Clinical Trials Register

Summary
EudraCT Number:	2015-001523-24
Sponsor's Protocol Code Number:	14744001
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2016-04-20
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

France - ANSM

A.2

EudraCT number

2015-001523-24

A.3

Full title of the trial

Evaluation of the analgesic effects of prolonged-release oxycodone and of L-Dopa, versus placebo, on central neuropathic pain in Parkinson's disease : OXYDOPA trial

Evaluation des effets antalgiques de l'oxycodone à libération prolongée et de la L-Dopa, versus placebo, sur la douleur neuropathique centrale du patient parkinsonien : Essai OXYDOPA.

A.3.1

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

Evaluation of the pain relief of prolonged-release oxycodone and of L-Dopa, versus placebo, in Parkinson's disease.

Evaluation de la diminution de la douleur liée à la maladie de Parkinson par l'oxycodone à libération prolongée et la L-Dopa versus placebo.

A.3.2

Name or abbreviated title of the trial where available

OXYDOPA

A.4.1

Sponsor's protocol code number

14744001

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	UHToulouse
B.1.3.4	Country	France
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	Ministry of health
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	UHToulouse
B.5.2	Functional name of contact point	Huguet
B.5.3	Address:
B.5.3.1	Street Address	Hotel-Dieu, 2 rue Viguerie, TSA 80039
B.5.3.2	Town/ city	Toulouse
B.5.3.3	Post code	31059
B.5.3.4	Country	France
B.5.4	Telephone number	05 61778490+33
B.5.5	Fax number	05 61778411+33
B.5.6	E-mail	huguet.a@chu-toulouse.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	Yes
D.2.1.1.1	Trade name	oxycontin LP 5mg
D.2.1.1.2	Name of the Marketing Authorisation holder	MUNDIPHARMA
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	Oxycontin LP 5mg
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	oxycodone
D.3.9.1	CAS number	124-90-3
D.3.9.3	Other descriptive name	OXYCODONE HYDROCHLORIDE
D.3.9.4	EV Substance Code	SUB03583MIG
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	oxycontin LP 10mg
D.2.1.1.2	Name of the Marketing Authorisation holder	MUNDIPHARMA
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	Oxycontin LP 10mg
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	oxycodone
D.3.9.1	CAS number	124-90-3
D.3.9.3	Other descriptive name	OXYCODONE HYDROCHLORIDE
D.3.9.4	EV Substance Code	SUB03583MIG
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	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.IMP: 3
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	oxycontin LP 20mg
D.2.1.1.2	Name of the Marketing Authorisation holder	MUNDIPHARMA
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	Oxycontin LP 20mg
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	oxycodone
D.3.9.1	CAS number	124-90-3
D.3.9.3	Other descriptive name	OXYCODONE HYDROCHLORIDE
D.3.9.4	EV Substance Code	SUB03583MIG
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.IMP: 4
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	Modopar 125
D.2.1.1.2	Name of the Marketing Authorisation holder	ROCHE
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	Modopar 125
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	levodopa
D.3.9.3	Other descriptive name	LEVODOPA
D.3.9.4	EV Substance Code	SUB08468MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	150
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	BENSERAZIDE
D.3.9.1	CAS number	322-35-0
D.3.9.4	EV Substance Code	SUB05731MIG
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	25
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: 5
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	Modopar 62,5
D.2.1.1.2	Name of the Marketing Authorisation holder	ROCHE
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	Modopar 62,5
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	levodopa
D.3.9.3	Other descriptive name	LEVODOPA
D.3.9.4	EV Substance Code	SUB08468MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	150
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	BENSERAZIDE
D.3.9.1	CAS number	322-35-0
D.3.9.4	EV Substance Code	SUB05731MIG
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	14.25
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
D.8 Placebo: 3
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: 4
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
D.8 Placebo: 5
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

Central neuropathic pain in Parkinson's disease

douleurs neuropathique liées à la maladie de Parkinson

E.1.1.1

Medical condition in easily understood language

Pain in parkinson's disease

douleurs liées à la maladie de parkinson

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	19.0
E.1.2	Level	LLT
E.1.2	Classification code	10054095
E.1.2	Term	Neuropathic pain
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 evaluate the respective effects of two drugs, oxycodone and levodopa, administered over a period of 8 weeks at stable dosage, versus placebo, on PD-related central neuropathic pain intensity (average intensity over the preceding week) in PD patients.

L’objectif principal de cette étude est d’évaluer les effets respectifs de deux médicaments, l’oxycodone et la lévodopa, administrés pendant 8 semaines, contre placebo, sur l’intensité des douleurs neuropathiques centrales liées à la maladie de Parkinson (intensité moyenne sur la semaine précédente) chez les patients parkinsoniens.

