Clinical Trials Register

Summary
EudraCT Number:	2017-003505-17
Sponsor's Protocol Code Number:	CRO-17-134,CB-17-01-15
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:	2021-10-01
Trial results	View 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

2017-003505-17

A.3

Full title of the trial

Colonic lesion staining and flagging efficacy of methylene blue administered as MMX® 25 mg modified release tablets to patients receiving a split dose regimen of bowel cleansing preparation for colonoscopy

Efficacia della colorazione e dell'identificazione delle lesioni del colon con blu di metilene somministrato sotto forma di compresse a rilascio modificato MMX® da 25 mg a pazienti a cui viene somministrato un regime con dosi suddivise di preparato per la pulizia dell'intestino prima della colonscopia

A.3.1

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

Colonic lesion staining and flagging efficacy of methylene blue in patients receiving a bowel cleansing preparation for colonoscopy

Efficacia della colorazione e dell'identificazione delle lesioni del colon con blu di metilene in pazienti a cui viene somministrato un preparato per la pulizia dell'intestino prima della colonscopia

A.3.2

Name or abbreviated title of the trial where available

Colonic lesion staining and flagging efficacy of methylene blue in patients receiving a bowel cleans

Efficacia della colorazione e dell'identificazione delle lesioni del colon con blu di metilene in pa

A.4.1

Sponsor's protocol code number

CRO-17-134,CB-17-01-15

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	CROSS Research SA
B.5.2	Functional name of contact point	Diego Scanniffio
B.5.3	Address:
B.5.3.1	Street Address	via FA Giorgioli 14
B.5.3.2	Town/ city	Arzo
B.5.3.3	Post code	6864
B.5.3.4	Country	Switzerland
B.5.4	Telephone number	0041916300510
B.5.5	Fax number	0041916300511
B.5.6	E-mail	diego.scanniffio@croalliance.com

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	Compresse a rilascio modificato di blu di metilene MMX® da 25 mg
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	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	BLU DI METILENE
D.3.9.1	CAS number	61-73-4
D.3.9.2	Current sponsor code	CB-17-01
D.3.9.3	Other descriptive name	3, 7-bis (dimethylamino-) phenothiazin-5-ium chloride
D.3.9.4	EV Substance Code	PRD1589130
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	200
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	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	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 undergoing a screening or surveillance colonoscopy to detect colonic lesions

I pazienti che riceveranno il prodotto sono persone che si sottopongono a colonscopia di screening o di controllo per l' identificazione delle lesioni del colon

E.1.1.1

Medical condition in easily understood language

Patients undergoing a screening or surveillance colonoscopy

Pazienti che si sottopongono a colonscopia di screening o di controllo

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	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10042759
E.1.2	Term	Symptoms involving digestive system
E.1.2	System Organ Class	100000004856

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the colonic lesion staining and flagging efficacy of single 200 mg oral doses of Methylene Blue MMX® 25 mg tablets administered to patients undergoing colonoscopy, in association with a high volume split dose regimen of bowel preparation, or a low volume split dose regimen of bowel preparation. Bowel cleansing quality will also be evaluated according to the validated Boston Bowel Preparation Scale (BBPS) after the intake of the bowel cleansing preparation and of a total dose of 200 mg of Methylene Blue MMX® 25 mg tablets administered the day before the colonoscopy procedure, with bowel preparation or water indicated volumes.

Valutare l'efficacia della colorazione e dell'identificazione delle lesioni del colon con compresse da 25 mg di blu di metilene MMX® a dosi orali singole di 200 mg, somministrate a pazienti che devono essere sottoposti a colonscopia, in associazione con un regime a dosi suddivise di preparato per la pulizia intestinale ad alto volume o a basso volume. Sarà inoltra valutata la qualità della pulizia degli intestini secondo la scala convalidata di preparazione intestinale di Boston (Boston Bowel Preparation Scale, BBPS) dopo l'assunzione del preparato per la pulizia intestinale e di una dose totale di 200 mg di blu di metilene MMX® in compresse da 25 mg, somministrata il giorno antecedente la procedura di colonscopia, con il preparato per la pulizia intestinale o acqua ai volumi indicati.

E.2.2

Secondary objectives of the trial

Polyp detection rate will be assessed.
Safety and tolerability of oral Methylene Blue MMX® 25 mg tablets in association with different bowel preparations administered according to different schedules will be evaluated

Sarà valutato il tasso di rilevamento dei polipi.
Sarà valutata la sicurezza e la tollerabilità delle compresse di blu di metilene MMX® 25mg in associazione con la somministrazione, secondo diversi schemi, di diversi preparati per la pulizia intestinale.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Informed consent: signed written informed consent before inclusion in the study
2. Sex and Age: men and women, = 50 years old inclusive
3. Indication: outpatients scheduled for screening or surveillance colonoscopy
4. Contraception: women of childbearing potential must use at least one reliable method of contraception or be abstinent. Women of non-childbearing potential or in post-menopausal status must have been in that status for at least 1 year. For all women of childbearing potential, serum pregnancy test result must be negative at screening.
5. Full comprehension: ability to comprehend the full nature and purpose of the study, including possible risks and side effects; ability to co-operate with the investigator and to comply with the requirements of the entire study.

