Clinical Trials Register

Summary
EudraCT Number:	2021-002217-34
Sponsor's Protocol Code Number:	FITO-01/21
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2021-10-19
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2021-002217-34

A.3

Full title of the trial

Tuscany project to investigate on efficacy and safety of Cannabis phytotherapic preparations for the treatment of Aromatase iNhibitor-induced chronic resistaNt pAin in Breast cancer patIents: a prospective multicenter randomized placebo-controlled phase III Study.

Progetto in Toscana per studiare l'efficacia e la sicurezza dei preparati fitoterapici a base di cannabis per il trattamento del dolore cronico resistente indotto da inibitori dell'aromatasi in pazienti con carcinoma mammario: uno studio prospettico monocentrico randomizzato controllato di fase III

A.3.1

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

efficacy and safety of Cannabis phytotherapic preparations

Efficacia e sicurezza di una preparazione fitoterapica di Cannabis

A.3.2

Name or abbreviated title of the trial where available

TosCannabis

A.4.1

Sponsor's protocol code number

FITO-01/21

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	AZIENDA OSPEDALIERO-UNIVERSITARIA CAREGGI
B.1.3.4	Country	Italy
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	Regione Toscana
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Aou-Careggi
B.5.2	Functional name of contact point	Cerfit
B.5.3	Address:
B.5.3.1	Street Address	Via delle Oblate, 4
B.5.3.2	Town/ city	firenze
B.5.3.3	Post code	50141
B.5.3.4	Country	Italy
B.5.4	Telephone number	3665645891
B.5.6	E-mail	fabio.firenzuoli@unifi.it

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	Cannabis FM2 Olio
D.3.2	Product code	[Cannabis FM2]
D.3.4	Pharmaceutical form	Oral liquid
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.3.9.1	CAS number	23978-85-0
D.3.9.2	Current sponsor code	1
D.3.9.3	Other descriptive name	delta-9-tetrahydrocannabinolic acid
D.3.10	Strength
D.3.10.1	Concentration unit	% percent
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	5 to 8
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.1	CAS number	13956-29-1
D.3.9.2	Current sponsor code	2
D.3.9.3	Other descriptive name	CANNABIDIOL
D.3.10	Strength
D.3.10.1	Concentration unit	% percent
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	7 to 12
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)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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	Oral drops
D.8.4	Route of administration of the placebo	Buccal use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Aromatase iNhibitor-induced chronic resistaNt pAin in Breast cancer patIents

DOLORE CRONICO RESISTENTE IN DONNE IN TRATTAMENTO CON INIBITORI DELL'AROMATASI PER CANCRO AL SENO

E.1.1.1

Medical condition in easily understood language

Aromatase iNhibitor-induced chronic resistaNt pAin in Breast cancer patIents

DOLORE CRONICO RESISTENTE IN DONNE IN TRATTAMENTO CON INIBITORI DELL'AROMATASI PER CANCRO AL SENO

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	SOC
E.1.2	Classification code	10029205
E.1.2	Term	Nervous system disorders
E.1.2	System Organ Class	10029205 - Nervous system disorders

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 project is to assess the efficacy and safety of Cannabis when added to the usual care of chronic pain induced by the aromatase inhibitors in breast cancer patients.

L'obiettivo principale del progetto è valutare efficacia e sicurezza della Cannabis in aggiunta al trattamento standard del dolore cronico indotta dagli inibitori dell'aromatasi nei pazienti con cancro mammario.

E.2.2

Secondary objectives of the trial

Secondary objectives are:
- to evaluate the impact of pain on the quality of life of patient;
- to examine the pharmacokinetics of Cannabis (i.e. THC, CBD and myrcene blood concentration);
- to explore Cannabis preparations in terms of active principles composition;
- to evaluate adherence to aromatase inhibitor therapy

Gli obiettivi secondari sono:
- valutare l'impatto del dolore sulla qualità della vita del paziente;
determinare la farmacocinetica della Cannabis (cioè concentrazione di THC, CBD e mircene nel sangue);
- analizzare i preparati di Cannabis in termini di composizione dei principi attivi;
- valutare l’aderenza alla terapia con IA.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

¿ Women
¿Age 18 years or older
¿Patients on aromatase inhibitor therapy for breast cancer
¿ Menopausal patients defined as 12 continuous months of amenorrhea related to elevated FSH levels (>19.3 IU/mL)
¿ Menopausal patients as a result of medications such as: in chemotherapy or antihormonal therapy, suffering from estrogen- and progesterone-sensitive breast cancer;
in pelvic radiation therapy, for carcinomas of the cervix, usually from HPV, with heavy genital and sexual damage, because of the vascular damage and fibrosis they generate in the genital area (Graziottin and Basson 2004; Graziottin and Lukasiewicz 2015); in total-body radiation therapy, which is required before marrow transplantation (Graziottin and Lukasiewicz 2015). Postmenopausal FSH values IU/mL: 19.3-100.6.
¿ Patients with high FSH values (>19.3 IU/mL) and undergoing hysterectomy, hysteroannessiectomy, bilateral adnexiectomy, for whom the criterion of absence of menstrual cycles is not usable
¿ Patients with chronic pain (persistent for more than 3 months; IASP Classification - Treede, 2019)
¿ Patients with pain resistant to conventional therapies (patients treated with usual care who do not achieve at least 50% pain reduction; Moore, 2013)
¿ Ability to give informed consent
¿ Written adherence to the protocol with willingness to participate in the study (signing of Informed Consent)

