Clinical Trials Register

Summary
EudraCT Number:	2015-004561-85
Sponsor's Protocol Code Number:	P1513/BF2.649
National Competent Authority:	Bulgarian Drug Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2016-01-05
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Bulgarian Drug Agency

A.2

EudraCT number

2015-004561-85

A.3

Full title of the trial

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

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Efficacy and safety of pitolisant (BF2.649) in the treatment of excessive daytme sleepiness in patients with excessive daytime sleepiness in patients with obstructive sleep apnea syndrome treated or not by nCPAP ans still complaning of excessive daytime sleepiness

A.3.2

Name or abbreviated title of the trial where available

HAROSA III

A.4.1

Sponsor's protocol code number

P1513/BF2.649

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Bioprojet Pharma
B.1.3.4	Country	France
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Bioprojet Pharma
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Bioprojet Pharma
B.5.2	Functional name of contact point	Bioprojet clinical department
B.5.3	Address:
B.5.3.1	Street Address	9, rue rameau
B.5.3.2	Town/ city	Paris
B.5.3.3	Post code	75002
B.5.3.4	Country	France
B.5.4	Telephone number	+330147 03 66 33
B.5.5	Fax number	+330147 03 66 30
B.5.6	E-mail	contact@bioprojet.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Wakix
D.2.1.1.2	Name of the Marketing Authorisation holder	Bioprojet Pharma
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	pitolisant
D.3.2	Product code	BF2.649
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Pitolisant
D.3.9.1	CAS number	903576-44-3
D.3.9.3	Other descriptive name	BF2.649
D.3.9.4	EV Substance Code	SUB29188
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Wakix
D.2.1.1.2	Name of the Marketing Authorisation holder	Bioprojet Pharma
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	pitolisant
D.3.2	Product code	BF2.649
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	pitolisant
D.3.9.1	CAS number	903576-44-3
D.3.9.3	Other descriptive name	BF2.649
D.3.9.4	EV Substance Code	SUB29188
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Patients with Obstructive Sleep Apnoea Syndrome, Treated or Not by Nasal Continuous Positive Airway Pressure, but Still Complaining of Excessive Daytime Sleepiness (EDS)

E.1.1.1

Medical condition in easily understood language

Excessive Daytime Sleepiness associated with Obstructive Sleep Apnoea Syndrome, Treated or Not by Nasal Continuous Positive Airway Pressure

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	LLT
E.1.2	Classification code	10015595
E.1.2	Term	Excessive daytime sleepiness
E.1.2	System Organ Class	100000004852

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The main objective of this study is 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 will be assessed separately in patients treated with nCPAP and in patients without nCPAP use.

E.2.2

Secondary objectives of the trial

The secondary objectives of the Open Label Extension period are to assess the long-term tolerance as well as the maintenance of efficacy of pitolisant.and further investigating the co-variates or co-medications that affect the pharmacokinetics of pitolisant in the target population.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Male and/or female outpatients aged from at least 18 years
• Patients complaining of EDS refusing to be treated by nCPAP therapy or having been submitted to nCPAP therapy for a minimum period of 3 months, and still complaining of EDS despite the efforts made beforehand to obtain an efficient nCPAP therapy
• Polysomnography performed (for patients submitted to nCPAP therapy – under nCPAP) between V1 and V2 or during the last 12 months with:
- Apnea-Hypopnea Index (AHI): for patients without nCPAP therapy ≥ 15; for patients under nCPAP therapy ≤ 10;
- Periodic limbs movement (PLM) disorders as defined by a PLM Arousal Index (PLMAI) ≤10 per hour.
• For patients submitted to nCPAP therapy: nCPAP ≥ 4 hours / day (compliance checked on the clock-time counter of the CPAP machine)
• Mini Mental State Examination (MMSE) ≥ 28
• Beck Depression Inventory – 13 items (BDI-13) score < 16 and item G (suicidal ideation) of BDI-13 = 0
• Body Mass Index (BMI) ≤40 kg/m²
• Epworth Sleepiness Scale (ESS) ≥ 12
• Female patients with child-bearing potential using a medically accepted method of birth control (i.e. oral contraceptives of normal average dosage) agreeing to continue this method throughout the study, and during the month following treatment discontinuation, being negative to serum pregnancy test performed at the screening visit
• If specified by the investigator, the patient must be willing not to operate a car (if sleepy at wheel) or heavy machinery for the duration of the trial or as long as the investigator deems it clinically indicated. In addition, the patient should be willing to maintain during the study their usual behaviors which could affect their diurnal sleepiness (e.g. circadian rhythm, caffeine consumption, nocturnal sleep duration).
• Patients having signed and dated the informed consent form