E.2.2

Secondary objectives of the trial

Evaluate :
-The respective effects of oxycodone and levodopa, versus placebo, on the different components of pain through various clinical pain questionnaires
-The response rates based on 30% and 50% in each groups
-The use of rescue analgesic medication (acetaminophen) in the three groups
-The respective effects of oxycodone and levodopa, versus placebo, on behavioral symptoms (depression, anxiety, apathy, fatigue, sleep disorders), motor symptoms and quality of life
-The putative correlation between changes in motor status and variations of pain intensity
- A head-to-head comparison of the effects of oxycodone versus levodopa on clinical pain parameters
-The safety and tolerability of each drug

The exploratory objective is to evaluate the respective effects of oxycodone and levodopa, versus placebo, on resting-state brain network changes (3T fMRI), to identify the pathophysiological mechanisms underlying the analgesic effect of each drug.

Evaluer:
-Les effets respectifs de l’oxycodone et de la lévodopa, contre placebo, sur les différentes composantes de la douleur via différents questionnaires cliniques de douleur.
-Les taux de patients répondeurs c’est-à-dire ayant une amélioration de 30% et de 50% de leur intensité douloureuse dans chaque groupe.
-Le recours à des traitements antalgiques de secours (paracétamol) dans les trois groupes.
-Les effets respectifs de l’oxycodone et de la lévodopa, contre placebo, sur les symptômes comportementaux (dépression, anxiété, apathie, fatigue, troubles du sommeil), les symptômes moteurs et la qualité de vie.
-L’éventuelle corrélation entre les modifications de l’état moteur et les variations de l’intensité douloureuse.
-La comparaison des effets de l’oxycodone par rapport à ceux de la lévodopa sur les paramètres cliniques de douleur
-Le profil de sécurité et la tolérance de chaque médicament

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

-Patients with Parkinson’s disease according to the UKPDSBB criteria
-Patients aged 40 to 75 years (male or female)
-Patients suffering from chronic pain (lasting for more than 3 months)
-Patients suffering from central neuropathic pain caused by PD, as identified with a two-part clinical questionnaire:
The first part assesses the causality of the link between PD and pain i.e. pain is considered to be related to PD if the patient reports at least three of the following five features:
- Pain is chronologically related to PD (occurring at the onset of PD or influenced by motor condition)
- Pain located in the half of the body most severely affected by PD (topographical relationship to PD)
- Pain is influenced by dopaminergic drugs
- Pain is not related to any other evident etiology (rheumatic, traumatic or orthopedic disorders)
- The patient identifies a link between pain and disease
The second part identifies central neuropathic pain i.e. pain is considered to be central neuropathic pain if it fulfills the two following criteria:
- There is no radicular systematization
- Symptoms are defined as having the clinical characteristics of neuropathic pain with the DN4 interview questionnaire

-Patients with a PD-related central neuropathic pain intensity of at least 3 points on the VAS (average intensity over the last month),
-Patients with both types of pain (neuropathic and nociceptive) will be included if the neuropathic pain predominates (higher intensity)
-Patients treated with a stable regimen of dopaminergic drugs (levodopa and/or dopamine agonists) for at least 4 weeks before the study dan thoughout the study
-Patients with a stable step 1 analgesic (NSAIDS, acetaminophen) or coanalgesic (antidepressants, antiepileptic) treatment for at least 4 weeks before the study and throughout the study
-Patients with health insurance
-Patients who have signed a written informed consent form

-Patients présentant une maladie de Parkinson selon les critères de l’UKPDSBB
-Patients âgés de 40 à 75 ans (homme ou femme)
-Patients souffrant d’une douleur chronique (durant depuis au moins 3 mois)
-Patients souffrant d’une douleur neuropathique centrale liée à la maladie de Parkinson, identifiée à l’aide d’un questionnaire clinique composé de deux parties :
La première partie évalue le lien entre la maladie de Parkinson et la douleur. La douleur est considérée comme liée à la maladie de Parkinson si elle répond à au moins 3 de ces 5 caractéristiques :
- La douleur est liée chronologiquement à la MP (apparue en début de maladie ou influencée par l’état moteur)
- La douleur est localisée dans l’hémicorps le plus atteint par la maladie (relation topographique avec la MP)
- La douleur est influencée par les traitements dopaminergiques
- La douleur n’est pas attribuée à aucune autre cause évidente (rhumatisme, pathologie orthopédique ou traumatique)
- Le patient établit un lien entre sa douleur et sa MP
La seconde partie permet d’identifier la nature neuropathique centrale de la douleur. La douleur est considérée comme étant de type neuropathique si elle répond aux deux critères suivants :
- Elle ne présente pas de systématisation périphérique
- Les symptômes douloureux présentent les caractéristiques cliniques de la douleur neuropathique selon la partie « Interrogatoire du patient » du DN4

