benefits worth the harms and costs?	See Key points
Study limitations	Small numbers of participants in the trial Short duration of the trial Flexible dosage and multiple visits could have affected efficacy Limited generalisability to excluded populations Conducted mainly in Eastern European countries, which may not reflect UK clinical practice High placebo effect on weekly cataplexy rate Baseline differences between groups in the mean number of cataplexy episodes per week and proportion of people who had previously taken or were continuing to take cataplexy medicines
Comments	^a The intention to treat population included all participants who had at least 1 dose of study medication. One person did not receive treatment in the placebo group. ^b For the first 7 days all participants took 5 mg pitolisant or placebo. For the next 7 days all participants took 10 mg pitolisant or placebo. At day 14, doses were adjusted based on individual clinical efficacy and safety assessed by investigators. Participants could take 5 mg, 10mg or 20 mg of pitolisant; or placebo. At day 21 the dose could be adjusted again to the final dose of 5 mg, 10 mg, 20 mg or 40 mg. Participants then continued on their assigned stable dose for 4 weeks. Treatment was then stopped and all participants received 1 week of placebo. Pitolisant was given once daily in the morning, as pitolisant hydrochloride 5 mg, 10 mg, 20 mg or 40 mg (which is equivalent to 4.5 mg, 9 mg, 18 mg or 36 mg of pitolisant). ^c Participants reported in diaries all cataplexy attacks defined as sudden and transient partial or generalised loss of muscle tone triggered by emotion. ^d The method of randomisation suggests allocation was concealed. Participants were randomised to each treatment group (1:1) via an interactive web response system with a computer generated randomisation sequence. ^e Treatment allocation was masked to both patients and investigators using medication in sealed capsules. However, because of its effects, people taking pitolisant may have become aware of their treatment allocation. ^f There were baseline differences between the pitolisant and placebo group in the mean number of cataplexy episodes per week (11 in the pitolisant group; 9 in the placebo group) and proportion of people who had taken cataplexy medicines in the previous 3 months (41% in the pitolisant group at baseline with 7% continuing during the trial; 80% in the placebo group at baseline with 16% continuing during the trial). ^g There is limited generalisability to excluded populations (children, those with unstable comorbidities, and those who declined to participate because they didn't want to receive placebo).
Abbreviations: CGI‑C, clinical global impression of change; DSM‑4, Diagnostic and Statistical Manual of Mental Disorders, 4^th edition; EQ-5D, European quality of life questionnaire; ESS, Epworth Sleepiness Scale; ITT, intention to treat analysis; MWT, maintenance of wakefulness test; RCT, randomised controlled trial.