Clinical Trials Register

Summary
EudraCT Number:	2011-005694-23
Sponsor's Protocol Code Number:	CB-17-01/05
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-03-01
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

2011-005694-23

A.3

Full title of the trial

Polyp detection rate after single oral dose of methylene blue MMX(R) modified release tablets administered to subjects undergoing outpatients colonoscopy

Tasso di rilevamento dei polipi dopo somministrazione orale in dose singola di compresse a rilascio modificato MMX(R) di blu di metilene a pazienti sottoposti a colonscopia ambulatoriale

A.3.1

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

Polyp detection rate after single oral dose of methylene blue MMX(R) modified release tablets administered to subjects undergoing outpatients colonoscopy

Tasso di rilevamento dei polipi dopo somministrazione orale in dose singola di compresse a rilascio modificato MMX(R) di blu di metilene a pazienti sottoposti a colonscopia ambulatoriale

A.3.2

Name or abbreviated title of the trial where available

Methylene blue MMX polyp detection rate

Tasso di detezione di polipi con blu di metilene

A.4.1

Sponsor's protocol code number

CB-17-01/05

A.5.4

Other Identifiers

Name:

Study code and Sponsor code

Number:

CRO-11-110 - CB-17-01/05

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	COSMO TECHNOLOGIES LTD
B.1.3.4	Country	Ireland
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	Cosmo Technologies Ltd.
B.4.2	Country	Ireland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Unita' d’Endoscopia Digestiva, Istituto di Ricovero e Cura a Carattere Scientifico IRCCS, Istituto Clinico Humanitas
B.5.2	Functional name of contact point	Unita' d’Endoscopia Digestiva
B.5.3	Address:
B.5.3.1	Street Address	Via Alessandro Manzoni, 56
B.5.3.2	Town/ city	Rozzano
B.5.3.3	Post code	20089
B.5.3.4	Country	Italy
B.5.4	Telephone number	+39.02.822.42579
B.5.5	Fax number	+39.02.822.44590
B.5.6	E-mail	alessandro.repici@humanitas.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	Methylene blue MMX® 25 mg modified release tablets
D.3.2	Product code	CB-17-01
D.3.4	Pharmaceutical form	Modified-release tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Gastroenteral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	METHYLENE BLUE
D.3.9.1	CAS number	61-73-4
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	NA
D.3.9.4	EV Substance Code	SUB21957
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.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

patients scheduled for the screening or surveillance colonoscopy and meeting the joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer and the American College of Radiology, i.e. patients with history of polyps at prior colonoscopy, patients with colorectal cancer and patients with family history

pazienti designati per lo screening e le colonoscopie profilattiche che corrispondano ai criteri della linea guida delle tre American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer and the American College of Radiology, vale a dire pazienti con anamnesi di polipi ad una precedente colonoscopia, pazienti con cancro colorettale e pazienti con familiarità

E.1.1.1

Medical condition in easily understood language

patients scheduled for the screening or surveillance colonoscopy for colorectal cancers and polyps.

pazienti che si sottopongono a colonoscopia integrale di controllo per via di diagnosi già nota di polipi, cancri colorettali o familiarità di cancri colorettali

E.1.1.2

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	PT
E.1.2	Classification code	10014805
E.1.2	Term	Endoscopy
E.1.2	System Organ Class	10022891 - Investigations

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	PT
E.1.2	Classification code	10048832
E.1.2	Term	Colon adenoma
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	PT
E.1.2	Classification code	10048646
E.1.2	Term	Polyp colorectal
E.1.2	System Organ Class	10017947 - Gastrointestinal 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

Evaluation of the polyp and adenoma detection rate in patients undergoing a full colonoscopy after colonic mucosal staining obtained with methylene blue MMX tablets.

Valutazione del tasso di rilevamento di polipi ed adenomi in pazienti che si sottopongono ad una colonoscopia totale in seguito a colorazione della mucosa colonica ottenuta con le compresse di blu di metilene MMX

E.2.2

Secondary objectives of the trial

To classify polyps and adenomas detected after colonic mucosal staining obtained with a single dose of 200 mg of methylene blue MMX tablets administered during and at the end of the intake of the bowel cleansing preparation.
To evaluate the serrated lesion detection rate.
To evaluate the mucosal staining efficacy of methylene blue MMX 25 mg modified release tablets after a single oral dose of 200 mg administered during and at the end of the intake of the bowel cleansing preparation.
Bowel cleansing quality evaluated according to the validated Boston Bowel Preparation Scale (BBPS) after the intake of the bowel cleansing formulation and of a single dose of 200 mg of methylene blue MMX modified release tablets administered during and at the end of the intake of the bowel cleansing formulation.
To collect data about safety and tolerability of methylene blue modified tablets

