Clinical Trials Register

Summary
EudraCT Number:	2018-003144-23
Sponsor's Protocol Code Number:	2017/81
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2018-08-09
Trial 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

2018-003144-23

A.3

Full title of the trial

Treating severe brain-injured patients with apomorphine : a behavioural and neuroimaging study

Traitement des patients cérébro-lésés avec l'apomorphine : une étude comportementale et de neuroimagerie

A.3.1

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

Treating severe brain-injured patients with apomorphine

Traitement des patients cérébro-lésés avec l'apomorphine

A.4.1

Sponsor's protocol code number

2017/81

A.5.4

Other Identifiers

Name:

Belgian national number

Number:

B707201731937

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	University of Liège
B.1.3.4	Country	Belgium
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Britannia Pharmaceuticals Limited
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	University of Liège
B.5.2	Functional name of contact point	Coma Science Group
B.5.3	Address:
B.5.3.1	Street Address	CHU de Liège, B34, Avenue de l'Hopital, 1
B.5.3.2	Town/ city	Liège
B.5.3.3	Post code	4000
B.5.3.4	Country	Belgium
B.5.4	Telephone number	+3243233614
B.5.6	E-mail	coma@uliege.be
B.Sponsor: 2
B.1.1	Name of Sponsor	CHU Liège
B.1.3.4	Country	Belgium
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Britannia Pharmaceuticals Ltd
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	CHU Liège
B.5.2	Functional name of contact point	Clinical Trial Center
B.5.3	Address:
B.5.3.1	Street Address	Avenue de l'Hôpital 1
B.5.3.2	Town/ city	Liège
B.5.3.3	Post code	4000
B.5.3.4	Country	Belgium
B.5.6	E-mail	audrey.janssen@chuliege.be

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	APO-go® PFS 5 mg/ml Solution for Infusion
D.2.1.1.2	Name of the Marketing Authorisation holder	Britannia Pharmaceuticals Ltd.
D.2.1.2	Country which granted the Marketing Authorisation	Belgium
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.3.4	Pharmaceutical form	Solution for infusion in pre-filled syringe
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Apomorphine Hydrochloride
D.3.9.1	CAS number	314-19-2
D.3.9.3	Other descriptive name	ANHYDROUS APOMORPHINE HYDROCHLORIDE
D.3.9.4	EV Substance Code	SUB127079
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
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	Solution for injection
D.8.4	Route of administration of the placebo	Subcutaneous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Disorders of consciousness

Troubles de la conscience

E.1.1.1

Medical condition in easily understood language

Disorders of consciousness

Troubles de la conscience

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

This clinical trial aims to clarify the prevalence of responders and the efficacy of apomorphine hydrochloride subcutaneous infusions for the treatment of patients with disorders of consciousness.

Cet essai clinique vise à clarifier la prévalence des répondeurs et l'efficacité du chlorhydrate d'apomorphine par infusions sous-cutanées pour le traitement des patients présentant des troubles de la conscience.

E.2.2

Secondary objectives of the trial

This study aims to also better characterize the phenotype of potential good candidates to apomorphine treatment and identify a set of biomarkers that correlate with responsiveness (or non-responsiveness) to the therapy, as well as help underpin the neural networks underlying the modulating action of apomorphine on consciousness.

Cette étude vise également à mieux caractériser le phénotype des candidats potentiels répondeurs au traitement par apomorphine et à identifier les biomarqueurs en corrélation avec le degré de réponse au traitement, ainsi qu'à mettre en évidence les réseaux neuronaux sous-jacents à l'action modulatrice de l'apomorphine sur la conscience.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

"Treating severe brain-injured patients with apomorphine: a behavioral and neuroimaging pilot study", protocol version 5.1, dated 07/06/2024.

The open-label pilot part on 6 patients with disorders of consciousness is designed to evaluate the feasibility of the subsequent randomized clinical trial, as well as provide initial data on responsiveness rates to apomorphine treatment, phenotype of responders and effect size.

The double-blind randomized controlled part on 48 patients (24 patients will be randomly assigned to the apomorphine and 24 to the placebo group) is designed to verify the effects of apomorphine subcutaneous infusion in patients with disorders of consciousness and investigate the neural networks targeted by this treatment.

"Traitement des patients cérébro-lésés avec l'apomorphine : une étude pilote comportementale et en neuroimagerie", protocole version 5.1, daté du 07/06/2024.