-Patients présentant une intensité douloureuse supérieure ou égale à 3 sur l’EVA de leur douleur neuropathique centrale liée à la MP (intensité moyenne sur le dernier mois)
-Les patients présentant les deux types de douleurs (neuropathique et nociceptif) pourront être inclus si la douleur neuropathique est prédominante (intensité supérieure)
-Patients ayant un traitement dopaminergique (lévodopa et/ou agonistes dopaminergiques) stable depuis au moins 4 semaines avant le début de l’étude et restant stable durant toute l’étude
-Patients prenant un traitement antalgique de palier 1 (AINS, paracétamol) ou des coanalgésiques (antidépresseurs, antiépileptiques) de façon stable depuis au moins 4 semaines avant le début de l’étude
-Patients affiliés à un régime de sécurité sociale
-Patients ayant signé le formulaire de consentement éclairé

E.4

Principal exclusion criteria

General exclusion criteria:
-Patients suffering from another parkinsonian syndrome (multiple system atrophy, progressive supranuclear palsy etc.)
-De Novo patients (patients never before treated with dopaminergic drugs)
-Patients with intercurrent acute pain
-Patients suffering from a chronic disease causing pain (rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathy, cancer etc.)Patients treated with neuroleptics (clozapine, risperidone etc.)
-Patients treated by deep brain stimulation
-Patients with clinically detectable behavioural disorders (impulse control disorder, hallucinations, delirium) and addiction
-Patients with disabling dyskinesias (items MDS-UPDRS 4.1 and 4.2 >1)
-Patients with painful restless legs syndrome
-Patients with cognitive impairment (MMS < 25) or unable to complete the various scales used in the study
-Patients under juridical protection
-Patients refusing to participate
-Women pregnant, nursing or of childbearing age without effective contraception.

Exclusion criteria relating to treatments:
-Hypersensitivity to oxycodone, levodopa, benserazide or a combination of these drugs
-Patients treated with opioid drugs (step 2 and 3)
-Patients treated with non-selective monoamine oxidase inhibitors (MAOI)
-Patients with severe hepatocellular insufficiency
-Patients with uncontrolled cardiovascular and pulmonary diseases
-Persistent constipation that has already resulted in a subocclusive state
-Patients treated with antiemetic neuroleptics
-Patients with angle-closure glaucoma

Exclusion criteria relating to MRI:
-Patients with claustrophobia
-Patients with a hearing aid, cardiac prosthesis, pacemaker, surgical clip
-Patients refusing to be informed of abnormalities are detected on MRI

Critères de non-inclusion généraux :
-Patients souffrant d’un syndrome n’évoquant pas une maladie de Parkinson idiopathique (atrophie multisystématisée, paralysie supranucléaire progressive, etc.)
-Patients de novo (jamais traités par des médicaments dopaminergiques)
-Patients présentant une douleur aigue intercurrente
-Patients souffrant d’une pathologie chronique occasionnant des douleurs (polyarthrite rhumatoïde, spondylarthrite ankylosante, neuropathie diabétique, cancer, etc.)
-Patients traités par neuroleptiques (clozapine, rispéridone, etc.)
-Patients traités par stimulation cérébrale profonde
-Patients présentant des troubles du comportement cliniquement décelables (trouble du contrôle des impulsions, hallucinations, délire) et une addiction
-Patients présentant des dyskinésies invalidantes (items 4.1 et 4.2 de la MDS-UPDRS > 1)
-Patients présentant un syndrome des jambes sans repos douloureux
-Patients présentant une altération cognitive (MMS < 25) ou incapable de compléter les différentes échelles de l’étude
-Patients sous régime de protection des majeurs
-Patients refusant de participer
-Femmes enceintes ou allaitantes
-Femmes en âge de procréer sans méthode de contraception efficace

Critères de non-inclusion liés aux traitements de l’étude :
-Hypersensibilité connue à l’oxycodone, à la lévodopa, au benserazide ou à un des composants de ces médicaments
-Patients traités par des médicaments opioïdes faibles ou forts (paliers 2 et 3)
-Patients traités par des inhibiteurs non sélectifs de la monoamine oxydase (IMAO)
-Patients présentant une insuffisance hépato-cellulaire sévère
-Patients souffrant d’une pathologie cardiovasculaire ou pulmonaire non contrôlée
-Patients présentant une constipation sévère ayant déjà résulté en un état sub-occlusif
-Patients traités par un antiémétique neuroleptique
-Patients avec un glaucome à angle fermé

