Clinical Trials Register

Summary
EudraCT Number:	2019-004740-30
Sponsor's Protocol Code Number:	PHRCN2018
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2022-01-19
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

2019-004740-30

A.3

Full title of the trial

Cannabidiol for reducing drinking in alcohol use disorder and modifying the effects of alcohol on the brain and the liver: a phase 2 clinical trial.

Le cannabidiol dans la réduction de la consommation d'alcool chez les patients souffrant de troubles liés à l’usage d'alcool et dans la modification des effets de l'alcool sur le cerveau et le foie : un essai clinique de phase 2.

A.3.1

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

Cannabidiol for reducing drinking in alcohol use disorder and modifying the effects of alcohol on the brain and the liver

A.3.2

Name or abbreviated title of the trial where available

The CARAMEL Study

Etude CARAMEL

A.4.1

Sponsor's protocol code number

PHRCN2018

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	Centre Hospitalier Le Vinatier
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	DGOS-PHRCN2018
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	Centre Hospitalier Le Vinatier
B.5.2	Functional name of contact point	Principal investigator
B.5.3	Address:
B.5.3.1	Street Address	95 Boulevard Pinel - BP 30039
B.5.3.2	Town/ city	BRON Cedex
B.5.3.3	Post code	69678
B.5.3.4	Country	France
B.5.4	Telephone number	00330437915075
B.5.5	Fax number	00330437915076
B.5.6	E-mail	benjamin.rolland@univ-lyon1.fr

D. IMP Identification
D.IMP: 1
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	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	cannabidiol
D.3.4	Pharmaceutical form	Sublingual tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Sublingual use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Cannabidiol
D.3.9.1	CAS number	13956-29-1
D.3.9.3	Other descriptive name	CANNABIDIOL
D.3.9.4	EV Substance Code	SUB26600
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	40 to 600
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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	Sublingual tablet
D.8.4	Route of administration of the placebo	Sublingual use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

CARAMEL is an exploratory phase-2 study conducted in subjects with AUD (alcohol use disorder) and current heavy drinking level, aiming to confirm the different properties of CBD observed in animal studies on models of AUD.

CARAMEL est une étude exploratoire de phase 2 menée chez des sujets gros consommateurs présentant un TUA (trouble de l'usage d'alcool), dans le but de confirmer les différentes propriétés du CBD observées lors d'études animales.

E.1.1.1

Medical condition in easily understood language

Participants meeting the DSM-5 criteria for AUD, with a current drinking level of 12 sd/d (120g/d of ethanol) or more, every day, over 28 days preceding the study.

Participants répondant aux critères de TUA du DSM-5, avec un niveau de consommation à l’inclusion de 12 verres standards / jour (120 g d’éthanol /jour) ou plus sur les 28 jours précédant l'étude.

E.1.1.2

Therapeutic area

Psychiatry and Psychology [F] - Mental Disorders [F03]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10001590
E.1.2	Term	Alcohol addiction
E.1.2	System Organ Class	100000004873

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 primary objective of the CARAMEL study is to compare the reduction in alcohol drinking between CBD and placebo (PCB), in a population of patients with AUD and heavy drinking level at baseline (i.e., 12 standard drinks (sd)/day or more).

The drinking reduction level will be defined by the total consumption in the 28 days prior to inclusion, minus the total consumption of the 28 last days of the study (weeks 8 to 12).

L’objectif principal de l’étude CARAMEL est de comparer la réduction de la consommation d’alcool entre le CBD et un placebo (PCB) dans une population de patients souffrant d’un TUA et consommant a l’inclusion à minima 12 verres standards/jour.

Le niveau de réduction de consommation sera définit par le différentiel entre la consommation totale au cours des 28 jours précédents l'inclusion et la consommation totale des 28 derniers jours de l'étude (semaines 8 à 12).

E.2.2

Secondary objectives of the trial

Between-group comparison V0 (inclusion) and end of treatment (V4) :
important drinking outcomes (percentage of heavy drinking days, percentage of days with no drinking, difference in craving scores)
Other clinical parameters (anxiety and depression using the Hospital Anxiety and Depression Scale score).
Reduction of the Controlled Attenuation Parameter which measures liver steatosis using transient ultra-sound elastography
biological liver parameters (GGT, CDT, SGOT, SGPT, bilirubin).
biological parameters (PEth).
reduction in steatosis scores, using Proton Density Fat Fraction (PDFF) estimated on the structural liver based on Chemical Shift Encoding-MRI (CSE-MRI) and MR Spectroscopy (MRS).
Recovery of grey matter integrity in corticostriatal-limbic circuits, using MRI Voxel Based Morphometry (VBM) and cortical thickness measures.
Improvement in neuropsychological measures
comparison of the drinking level difference between last visit (V5) and end of treatment visit (V4).