Classificazione di polipi ed adenomi dopo colorazione della mucosa colonica ottenuta con un a dose singola di 200 mg di compresse di blu di metilene MMX somministrate durante ed al termine dell’assunzione del preparato per la pulizia intestinale.
Valutazione del rilevamento di lesioni serrate.
Valutazione dell’efficacia della colorazione mucosale delle compresse a rilascio modificato di blu di metilene MMX dopo una dose orale singola da 200 mg somministrata durante od al termine dell’assunzione del preparato per la pulizia intestinale.
Qualità della pulizia degli intestini valutata secondo la scala di preparazione intestinale di Boston in seguito ad assunzione del preparato per la pulizia intestinale ed in seguito a dose orale singola da 200 mg somministrata.
Raccolta di dati sulla sicurezza e la la tollerabilità delle compresse a rilascio modificato di blu di metilene

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Sex: males/females;
2. Age: 18</=age years;
3. Indication: patients scheduled for the screening or surveillance colonoscopy and meeting the joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer and the American College of Radiology, i.e. patients with history of polyps at prior colonoscopy, patients with colorectal cancer and patients with family history;
4. Contraception: either sterile subjects or subjects practising at least one reliable methods of contraception or in post-menopausal status for at least 1 year;
5. Informed Consent: signed written informed consent prior to inclusion in the study.

Maschi e femmine d’età uguale o superiore ai 18 anni; pazienti designati per lo screening e le colonoscopie profilattiche che corrispondano ai criteri della linea guida delle tre American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer and the American College of Radiology, vale a dire pazienti con anamnesi di polipi ad una precedente colonoscopia, pazienti con cancro colorettale e pazienti con familiarità; se donne dovranno essere sterili o in menopausa da almeno 1 anno oppure. Se fertili, dovranno utilizzare un metodo contraccettivo sicuro; dovranno firmare il consenso informato prima che venga effettuata qualsiasi procedura.

E.4

Principal exclusion criteria

1. Pregnancy: pregnant or lactating women or at a risk of becoming pregnant;
2. Allergy: known or suspected hypersensitivity to the methylene blue and/or formulations' ingredients; history of anaphylaxis to drugs or allergic reactions in general;
3. Diseases: known or suspected gastrointestinal obstruction or perforation, toxic megacolon, major colonic resection, severe diverticulosis with diverticulitis, heart failure (Class III or IV), serious cardiovascular disease, severe liver failure, end-stage renal insufficiency, any other relevant disease that might interfere with the aim of the study.
4. Previous colonoscopy: known intraepithelial neoplasia or colorectal cancer or any other malignancy;
5. Coagulation: subjects with prothrombin time <50% of control and/or partial thromboplastin time >50 s and/or creatinine >1.2 mg/dL;
6. Comprehension: inability to comprehend the full nature and purpose of the study and unwillingness to co-operate with the investigator and to comply with the requirements of the entire study.

donne incinte oppure in allattamento. individui che preesentino ipersensibilità accertata/presunta o allergia al principio attivo e/o ad altri ingredienti delle formulazioni; individui che abbiano avuto ostruzioni o perforazioni gastrointestinali, megacolon tossico, resezioni del colon, grave diverticolosi con diverticolite, infarto del miocardio (classe III o IV), gravi malattie cardiovascolari o insufficienza epatica grave, insufficienza renale all’ultimo stadio, neoplasie intraepiteliali già note, cancro colorettale o altri tumori o qualsiasi altra patologia che, a giudizio del medico sperimentatore, possa interferire con gli scopi del presente studio clinico. Individui con un tempo di protrombina inferiore al 50% del valore normale e/o un tempo di tromboplastina parziale maggiore di 50 secondi e/o un valore di creatinina maggiore di 1.2 mg/dL; incapacità di comprendere completamente la natura e lo scopo dello studio che verrà proposto, inclusi i rischi e i possibili eventi avversi.

E.5 End points

E.5.1

Primary end point(s)

To evaluate and describe the polyp detection rate and the adenoma detection rate after colonic mucosal staining obtained with single dose of 200 mg of methylene blue MMX tablets administered during and at the end of the intake of the bowel cleansing preparation.