E.4

Principal exclusion criteria

• Patients having previously been exposed to pitolisant either in previous clinical trials, or in compassionate program or being prescribed the commercial form (Wakix®), for those enrolled patients from January 2018
• Patients suffering from chronic severe insomnia in accordance with the International Classification of Sleep Disorders (ICSD 2005) without OSA.
• Patients with co-existing narcolepsy (ICSD 2005), judged on clinical criteria
• Patients with sleep debt not due to OSA (according to the physician‘ s judgment)
• Patients with non-respiratory sleep fragmentation (restless leg syndrome…)
• Shift work, professional drivers
• Refusal from the patient to stop any current therapy for EDS or predictable risk for the patient to stop the therapy
• Patients suffering from a psychiatric disease
• Acute or chronic disease preventing the improvement assessment, e.g. severe chronic obstructive pulmonary disease (COPD)
• Current or recent (within one year) history of drug, alcohol, narcotic or other substance abuse or dependence
• Any significant serious abnormality of the cardiovascular system, e.g. recent myocardial infarction, angina, hypertension or dysrhythmias (within the previous 6 months), Electrocardiogram Fredericci corrected QT interval higher than 450 ms, history of left ventricular hypertrophy or mitral valve prolapse.
• Severe co-morbid medical or biological conditions that may jeopardize study participation at the discretion of the investigator (particularly in the cardiovascular system and the instable diabetes)
• Positive serology tests (optional HIV, HCV and HbsAg)
• Pregnant or breast-feeding women
• Women with child-bearing potential and no efficient birth-control method
• Patients unable to understand the study protocol
• Patients with suspected or known hypersensitivity to study medication
• Patients with a dominant arm deficiency impeding the achievement of the tests
• Patients using a prohibited medication
• Congenital galactose poisoning, glucose and galactose malabsorption, deficit in lactase (lactose in placebo)
• Patients participating in another study or being in a follow-up period for another study

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint efficacy criterion is based on the score of Epworth Sleepiness Scale (ESS) by comparing the score differences between baseline (score at V2) and at the end of the Double Blind period (mean between V5 and V6) in pitolisant and placebo groups and the sustained improvement of ESS from baseline at week 52 in the Open Label Extension period.

E.5.1.1

Timepoint(s) of evaluation of this end point

see protocol

E.5.2

Secondary end point(s)

- Percentage of ESS responders
- Reduction of sleepiness and sleep episodes on the sleep diary
- Improvement in vigilance according to Oxford Sleep Resistance (OSleR) test
- Increase in quality of life
- Improvement in cognitive function :Trail Making Test (TMT) Parts A & B
- Clinical Global Impression (CGI)assesment of illness severity and Improvement
- The Pichot fatigue scale
- PK assessment
- Z-score: composite score including ESS and OSLER results

E.5.2.1

Timepoint(s) of evaluation of this end point

see protocol

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

pharmacokinetics

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Bulgaria

Macedonia, the former Yugoslav Republic of

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

end of trial is LPLV

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

380

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

340

F.4.2

For a multinational trial

F.4.2.1

In the EEA

340

F.4.2.2

In the whole clinical trial

400

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

normal treatment

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2016-02-24

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-01-27

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2020-04-29

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