¿ Donne
¿ Età maggiore o uguale a anni 18
¿ Pazienti in terapia con inibitori dell’aromatasi per neoplasia mammaria
¿ Pazienti in stato di menopausa definita come 12 mesi continuativi di amenorrea correlata ad elevati livelli di FSH (>19,3 UI/mL)
¿ Pazienti in menopausa in conseguenza di farmaci come: nella chemioterapia o nella terapia antiormonale, affette da carcinoma mammario estrogeno e progesterone sensibile;
nella radioterapia pelvica, per carcinomi del collo dell’utero, in genere da HPV, con danni pesanti genitali e sessuali, per il danno vascolare e la fibrosi che generano nella zona genitale (Graziottin e Basson 2004; Graziottin e Lukasiewicz 2015);
nella radioterapia total-body, necessaria prima di un trapianto di midollo (Graziottin e Lukasiewicz 2015). Valori di FSH in fase postmenopausale UI/mL: 19,3-100,6.
¿ Pazienti con elevati valori di FSH (>19,3 UI/mL) e sottoposte a isterectomia, isteroannessiectomia, annessiectomia bilaterale, per le quali il criterio dell’assenza di cicli mestruali non è utilizzabile
¿ Pazienti con dolore cronico (persistente da oltre 3 mesi; IASP Classification - Treede, 2019)
¿ Pazienti con dolore resistente alle terapie convenzionali (pazienti trattati con usual care che non raggiungono almeno il 50% di riduzione del dolore; Moore, 2013)
¿ Capacità di dare consenso informato
¿ Adesione scritta al protocollo con disponibilità a partecipare allo studio (firma del Consenso informato)

E.4

Principal exclusion criteria

¿ Patients with respiratory failure (arterial partial pressure of oxygen <60 mmHg)
¿ Patients with severe cardiac disorders: heart failure (NYHA>=2), arrhythmia, uncontrolled hypertension (>135/85)
¿ Patients with myocardial infarction in the 12 months before study entry
¿ Patients with severe hepatic impairment (aspartate aminotransferase three times greater than the upper limit)
¿Patients with severe renal impairment (eGFR <30)
¿Patients with chronic hepatitis C
¿ Personal history of psychiatric disorders (psychosis, bipolar disorder, major depression) and/or family history of schizophrenia
¿ Previous and/or current history of drug or psychotropic substance or alcohol abuse
¿ Patients treated with sedative hypnotic, antidepressant, or psychoactive medications 11
¿ Non-compliance with study procedure for medical judgment
¿ Cannabis abuse and/or Use of cannabis for other illnesses within the past 3 months. A negative analytical control test on biological matrix (urine test) for the absence of cannabinoids must be available for all patients before the start of the study (time 0)

¿ Pazienti con insufficienza respiratoria (pressione parziale arteriosa di ossigeno <60 mmHg)
¿ Pazienti con gravi disturbi cardiaci: scompenso cardiaco (NYHA>=2), aritmia, ipertensione non controllata (>135/85)
¿ Pazienti con infarto del miocardio nei 12 mesi precedenti l’entrata nello studio
¿ Pazienti con grave insufficienza epatica (aspartato aminotransferasi tre volte maggiore del limite massimo)
¿ Pazienti con grave insufficienza renale (eGFR <30)
¿ Pazienti con epatite cronica C
¿ Storia personale di disturbi psichiatrici (psicosi, disturbo bipolare, depressione maggiore) e/o storia familiare di schizofrenia
¿ Precedente e/o attuale storia di tossicodipendenza o abuso di sostanze psicotrope o alcol
¿ Pazienti trattati con farmaci ipnotici sedativi, antidepressivi o psicoattivi 11
¿ Non conformità alla procedura di studio per il giudizio medico
¿ Abuso di cannabis e/o Uso di cannabis per altre malattie negli ultimi 3 mesi. Un test di controllo analitico negativo su matrice biologica (test delle urine) per l’accertamento di assenza di cannabinoidi, deve essere disponibile per tutte le pazienti
prima dell’inizio dello studio (tempo 0)

E.5 End points

E.5.1

Primary end point(s)

efficacy and safity Cannabis galenic Preparations

efficacia e sicurezza della preparazione galenica di Cannabis

E.5.1.1

Timepoint(s) of evaluation of this end point

Duration of study per patient 12 months
Duration of enrollment 18 months
Duration of the study in full 36 months

Durata dello studio per paziente 12 mesi
Durata dell’arruolamento 18 mesi
Durata dello studio in toto 36 mesi

E.5.2

Secondary end point(s)

quality of life of patients

Qualità della vita dei pazienti

E.5.2.1

Timepoint(s) of evaluation of this end point

Duration of study per patient 12 months
Duration of the study in full 36 months

Durata dello studio per paziente 12 mesi
Durata dello studio in toto 36 mesi

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

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

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:

170

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

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

170

F.4.2

For a multinational trial

F.4.2.1

In the EEA

170

F.4.2.2

In the whole clinical trial

170

F.5

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

normal clinical practice

normale pratica clinica

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

2022-05-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-07-26

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

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