Cette étude pilote préliminaire en open-label sur 6 patients présentant des troubles de la conscience vise à évaluer la faisabilité de l'essai clinique randomisé ultérieur et fournir des données initiales sur les taux de répondeurs au traitement par apomorphine, le phénotype des répondeurs et l'intensité de l'effet observé.

La partie contrôlée randomisée en double aveugle sur 48 patients (24 patients seront assignés aléatoirement au groupe apomorphine et 24 au groupe placebo) a pour objectif de vérifier les effets de l'apomorphine en perfusion sous-cutanée chez des patients présentant des troubles de la conscience et d'étudier les réseaux neuronaux ciblés par ce traitement.

E.3

Principal inclusion criteria

- 18-80 years old.
- Clinically stable, not dependent on medical ventilators for respiration.
- Diagnosed as in an unresponsive wakefulness syndrome or minimally conscious state according to the international criteria and based on at least 2 consistent CRS-R in the last 14 days (one CRS-R in the last 7 days).
- More than 6 weeks post-insult
- Informed consent from patient or legal representative of the patient.

- Patient âgé de 18 à 80 ans.
- Cliniquement stable, ne dépendant pas des ventilateurs médicaux pour la respiration.
- Diagnostic de syndrome d'éveil non-répondant ou d'état de conscience minimale selon les critères internationaux et basé sur au moins 2 CRS-R concordantes au cours des 14 derniers jours (une CRS-R au cours des 7 derniers jours).
- Plus de 6 semaines depuis la lésion cérébrale
- Consentement éclairé du patient ou du représentant légal du patient.

E.4

Principal exclusion criteria

- Use of dopamine agonists or antagonists (e.g. amantadine, bromocriptine, l-dopa, pramipexole, ropinirole, amphetamine, bupropion, methylphenidate / risperidone, haloperidol, chlorpromazine, flupentixol, clozapine, olanzapine, quetiapine) in the last 2 weeks or 4 half-lives of the drug.
- Use of neurological medications other than anti-epileptic or anti-spasticity drugs in the last 2 weeks or 4 half-lives of the drug.
- Use of drugs with known significant prolongation of the QT interval (e.g. class 1 antiarrythmics, sotalol, macrolides, quinolones, antipsychotic drugs, tricyclic antidepressants, methadone, chloroquine, quinine) in the last 2 weeks or 4 half-lives of the drug.
- A corrected QT interval over 480ms (calculated using Bazett’s formula on a standard 12-lead ECG recorded in the last 14 days) or other risk factors for arrhythmia (congestive cardiac failure, severe hepatic impairment or significant electrolyte disturbance).
- A history of previous neurological functional impairment other than related to their acquired brain injury.
- Contraindication to MRI, EEG, or PET (e.g., electronic implanted devices, active epilepsy, external ventricular drain).
- Use of nitrates or other vasodilators, central nervous system acting agents such as barbiturates, morphine and related drugs (relative exclusion criterion)

- Utilisation d'agonistes ou d'antagonistes de la dopamine (par exemple amantadine, bromocriptine, L-dopa, pramipexole, ropinirole, amphétamines, bupropion, méthylphénidate / risperidone, halopéridol, chlorpromazine, flupentixol, clozapine, olanzapine, quétiapine) au cours des 2 dernières semaines ou quatre demi-vies du médicament.
- Utilisation de médicaments à action neurologique autres que les médicaments antiépileptiques ou antispastiques au cours des 2 dernières semaines ou 4 demi-vies du médicament.
- Utilisation de médicaments provoquant prolongation documentée de l'intervalle QT (par exemple antiarythmiques de classe 1, sotalol, macrolides, quinolones, antipsychotiques, antidépresseurs tricycliques, méthadone, chloroquine, quinine) au cours des 2 dernières semaines ou 4 demi-vie du médicament.
- Un intervalle QT corrigé supérieur à 480ms (calculé en utilisant la formule de Bazett sur un ECG standard à 12 dérivations enregistré dans les 14 derniers jours) ou d'autres facteurs de risque d'arythmie (insuffisance cardiaque congestive, insuffisance hépatique grave ou perturbation électrolytique significative).
- antécédents d'atteinte neurologique autre que la lésion cérébrale acquise.
- Contre-indication à l'IRM, à l'EEG ou à la TEP (par exemple dispositifs implantés électroniques, épilepsie active, drain ventriculaire externe).
- Utilisation de nitrates ou d’autres vasodilatateurs, d’agents agissant sur le système nerveux central tels que les barbituriques, morphiniques (critère d’exclusion relative)

E.5 End points

E.5.1

Primary end point(s)

Change of diagnosis, total score and subscores from baseline in Coma Recovery Scale - Revised (CRS-R).

