Clinical Trials Register

Summary
EudraCT Number:	2015-005035-41
Sponsor's Protocol Code Number:	THN102-201
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2018-04-11
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

Belgium - FPS Health-DGM

A.2

EudraCT number

2015-005035-41

A.3

Full title of the trial

SAFETY AND EFFICACY OF THN102 ON SLEEPINESS IN NARCOLEPTIC PATIENTS

A.3.1

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

SAFETY AND EFFICACY OF THN102 ON SLEEPINESS IN NARCOLEPTIC PATIENTS

A.4.1

Sponsor's protocol code number

THN102-201

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	Theranexus SA
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	Theranexus SA
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	Theranexus SA
B.5.2	Functional name of contact point	Werner Rein
B.5.3	Address:
B.5.3.1	Street Address	86 rue de Paris
B.5.3.2	Town/ city	Orsay
B.5.3.3	Post code	91400
B.5.3.4	Country	France
B.5.4	Telephone number	+33680 02 67 79
B.5.6	E-mail	werner.rein@theranexus.fr

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	No
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	Flecainide acetate
D.3.2	Product code	THN02
D.3.4	Pharmaceutical form	Capsule
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	Flecainidum
D.3.9.1	CAS number	54143-56-5
D.3.9.2	Current sponsor code	THN02
D.3.9.3	Other descriptive name	FLECAINIDE ACETATE
D.3.9.4	EV Substance Code	SUB13894MIG
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	1
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	No
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	Flecainide acetate
D.3.2	Product code	THN02
D.3.4	Pharmaceutical form	Capsule
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	Flecainidum
D.3.9.1	CAS number	54143-56-5
D.3.9.2	Current sponsor code	THN02
D.3.9.3	Other descriptive name	FLECAINIDE ACETATE
D.3.9.4	EV Substance Code	SUB13894MIG
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	9
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: 3
D.1.2 and D.1.3	IMP Role	Comparator
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	Modafinil
D.2.1.1.2	Name of the Marketing Authorisation holder	TEVA
D.2.1.2	Country which granted the Marketing Authorisation	France
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	Modafinil 100 mg
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	MODAFINIL
D.3.9.1	CAS number	68693-11-8
D.3.9.4	EV Substance Code	SUB09026MIG
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	100
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	Capsule
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

This Proof-of-Concept, Phase IIa trial with THN102 should collect a sufficient body of information to assess efficacy and safety profile of THN102 versus modafinil alone in patient with a diagnosis of narcolepsy type 1 (i.e. with cataplexy) or type 2 (without cataplexy).

E.1.1.1

Medical condition in easily understood language

narcolepsy

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	20.0
E.1.2	Level	PT
E.1.2	Classification code	10028713
E.1.2	Term	Narcolepsy
E.1.2	System Organ Class	10029205 - Nervous system disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10028715
E.1.2	Term	Narcolepsy with cataplexy
E.1.2	System Organ Class	10029205 - Nervous system disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10007738
E.1.2	Term	Cataplexy and narcolepsy
E.1.2	System Organ Class	10029205 - Nervous system disorders

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To determine the superiority of THN102 (combination modafinil and flecainide acetate) vs modafinil for improving the residual daytime sleepiness assessed by Epworth Sleepiness Scale (ESS) in patients with narcolepsy treated by modafinil

E.2.2

Secondary objectives of the trial

• To quantify the added value of THN102 (modafinil/flecainide acetate combination) for both daily doses (300/27 mg and 300/9 mg) vs modafinil (300/0 mg) for improving cataplexy, sleep paralysis, fatigue, hallucinations, and quality of life
• To determine the dose response profile of THN102 vs. modafinil on efficacy parameters
• To assess the safety profile of THN102 doses vs. modafinil
• To determine the plasma levels of modafinil and flecainide at steady state

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Patients with a diagnosis of narcolepsy type 1 (i.e. with cataplexy) or type 2 (without cataplexy) according to the International Classification of Sleep Disorders (ICSD-3) criteria (see Appendix A for criteria).
2.The patient is willing and able to fulfill study restrictions and to attend regularly scheduled clinic visits as specified in this protocol, and has signed the informed consent prior to study start.
3.Males or females, aged between 18 and 65 year-old.
4.Body mass index >18 kg/m2 and <35 kg/m2.
5.Patients treated with modafinil at stable dosage for at least 2 months and still complaining of excessive daily somnolence (EDS) despite the treatment
6.Epworth Sleepiness Scale (ESS) score should be ≥ 14/24 during the baseline period.
7.Patients with cataplexy are permitted to remain on their anticataplectic medications at stable doses (mainly sodium oxybate or venlafaxine). The authorized anticataplectic treatment should have been administered for at least 2 months prior to entry in the trial and the doses should not be changed throughout the trial.
8.Patients should have a transthoracic Doppler echocardiography considered as normal (left ventricular ejection fraction >55%, no significant morphological and/or no physiological anomaly, even if not symptomatic).
9.Women of childbearing potential (not surgically sterile or 2 years postmenopausal), must use a medically accepted method of contraception, and must continue one method for the duration of the study (and for 30 days after participation in the study). Acceptable methods of contraception include: abstinence, barrier method with spermicide, steroidal contraceptive (oral, transdermal, implanted, and injected) in conjunction with a barrier method, or intrauterine device (IUD).
10.Informed consent must be obtained for all subjects before enrollment in the study (including specific request for HIV serology and hepatitis as well as for urine screen for drug).