Comparaison des groupes entre les visites d’inclusion (V0) et de fin de traitement (V4) des éléments suivants :
Critères de consommation d’alcool comme : pourcentage total de jours de forte consommation, pourcentage total de jours sans consommation d’alcool et la différence des scores de craving.
Paramètres cliniques : anxiété et la dépression à l'aide de l’échelle HADS.
Réduction du paramètre d’atténuation contrôlée : stéatose hépatique par élastographie impulsionnelle à vibration contrôlée.
Paramètres biologiques hépatiques : GGT, CDT, ALAT, ASAAT, bilirubine.
Marqueur biologique de consommation d’alcool : PEth.
Réduction des scores de stéatose (PDFF) estimée sur le foie structural via l'IRM codant l'effet chimique (CSE-MRI) et en spectroscopie à résonnance magnétique (MRS).
Volume de matière grise dans les circuits corticostriataux-limbiques mesuré par voxel-based morphometry (VBM), ainsi que mesure de l'épaisseur corticale.
Amélioration des mesures neuropsychologiques...

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Being aged 18 years, or more
Being fluent in French
Having read the information procedure and signed the informed consent sheet.
Being affiliated with health insurance.
DSM-5 criteria for AUD (all stages) (American Psychiatric Association, 2013)

Average drinking level of at least 12 standard-drinks (120g of ethanol) per day over the month prior to inclusion (i.e., a total alcohol consumption of 336 standard-drinks during the 28-day assessment period prior to inclusion), using the A-TLFB.

Etre majeur.
Comprendre le français
Les femmes en âge de procréer doivent avoir une contraception efficace (mesure de précaution).
Ne pas avoir consommé de cannabis dans les deux mois précédent l’étude.
Avoir un TUA selon le DSM-5
Niveau de consommation moyen d’au moins 12 verres standards (120 g d’éthanol) par jour sur le mois précédent l’inclusion (soit 336 verres standards sur les 28 jours précédant l’inclusion) en utilisant l’A-TLFB.

E.4

Principal exclusion criteria

At least one day of abstinence (no alcohol drinking) during the month prior to inclusion
Criteria for liver cirrhosis (Child-Pugh B or C)
DSM-5 criteria for schizophrenia, schizoaffective disorder, or bipolar disorder, using the MINI 7.0.2.
Current suicidality, using the MNI 7.0.2
Current DSM-5 criteria for substance use disorder (other than alcohol or nicotine) using the MINI 7.0.2.
Any detected use of cannabis or any other cannabinoid within 60 days prior to screen
Lifelong history of cannabis use disorder (DSM-5 criteria)
Patients with transaminase elevations greater than 3 times upper the limit of normal and bilirubin greater than 2 times upper the limit of normal.
Impaired medical condition (investigator's decision)
Pregnancy, lactation, or insufficient contraceptive measure (precautionary measure) (See 5.2 for acceptable birth control methods)
Patients with cancer, HIV, pulmonary arterial hypertension, epilepsy.
Patients receiving acamprosate, naltrexone, disulfiram, nalmefene, topiramate, baclofen for AUD within 30 days prior to screening.
MRI contraindication: pacemaker, insulin pump, heart metal valve, cochlear implant…
Known hypersensitivity to the active principle (cannabidiol) or excipients (sucralose, menthol, mannitol).
Person under tutorship.

Avoir au moins un jour d’abstinence (sans alcool) dans les 28 jours précédents l’inclusion.
Avoir des critères de cirrhose hépatique (Child-Pugh B ou C).
Avoir des critères du DSM-5 de schizophrénie, trouble schizoaffectif, bipolarité identifié à l’aide du MINI 7.0.2.
Avoir des idées suicidaires.
Avoir un trouble d’usage de substance autre qu’alcool ou nicotine identifié à l’aide du MINI 7.0.2.
Toute utilisation rapportée ou détectée de cannabis ou de tout autre cannabinoïde dans les 60 jours précédents l’inclusion.
Antécédent de trouble d’usage de cannabis (critère du DSM-5).
Les patients présentant des élévations de transaminases supérieures à 3 fois supérieures à la limite de la normale et la bilirubine supérieures à 2 fois supérieures à la limite de la normale.
Etat de santé altéré (décision médicale de l’investigateur).
Grossesse ou allaitement, absence de contraception efficace pour les femmes en âge de procréer.
Patients traités pour un cancer, le VIH, une hypertension artérielle pulmonaire ou une épilepsie.
Patients traités par acamprosate, naltrexone, disulfiram, nalmefène, topiramate, baclofène pour un TUA.
Patients contre-indiqués aux IRM : pacemaker, pompe à insuline, valve cardiaque métallique, implant cochléaire…
Hypersensibilité à la substance active (cannabidiol) ou aux excipients (sucralose, menthol, mannitol).
Personne sous tutelle (NB: la curatelle est possible)

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint will be the total consumption of alcohol (in standard-drinks, sd) in the 28 last days (week 8 to week 12) of the study, using the A-TLFB daily self-report of alcohol drinking. The difference between the total alcohol consumption during 28 days preceding the study, and the 28 last days of the study, will be compared between the two groups.