Valutazione e descrizione del tasso di rilevamento di polipi ed adenomi dopo colorazione della mucosa colonica ottenuta con un a dose singola di 200 mg di compresse di blu di metilene MMX somministrate durante ed al termine dell’assunzione del preparato per la pulizia intestinale.

E.5.1.1

Timepoint(s) of evaluation of this end point

Day before colonoscopy (day 1): patients will self administer the investigational product at home during the intake of the bowel cleansing preparation according to the given instructions.
Day of colonoscopy; Visit 2; day 2: patients will return to the clinic for colonoscopy. The investigator will perform the full colonoscopy and will record the detected mucosal abnormalities and their morphology and size and will classify the found polyps and adenomas. All polyps or mucosal abnormalities will be removed with standard technique of polyp resection. Bioptic specimens collected in formalin will be shipped to the histopathologist, who will grade the samples according to the revised Vienna classification. The histopathologist will classify the serrated lesions.

Giorno antecedente la colonoscopia (giorno 1): i pazienti assumeranno il prodotto da testare a casa propria durante la preparazione intestinale per la pulizia del colon in osservanza alle istruzioni impartite.
Giorno della colonoscopia; Visita 2; giorno 2; i pazienti faranno ritorno alla clinica per la colonoscopia. Lo Sperimentatore effettuerà una colonsocopia totale registrando ogni anomalia rilevata nella mucosa nonché la loro morfologia e la loro dimensione. Lo Sperimentatore classificherà i polipi e gli adenomi rilevati. Tutti i polipi o le anomalie mucosali saranno rimossi secondo le tecniche standard di resezione dei polipi. L’Istopatologo riceverà i campioni bioptici raccolti in formalina e classificherà le anomalie secondo la classificazione di Vienna riveduta.

E.5.2

Secondary end point(s)

Classificazione di polipi ed adenomi dopo colorazione della mucosa colonica ottenuta con un a dose singola di 200 mg di compresse di blu di metilene MMX somministrate durante ed al termine dell’assunzione del preparato per la pulizia intestinale.
Valutazione del rilevamento di lesioni serrate. Valutazione dell’efficacia della colorazione mucosale delle compresse a rilascio modificato di blu di metilene MMX dopo una dose orale singola da 200 mg somministrata durante od al termine dell’assunzione del preparato per la pulizia intestinale.
Qualità della pulizia degli intestini valutata secondo la scala di preparazione intestinale di Boston in seguito ad assunzione del preparato per la pulizia intestinale ed in seguito a dose orale singola da 200 mg somministrata durante od al termine dell’assunzione del preparato per la pulizia intestinale.
Raccolta di dati sulla sicurezza e la tollerabilità delle compresse a rilascio modificato di blu di metilene MMX da 25 mg in seguito a singola somministrazione di 200 mg

E.5.2.1

Timepoint(s) of evaluation of this end point

Day of colonoscopy; Visit 2; day 2: patients will return to the clinic for colonoscopy. The investigator will inquire the subjects about occurrence of any adverse event and the intake of concomitant medications. Vital signs (BP, HR, SpO2) will be measured prior to, during and after the end of the colonoscopy. The investigator will score and record the staining quality in each target colonic region: ascending colon, transverse colon, descending colon and rectosigmoid colon. The investigator will rate the colon cleansing according to the Boston scale.

Giorno della colonoscopia; Visita 2; giorno 2; i pazienti faranno ritorno alla clinica per la colonoscopia. Lo Sperimentatore interrogherà i pazienti per verificare l’insorgenza di eventi avversi e l’assunzione di farmaci concomitanti avvenute dal giorno precedente. Pressione sanguigna, frequenza cardiaca e saturazione d’ossigeno verranno misurate prima, durante e dopo l’endoscopia. Lo Sperimentatore assegnerà un punteggio e registrerà la qualità della colorazione di ogni regione colonica: colon ascendente, colon trasverso, colon discendente e colon rettosigmoide. Lo Sperimentatore valuterà anche la pulizia del viscere secondo la scala di Boston.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

Yes

E.6.2

Prophylaxis

Yes

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)

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

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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)

Information not present in EudraCT

E.8.2.2

Placebo

Information not present in EudraCT

E.8.2.3

Other

Information not present in EudraCT

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

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

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

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)

Yes

F.1.1.4

Infants and toddlers (28 days-23 months)

Yes

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

Yes

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

100

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)

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

2011-12-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-12-20

P. End of Trial
P.	End of Trial Status	Completed

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