Critères de non-inclusion liés à l’IRM :
-Patients présentant une claustrophobie
-Patients porteurs de prothèses auditives, cardiaques, pacemakers, clips chirurgicaux
-Patients refusant d’être informés en cas d’anomalies décelées à l’IRM

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint of this study is the change in average pain intensity over the preceding week, rated on a visual analog scale (VAS) (from 0 = no pain to 10 = maximal pain) between D0 (baseline) and D71 (after 8 weeks of treatment with a stable dose). Pain intensity on the VAS is a validated clinical criterion for the global assessment of both discriminative and emotional aspects of pain.

Le critère de jugement principal de cette étude est la variation de l’intensité douloureuse moyenne sur la semaine précédente, cotée sur une échelle visuelle analogique (EVA) (de 0 = pas de douleur à 10 = douleur maximale imaginable), entre J0 (inclusion) et J71 (après 8 semaines de traitement à dose fixe). L’intensité douloureuse sur l’EVA est un critère clinique validé pour l’évaluation globale des aspects discriminatifs et émotionnels de la douleur.

E.5.1.1

Timepoint(s) of evaluation of this end point

Between D0 (baseline) and D71 (after 8 weeks of treatment with a stable dose).

Entre J0 (inclusion) et J71 (après 8 semaines de traitement à dose fixe)

E.5.2

Secondary end point(s)

The secondary endpoints are:
-The change in maximal pain intensity over the preceding week rated on the VAS (maximum ΔVAS) between D0 and D71.
-The proportion of patients experiencing at least 30% and 50% pain relief between D0 and D71
-The change in scores for various validated questionnaires of pain, behavior, quality of life and motor status between D0 and D71:
- Pain: “Functional impact of pain” of the Brief Pain Inventory (BPI); Neuropathic Pain Symptoms Inventory (NPSI); McGill pain questionnaire (SF-MPQ)
- Depression and anxiety: the Hospital Depression and Anxiety (HAD) scale
- Apathy: the Lille Apathy Rating Scale (LARS)
- Fatigue : the Parkinson fatigue scale
- Sleep : the Pittsburg sleep quality index
- Motor assessment and motor fluctuations: MDS-UPDRS
- Quality of life: Parkinson’s Disease Questionnaire 39 items (PDQ-39)
-Acetaminophen consumption (diary)
-Adverse events, evaluated with an open-ended questionnaire

-The exploratory criterion will be the changes in resting-state cerebral networks between D0 and D71, as assessed by 3T fMRI.

Les critères de jugement secondaires sont :
-La variation de l’intensité douloureuse maximale sur la semaine précédente cotée sur l’EVA (ΔEVA maximale) entre J0 et J71
-La proportion de patients bénéficiant d’une amélioration de leur douleur d’au moins 30% ou 50% entre J0 et J71
-La variation des scores à différents questionnaire validés de douleur, d’état psychologique, de comportement, de qualité de vie, de sommeil et d’état moteur entre J0 et J71 :
- Douleur : Partie « Retentissement fonctionnel de la douleur » du questionnaire concis sur la douleur (Brief Pain Inventory – BPI) ; Questionnaire sur les douleurs neuropathiques (Neuropathic Pain Symptoms Inventory – NPSI) ; Questionnaire Mc Gill version courte (SF-MPQ)
- Dépression et anxiété : échelle « Hospital Depression and Anxiety » (HAD)
- Apathie : échelle « Lille Apathy Rating Scale » (LARS)
- Fatigue : échelle « Parkinson Fatigue Scale » (PFS)
- Sommeil : Index de qualité du sommeil de Pittsburg (PSQI)
- Etat moteur et fluctuations motrices : MDS-UPDRS
- Qualité de vie : Parkinson’s Disease Questionnaire 39 items (PDQ-39)

-Consommation de paracétamol (carnet de bord patient)
-Effets indésirables évalués à l’aide d’un questionnaire ouvert

-Le critère exploratoire est la modification des réseaux cérébraux au repos entre J0 et J71, évaluée en IRMf.

E.5.2.1

Timepoint(s) of evaluation of this end point

The secondary endpoints are evaluated between between D0 and D71.
The Acetaminophen consumption and the adverse events are evaluated pending the participation of each patient.

Les critères de jugement secondaires sont entre J0 et J71.
La consommation de paracetamol et les effets secondaires sont évalués durant toute la participation de chaque patient.

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

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)

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)

Yes

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

LVLS

Dernière visite du dernier patient

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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.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

2016-03-25

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-08-26

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2020-11-17

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