E.4

Principal exclusion criteria

1.Patients with an untreated sleep apnea syndrome (respiratory disorder index > 30/h) or who have any other cause of daytime sleepiness as assessed on patient history.
2.Patients working in an occupation requiring variable shift work or routine night shifts.
3.Patients with suicidal ideations or that has tried to commit suicide in the past 6 months.
4.Psychiatric and neurological disorders, other than narcolepsy/cataplexy, such as Parkinson’s disease, Alzheimer’s disease, Huntington’s Chorea, multiple sclerosis, moderate or severe psychosis or dementia, bipolar illness, epilepsy, severe clinical anxiety or depression, BDI ≥ 21 or with suicidal risk (if item > 0), or other problem that in the investigator’s opinion would preclude the patient’s participation and completion of this trial or comprise reliable representation of subjective symptoms.
5.Patients currently under one of the following medications (CNS indication):
a. Neuroleptic, anxiolytic, anticonvulsant, antiemetic (excepted domperidone), opioid, benzodiazepine (zolpidem/ zopiclone however authorized), psychostimulants (except modafinil).
b. Antidepressants (selective serotonin reuptake inhibitor or modulators, tri- and tetracyclic antidepressants, monoamine oxydase inhibitors) may be given to patients with mild or moderate unipolar depression providing the treatment is maintained at stable dose for at least 6 weeks, is anticipated to remain stable during the study, is well tolerated and devoid of orthostatic hypotension and QTc prolongation as documented at Visit 2 (baseline).
6.Current or recent (within one year) history of a substance abuse or dependence disorder including alcohol abuse as defined in Diagnostic and Statistical Manual of Mental Disorders (DSM-IV).
7.Other active clinically significant illness, including unstable cardiovascular, or neoplasic pathology which could interfere with the study conduct or counter-indicate the study treatments or place the patient at risk during the trial or compromise the study participation.
8.Contraindication to flecainide (2nd or 3rd grade atrioventricular block, bifascicular block, complete left bundle branch block, sick sinus syndrome and associated pathologies (such as alternating bradycardia-tachycardia), ventricular arrhythmias if considered as risk, cardiac insufficiency, documented Brugada syndrome, cardiogenic shock, recent or previous myocardial infarction).
9. Patients currently treated or planned to be treated with anti-arrhythmic drugs class I or with compounds eliciting bradycardia
10.Concomitant therapy which could elicit drug-drug interactions with flecainide as per SmPC, thus increasing or decreasing plasma concentrations
11.Patients with a known history of long QTc syndrome (e.g. syncope or arrhythmia) or presenting any significant serious abnormality of the ECG (e.g. recent myocardial infarction), or QTcf interval higher than 450 ms (electrocardiogram Fredericia’s corrected QT interval).
12.Patients with Severe Hepatic or Renal Impairment, or with any other significant abnormality in the physical examination or clinical laboratory results.
13.Known hypersensitivity to the tested treatment including active substances and excipients for modafinil SmPC and excipients for flecainide capsules (Section 5.1.1)
14.Women of childbearing potential who intend to be pregnant during the next few months.
15.Patients without any medical care insurance, or protected by the law (curatelle/tutelle).
16.Patients participating in any other clinical trial within 60 days prior to entry in this study or still in the protected period imposed by a previous study.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is the mean Epworth Sleepiness Scale (ESS) total score at the end of each treatment period

E.5.1.1

Timepoint(s) of evaluation of this end point

ESS done at each visit: pre-study, V 1 to V6

E.5.2

Secondary end point(s)

Efficacy
•Good response on ESS scale: decrease from baseline ΔESS ≥3
•Absence of residual somnolence: ESS <11
•Daily sleepiness assessment (modified ESS for EDS daily pattern)
•14-item fatigue scale
•European Scale of Quality of Life (EQ-5D)
•PGI-S (Patient Global Impression for Severity)
•PGI-C (Patient Global Impression for Change vs. baseline)
•CGI-S (Clinical Global Impression for Severity) for sleepiness and cataplexy
•CGI-C for change vs. baseline for sleepiness and cataplexy
• Information reported on patient diary – completed at home before each visit: Number of diurnal involuntary episodes of sleepiness, Number of diurnal involuntary sleep attacks, Number and duration of voluntary naps and total duration during day time, Number of cataplexy episodes: partial vs generalised, Occurrence of hypnagogic hallucinations and sleep paralysis, Nocturnal awakening, Total duration of nocturnal sleep time.

Safety and Tolerability
•Adverse events
•Vital signs
•ECG
•Physical examination
•Biological safety: With emphasis on renal and hepatic markers, urinalysis; Pregnancy test in urine for women of child-bearing potential)
•Beck Depression Inventory (BDI) evaluation for depressive symptoms

Plasma concentrations for modafinil and flecainide at steady state

E.5.2.1

Timepoint(s) of evaluation of this end point

Efficacy
6 times, V1 to V6

Safety and Tolerability
•Adverse events: spontaneous reporting from signing informed consent to study completion
•Vital signs at each visit: 6 times, V1 to V6)
•ECG: 6 times, V1 to V6
•Physical examination: 2 complete at V1 and V6, 4 abbreviated at V 2, V3, V4, and V5
•Biological safety: performed 6 times, 3 complete at V0 or V1, V2 and V6, 3 abbreviated for biochemistry for V3, V4, and V5
•BDI, 6 times, V1 to V6

Plasma concentrations for modafinil and flecainide at steady state:
•Time points: 5 plasma samples at V1 to V5
•Additional PK sample(s) if any additional visit for any reason between Day 16 and 60

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

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

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

Yes

E.6.13.1

Other scope of the trial description

IIa, Proof of concept

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

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

E.8.1.6

Cross over

Yes

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

Yes

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Modafinil

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

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

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

LVLS

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

E.8.9.2

In all countries concerned by the trial days

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:

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

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

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)

None

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

2018-05-29

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-04-25

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2018-12-17

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