Clinical Trial Results:
Efficacy and Safety of Pitolisant (BF2.649) in the Treatment of Excessive Daytime Sleepiness in Patients with Obstructive Sleep Apnoea Syndrome, Treated or Not by Nasal Continuous Positive Airway Pressure, but Still Complaining of Excessive Daytime Sleepiness
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Summary
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EudraCT number |
2015-004561-85 |
Trial protocol |
BG |
Global end of trial date |
29 Apr 2020
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Results information
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Results version number |
v1(current) |
This version publication date |
07 May 2022
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First version publication date |
07 May 2022
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
P1513/BF2.649
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02739568 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Bioprojet Pharma
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Sponsor organisation address |
9, rue Rameau, Paris, France, 75002
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Public contact |
Clinical Development Director, Bioprojet Pharma, +33 147 03 66 33, contact@bioprojet.com
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Scientific contact |
Clinical Development Director, Bioprojet Pharma, +33 147 03 66 33, contact@bioprojet.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
14 Jan 2022
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
24 Jul 2019
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Global end of trial reached? |
Yes
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Global end of trial date |
29 Apr 2020
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The main objective of this study was to demonstrate the efficacy and safety of pitolisant given at 10, 20, or 40 mg per day versus placebo during 12 weeks for the Double-blind period, to treat the Excessive Daytime Sleepiness (EDS) in patients with moderate to severe Obstructive Sleep Apnea (OSA) refusing the nasal Continuous Positive Airway Pressure (nCPAP) therapy or treated by nCPAP but still complaining of EDS. The efficacy of pitolisant was assessed separately in patients treated with nCPAP and in patients without nCPAP use.
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Protection of trial subjects |
The study was conducted in accordance with the Declaration of Helsinki 2008, and in compliance with the protocol and the International Council on Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) guidelines, as required by the major regulatory authorities, and following all other local requirements.
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Background therapy |
Patients receiving pitolisant or placebo were treated or not by Nasal Continuous Positive Airway Pressure (nCPAP) | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
07 Apr 2016
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Bulgaria: 325
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Country: Number of subjects enrolled |
North Macedonia: 36
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Worldwide total number of subjects |
361
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EEA total number of subjects |
325
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
361
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
- | ||||||||||||||||||||||||
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Pre-assignment
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Screening details |
A total of 389 patients were screened, and a total of 361 patients were randomized to pitolisant (242 patients) or placebo (119 patients). | ||||||||||||||||||||||||
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Period 1
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Period 1 title |
Double-blind period (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||
Roles blinded |
Investigator, Monitor, Data analyst, Subject, Carer, Assessor | ||||||||||||||||||||||||
Blinding implementation details |
Both the patient and the Investigator were blind during the Double-blind period. To make sure that the prescribed dose was appropriately administered to the patient to comply with the study conduct, tablets of pitolisant 5 mg and matching placebo, as well as tablets of pitolisant 20 mg and matching placebo, had the same mass, color, shape, and size.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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BF2.649 Treatment Arm (Double-blind) | ||||||||||||||||||||||||
Arm description |
Patients with OSA (obstructive sleep apnea) refusing the nCPAP therapy or treated by nCPAP but still complaining of EDS, treated by pitolisant. Treatment was initiated by an individual escalating dose phase over 2 weeks, followed by a dose adjustment phase and a stable dose phase for 9 weeks until the end of the Double-blind period (V6). | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
Pitolisant hydrochloride
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Investigational medicinal product code |
BF2.649
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Patients under pitolisant were to take, in the morning during breakfast with a glass of water, either:
o Low dose 10 mg: two 5 mg tablets;
o Medium dose 20 mg: one 20 mg tablet;
o High dose 40 mg: two 20 mg tablets;
The therapeutic units were prescribed to patients according to an individual treatment program and the posology was determined during the dose adjustment phase according to tolerance. The high dose of 40 mg (two 20 mg tablets) was the planned stable dose for the duration of the study, depending on tolerance.
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Arm title
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Placebo Arm (Double-blind) | ||||||||||||||||||||||||
Arm description |
Patients with OSA (obstructive sleep apnea) refusing the nCPAP therapy or treated by nCPAP but still complaining of EDS, treated by placebo. Treatment was initiated by an individual escalating dose phase over 2 weeks, followed by a dose adjustment phase and a stable dose phase for 9 weeks until the end of the Double-blind period (V6). | ||||||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Same dosage and administration as BF2.649 but with placebo.