Le critère d'évaluation principal sera, entre les groupes, la différence de consommation totale d'alcool (exprimé en verre standard) au cours des 28 derniers jours (de la semaine 8 à la semaine 12) de l'étude moins celle des 28 jours précédant l’étude, en utilisant l'auto déclaration quotidienne de consommation d'alcool via l'A-TLFB.

E.5.1.1

Timepoint(s) of evaluation of this end point

12 weeks

12 semaines

E.5.2

Secondary end point(s)

- Percentages of heavy drinking days (i.e., 6 standard-drinks or more) during the study period.
- Difference (i.e., inclusion minus end of study) in alcohol craving scores using the OCDS.
- Difference (i.e., inclusion minus end of study) in alcohol use disorder scores using the AUDIT-C.
- Difference (i.e., inclusion minus end of study) in GGT levels.
- Difference (i.e., inclusion minus end of study) in CDT levels.
- Difference (i.e., inclusion minus end of study) in PEth levels.
- Difference (i.e., inclusion minus end of study) in anxiety and depression (HADS) scores.
- Difference (i.e., inclusion minus end of study) in self-confidence to resist, quality of life (SF12v2), stigmatization, sleep quality (PSQI) scores.
- Difference (i.e., inclusion minus end of study) in CAP scores using ultra-sound electrography.
- Difference (i.e., inclusion minus end of study) in steatosis score using MRI morphometric assessment of fat composition of the liver.
- Difference (i.e., inclusion minus end of study) in steatosis score using SRM assessment of lipid peaks in the liver.
- Brain map of difference (i.e., inclusion minus end of study) in grey matter volumes in corticostriatal-limbic circuits.
- Brain difference (i.e., inclusion minus end of study) in cortical thickness of insula, superior temporal gyrus, dorso-lateral prefrontal cortex and anterior cingulate cortex.
- Difference (i.e., inclusion minus end of study) in attentional, memory and executive functions abilities using neuropsychological testing.
- Difference (i.e., last visit minus end of study) in total consumption of alcohol using the A-TLFB daily self-report of alcohol drinking.

Différence entre les visites d’inclusion (V0) et de fin de traitement (V4) des éléments suivants :

- Pourcentages de jours de forte consommation d'alcool (≥ 6 verres standards).
- Scores de craving en utilisant l’échelle OCDS.
- Scores de consommation d’alcool en utilisant l’échelle AUDIT-C
- Taux sanguins de GGT.
- Taux sanguins de CDT.
- Taux sanguins de PEth.
- Scores d’anxiété et de dépression en utilisant l’échelle HADS.
- Scores d’auto-confiance, de qualité de vie, de stigmatisation, de qualité du sommeil en utilisant les échelles appropriées (SF12v2, PSQI).
- Scores de stéatose hépatique (CAP) en utilisant l’élastographie impulsionnelle à vibration contrôlée.
- Scores de stéatose hépatique en utilisant les fractions de graisse en densité de proton par IRM.
- Scores de stéatose hépatique en utilisant la spectroscopie par résonnance magnétique.
- Volume de la matière grise cérébrale dans les circuits corticostriataux-limbiques.
- Epaisseur corticale de l’insula, du gyrus temporal supérieur, du cortex préfrontal dorso-latéral et du cortex cingulaire antérieur.
- Fonctions attentionnelles, mémorielles et exécutives en réalisant un bilan neuropsychogique.

E.5.2.1

Timepoint(s) of evaluation of this end point

12 weeks

12 semaines

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)

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

E.8.6.2

Trial being conducted completely outside of the EEA

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

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

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

curatorship

Sous curatelle

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)

If the treatment is effective, at the end of the trial, it is not possible (because not marketed in France) to continue the treatment. The patient should therefore direct himself, with the help of his doctor, to other available therapies.

Si le traitement est efficace, à l’issu de l’essai, il n’est pas possible (car pas commercialisé en France) de continuer le traitement. Le patient devra dont s’orienter, avec l’aide de son médecin, vers d’autres thérapeutiques disponibles.

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	Direction de la Recherche Clinique et de l’Innovation, Hospices Civils de Lyon
G.4.3.4	Network Country	France
G.4 Investigator Network to be involved in the Trial: 2
G.4.1	Name of Organisation	CLININFO
G.4.3.4	Network Country	France
G.4 Investigator Network to be involved in the Trial: 3
G.4.1	Name of Organisation	INSERM U1252, SESSTIM, Aix-Marseille Université
G.4.3.4	Network Country	France

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2021-09-15

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-07-21

P. End of Trial
P.	End of Trial Status	Ongoing

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