Changement de diagnostic, score total et sous-scores par rapport à la baseline en utilisant l'échelle de récupération du coma - Révisé (CRS-R).

E.5.1.1

Timepoint(s) of evaluation of this end point

Once a week from inclusion until day 90.

Une fois par semaine depuis l'inclusion jusqu'au jour 90.

E.5.2

Secondary end point(s)

1-Change of total score in Nociception Coma Scale - Revised (NCS-R).
2-Changes of total score in Disability Rating Scale (DRS).
3-Changes of total number of achieved items and highest achieved item in Wessex Head Injury Matrix (WHIM).
4-Change in circadian rhythmicity using actimetry.
5-Changes in MRI functional connectivity using a seed-voxel approach, between regions of interest (here: striatum, globus pallidus interna, thalamus and prefrontal cortex) and the time course from all other brain voxels.
6-Changes in quantification of PET signal using standardized uptake values of fluorodeoxyglucose (SUV).
7-Changes in conventional EEG spectral power within fixed bands or dynamic connectivity using median spectral connectivity and graph-theoretic topology metrics
8-Change in the architecture of sleep cycles using 24h-EEG.
9-Changes in the probabilty of consciousness using a multivariate EEG classifier based on a machine-learning approach using 120 EEG markers.
10-Change of score in Glasgow Outcome Scale - Extended (GOS-E).
11-Change in diagnosis in Phone-adapted CRS-R.

1-Changement du score total dans la Nociception Coma Scale - Revised (NCS-R).
2-Changement du score total dans la Disability Rating Scale (DRS).
3-Changement du nombre total d'items atteints et de l'item atteint le plus élevé dans la Wessex Head Injury Matrix (WHIM).
4-Changement de la rythmicité circadienne utilisant l'actimétrie.
5-Modification de la connectivité fonctionnelle en utilisant une approche seed-voxels, entre les régions d'intérêt (ici striatum, globus pallidus interna, thalamus et cortex préfrontal) et tous les autres voxels cérébraux.
6-Changements dans la quantification du signal en utilisant des valeurs d'absorption normalisées du fluorodésoxyglucose (SUV).
7-Changement de la puissance spectrale dans des bandes fixes de fréquences ou de connectivité dynamique en utilisant la connectivité spectrale médiane et des mesures topologiques de la théorie des graphes.
8-Changement de l'architecture des cycles de sommeil par EEG de 24h.
9-Changement de la probabilité de conscience donnée par un classificateur EEG multivarié basé sur une approche de machine-learning utilisant 120 marqueurs EEG.
10-Changement de score à la Glasgow Outcome Scale - Extended (GOS-E).
11-Changement de diagnostic à la CRS-R adaptée à l'entretien téléphonique.

E.5.2.1

Timepoint(s) of evaluation of this end point

1-Once a week from inclusion until day 90.
2-Once a week from inclusion until day 90.
3-Once a week from inclusion until day 90.
4-Continuously from inclusion until day 90.
5-Before treatment initiation.
6-Before treatment initiation and after treatment completion.
7-Once a week from inclusion until day 90.
8-Before treatment initiation and after treatment completion.
9-Before treatment initiation and after treatment completion.
10-At 6 months, 12 months and 24 months after treatment initiation.
11-At 6 months, 12 months and 24 months after treatment initiation.

1- Une fois par semaine de l'inclusion jusqu'au jour 90.
2-Une fois par semaine de l'inclusion jusqu'au jour 90.
3-Une fois par semaine de l'inclusion jusqu'au jour 90.
4-En continu depuis l'inclusion jusqu'au jour 90.
5-Avant le début du traitement.
6-Avant le début du traitement et après la fin du traitement.
7-Une fois par semaine de l'inclusion jusqu'au jour 90.
8-Avant le début du traitement et après la fin du traitement.
9-Avant le début du traitement et après la fin du traitement
10-A 6 mois, 12 mois et 24 mois après le début du traitement.
11-A 6 mois, 12 mois et 24 mois après le début du traitement.

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

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

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)

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

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

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

Last follow-up phone call of the last subject

Dernier appel téléphonique de suivi du dernier sujet

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

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