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Baseline characteristics reporting groups
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Reporting group title |
BF2.649 Treatment Arm (Double-blind)
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Reporting group description |
Patients with OSA (obstructive sleep apnea) refusing the nCPAP therapy or treated by nCPAP but still complaining of EDS, treated by pitolisant. Treatment was initiated by an individual escalating dose phase over 2 weeks, followed by a dose adjustment phase and a stable dose phase for 9 weeks until the end of the Double-blind period (V6). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo Arm (Double-blind)
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Reporting group description |
Patients with OSA (obstructive sleep apnea) refusing the nCPAP therapy or treated by nCPAP but still complaining of EDS, treated by placebo. Treatment was initiated by an individual escalating dose phase over 2 weeks, followed by a dose adjustment phase and a stable dose phase for 9 weeks until the end of the Double-blind period (V6). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
nCPAP use + BF2.649
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Subject analysis set type |
Sub-group analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Patients with Obstructive Sleep Apnea (OSA) treated by Nasal Continuous Positive Airway Pressure (nCPAP) but still complaining of Excessive Daytime Sleepiness (EDS) who received pitolisant.
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Subject analysis set title |
nCPAP use + placebo
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Subject analysis set type |
Sub-group analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Patients with Obstructive Sleep Apnea (OSA) treated by Nasal Continuous Positive Airway Pressure (nCPAP) but still complaining of Excessive Daytime Sleepiness (EDS) who received placebo.
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Subject analysis set title |
No nCPAP use + BF2.649
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Subject analysis set type |
Sub-group analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Patients with Obstructive Sleep Apnea (OSA) refusing Nasal Continuous Positive Airway Pressure (nCPAP) but still complaining of Excessive Daytime Sleepiness (EDS) who received pitolisant.
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Subject analysis set title |
No nCPAP use + placebo
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Subject analysis set type |
Sub-group analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Patients with Obstructive Sleep Apnea (OSA) refusing Nasal Continuous Positive Airway Pressure (nCPAP) but still complaining of Excessive Daytime Sleepiness (EDS) who received placebo.
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End points reporting groups
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Reporting group title |
BF2.649 Treatment Arm (Double-blind)
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Reporting group description |
Patients with OSA (obstructive sleep apnea) refusing the nCPAP therapy or treated by nCPAP but still complaining of EDS, treated by pitolisant. Treatment was initiated by an individual escalating dose phase over 2 weeks, followed by a dose adjustment phase and a stable dose phase for 9 weeks until the end of the Double-blind period (V6). | ||
Reporting group title |
Placebo Arm (Double-blind)
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Reporting group description |
Patients with OSA (obstructive sleep apnea) refusing the nCPAP therapy or treated by nCPAP but still complaining of EDS, treated by placebo. Treatment was initiated by an individual escalating dose phase over 2 weeks, followed by a dose adjustment phase and a stable dose phase for 9 weeks until the end of the Double-blind period (V6). | ||
Subject analysis set title |
nCPAP use + BF2.649
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Patients with Obstructive Sleep Apnea (OSA) treated by Nasal Continuous Positive Airway Pressure (nCPAP) but still complaining of Excessive Daytime Sleepiness (EDS) who received pitolisant.
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Subject analysis set title |
nCPAP use + placebo
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Patients with Obstructive Sleep Apnea (OSA) treated by Nasal Continuous Positive Airway Pressure (nCPAP) but still complaining of Excessive Daytime Sleepiness (EDS) who received placebo.
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Subject analysis set title |
No nCPAP use + BF2.649
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Patients with Obstructive Sleep Apnea (OSA) refusing Nasal Continuous Positive Airway Pressure (nCPAP) but still complaining of Excessive Daytime Sleepiness (EDS) who received pitolisant.
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Subject analysis set title |
No nCPAP use + placebo
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Patients with Obstructive Sleep Apnea (OSA) refusing Nasal Continuous Positive Airway Pressure (nCPAP) but still complaining of Excessive Daytime Sleepiness (EDS) who received placebo.
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End point title |
Epworth Sleepiness Scale (ESS) | ||||||||||||||||||||||||||||
End point description |
The primary efficacy endpoint was the change of the ESS score between the baseline and the end of the Double-blind period. ESS score measured persistent daytime sleepiness or sleep propensity for adult patients in the Full Analysis Set (FAS) population. The ESS score was the sum of the eight sub-scores and can range from 0 to 24 with higher scores representing greater sleepiness. A score greater than 10 was considered as abnormal sleepiness.
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End point type |
Primary
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End point timeframe |
Between the baseline (V2) and the end of the Double-blind period (mean between V5 and V6)
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Statistical analysis title |
Primary analysis | ||||||||||||||||||||||||||||
Statistical analysis description |
The primary analysis on the final ESS score demonstrated a statistically significantly greater reduction in final ESS with pitolisant than with placebo, with a least square (LS) mean difference of -2.6 (95% CI [-3.4; -1.8]; p < 0.001). The sensitivity analyses confirmed this result and showed no statistically significant effect of nCPAP use and no treatment nCPAP interaction.
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Comparison groups |
BF2.649 Treatment Arm (Double-blind) v Placebo Arm (Double-blind)
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Number of subjects included in analysis |
361
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||||||||||||
P-value |
< 0.001 | ||||||||||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||||||||||||||
Confidence interval |
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95% | ||||||||||||||||||||||||||||
sides |
2-sided
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lower limit |
- | ||||||||||||||||||||||||||||
upper limit |
- | ||||||||||||||||||||||||||||
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End point title |
Pichot Fatigue Scale | ||||||||||||
End point description |
The asthenia-fatigue scale used in this study, consists of eight questions scored progressively from “0” (not at all) to “4” (extremely) in the following situations (score min 0- score max 32). A score > 22 indicates excessive fatigue. This endpoint was measured in the Full Analysis Set (FAS) population.
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End point type |
Secondary
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End point timeframe |
The Pichot Fatigue Scale was evaluated at V2, V6, and V7 (for the double-blind period).
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Clinical Global Impression (CGI) | ||||||||||||
End point description |
The clinical global impression (CGI) is a 3-item observer rated scale which measures illness severity (CGI of illness severity, CGI-S), global improvement or change (CGI-C), and therapeutic response.
CGI-S was evaluated at V1 and V2, and CGI-C was evaluated at V6 and V7 (for the Double-blind period). This endpoint was measured in the Full Analysis Set (FAS) population.
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End point type |
Secondary
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End point timeframe |
CGI was evaluated at baseline (V1 and V2) and at the end of the Double-blind period (V6 and V7).
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Therapy Response R1 | ||||||||||||
End point description |
Therapy response R1 is the % of patients with an absolute value of the ESS score ≤10 at the end of the Double-blind period. This endpoint was measured in the Full Analysis Set (FAS) population.
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End point type |
Secondary
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End point timeframe |
From baseline to the end of the Double-blind period.
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Therapy Response R2 | ||||||||||||
End point description |
Therapy response R2 is the % of patients with an absolute value of the ESS score ≤10 or a value of ≤-3 for the difference between DBF LOCF (Double-Blind Period Final Value, Last Observation Carried Forward) ESS and baseline (V2) ESS. This endpoint was measured in the Full Analysis Set (FAS) population.
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End point type |
Secondary
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End point timeframe |
From baseline to the end of the Double-Blind period.
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| No statistical analyses for this end point | |||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
The period of observation of AEs extended from the time the patient gave informed consent (V1) until 1 month after the last visit (V7). The occurrence of any AE was monitored at each visit and at each phone contact (Ph1, Ph2, and Ph3).
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||
Dictionary version |
19.1
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Reporting groups
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Reporting group title |
BF2.649 Treatment Arm (Double-blind)
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Reporting group description |
Patients with OSA (obstructive sleep apnea) refusing the nCPAP therapy or treated by nCPAP but still complaining of EDS, treated by pitolisant. Treatment was initiated by an individual escalating dose phase over 2 weeks, followed by a dose adjustment phase and a stable dose phase for 9 weeks until the end of the Double-blind period (V6). | |||||||||||||||||||||||||||||||||
Reporting group title |
Placebo Arm (Double-blind)
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Reporting group description |
Patients with OSA (obstructive sleep apnea) refusing the nCPAP therapy or treated by nCPAP but still complaining of EDS, treated by placebo. Treatment was initiated by an individual escalating dose phase over 2 weeks, followed by a dose adjustment phase and a stable dose phase for 9 weeks until the end of the Double-blind period (V6). | |||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 2% | ||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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01 Feb 2018 |
The aim of the protocol amendment was to strengthen and enhance the level of evidence of the study by assessing the efficacy and safety of pitolisant separately in patients using nCPAP and in those refusing nCPAP as therapy for OSA. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