1. Consenso informato: consenso informato scritto firmato prima dell'inclusione nello studio
2. Sesso ed età: uomini e donne, =50 anni di età
3. Indicazione: pazienti ambulatoriali per i quali sia pianificata una colonscopia di screening o di monitoraggio
4. Contraccezione: le donne potenzialmente fertili devono utilizzare almeno un metodo anticoncezionale affidabile o praticare l'astinenza. Le donne non potenzialmente fertili o in stato post-menopausale devono essere in tale stato da almeno 1 anno. Per le donne potenzialmente fertili, allo screening dovrà essere disponibile un risultato negativo del test di gravidanza sul siero.
5. Comprensione totale: capacità di comprendere l'intera natura e lo scopo dello studio, compresi i possibili rischi ed effetti indesiderati; capacità di collaborare con lo sperimentatore e di rispettare i requisiti dell'intero studio.

E.4

Principal exclusion criteria

1. Pregnancy: pregnant or lactating women or women undergoing fertility treatment or women at risk of becoming pregnant or women with a positive pregnancy test, if applicable.
2. Physical findings: clinically significant abnormal physical findings which could interfere with the objectives of the study.
3. Laboratory analyses: clinically significant abnormal laboratory values indicative of physical illness; in particular, ALT, AST, ¿-GT, bilirubin, creatinine or urea greater than 2.5 x the upper limit for normal, based on laboratory testing.
4. Allergy: ascertained or presumptive hypersensitivity to methylene blue and/or ingredients of Methylene Blue MMX® tablets or PEG-based bowel cleansing preparations; history of anaphylaxis to drugs or allergic reactions in general, which the investigator considers may affect the outcome of the study.
5. Diseases: known or suspected gastrointestinal obstruction or perforation, toxic megacolon, major known colonic resection, severe known diverticulosis with diverticulitis, heart failure (Class III or IV), serious cardiovascular disease, severe liver failure, end-stage renal insufficiency, clinical alarm symptoms or history of anaemia (previously recorded haemoglobin of less than 10mg/dL), frank blood in the stool within the last 30 days prior to enrolment, known deficiency of glucose-6-phosphate dehydrogenase, known deficiency of NADPH reductase, methaemoglobinemia and any other medical condition that in the investigator’s opinion would make the administration of the study drug or procedures hazardous to the patient.
6. Medications: previous or concomitant treatment with any serotonergic psychiatric medications within 2 weeks before the study, in accordance with a drug safety alert published by FDA. In particular, previous or concomitant treatment with the selective serotonin reuptake inhibitors (paroxetine, fluvoxamine, sertraline, citalopram, escitalopram, vilazodone etc.), the serotonin-norepinephrine reuptake inhibitors (venlafaxine, devenlafaxine, duloxetine), tricyclic antidepressants (amitriptyline, desipramine, clomipramine, imipramine, nortriptyline, protriptyline, doxepin, trimipramine), monoamine oxidase inhibitors (isocarboxazid, phenelzine, transdermal selegiline, tranylcypromine, etc.) and other psychiatric drugs (amoxapine, maprotiline, nefazodone, trazodone, bupropion, buspirone, vilazodone, mirtazapine) within 2 weeks before the study, previous or concomitant treatment with fluoxetine within 5 weeks before the study and/or previous or concomitant treatment with anticoagulants or antiaggregants inducing an INR>1.5.

1. Gravidanza: donne in gravidanza, che allattano al seno o che siano sottoposte a un trattamento per la fertilità oppure donne a rischio di entrare in gravidanza o che presentino un test di gravidanza positivo, se applicabile.
2. Osservazioni fisiche: osservazioni fisiche anormali clinicamente significative che potrebbero interferire con gli obiettivi dello studio.
3. Analisi di laboratorio: valori di laboratorio anormali clinicamente significativi indicativi di malattia fisica; in particolare, ALT, AST, ¿-GT, bilirubina, creatinina o urea maggiori di 2,5 volte il limite superiore della norma, in base alle analisi di laboratorio.
4. Allergie: ipersensibilità accertata o presunta al blu di metilene e/o agli ingredienti delle compresse di blu di metilene MMX® o ai preparati per la pulizia intestinale a base di PEG; anamnesi di anafilassi dovuta a farmaci o reazioni allergiche in generale, che lo sperimentatore ritenga possano influire sull'esito dello studio.
5. Malattie: casi accertati o sospetti di occlusione o perforazione gastrointestinale, megacolon tossico, resezione maggiore del colon accertata, diverticolosi grave accertata con diverticolite, insufficienza cardiaca (Classe III o IV), malattia cardiovascolare seria, insufficienza epatica grave, insufficienza renale in stadio terminale, sintomi di allarme clinico o anamnesi di anemia (valore di emoglobina registrato precedentemente inferiore a 10 mg/dl), sangue evidente nelle feci nei 30 giorni antecedenti l'arruolamento, carenza accertata di glucosio-6-fosfato deidrogenasi, carenza accertata di NADPH reduttasi, metaemoglobinemia e qualsiasi altra condizione medica che secondo il parere dello sperimentatore renderebbe la somministrazione del farmaco dello studio o l'esecuzione delle procedure dello studio pericolose per il paziente.
6. Farmaci: trattamento precedente o concomitante con qualsiasi farmaco psichiatrico serotoninergico nelle 2 settimane antecendenti lo studio, in conformità a un avviso sulla sicurezza dei farmaci pubblicato dall'FDA. In particolare, trattamento precedente o concomitante con inibitori selettivi della ricaptazione della serotonina (paroxetina, fluvoxamina, sertralina, citalopram, escitalopram, vilazodone ecc.), inibitori della ricaptazione della serotonina e della noradrenalina (venlafaxina, devenlafaxina, duloxetina), antidepressivi triciclici (amitriptilina, desipramina, clomipramina, imipramina, nortriptilina, protriptilina, doxepina, trimipramina), inibitori delle monoamminossidasi (isocarboxazide, fenelzina, selegilina transdermica, tranilcipromina ecc.) e altri farmaci per uso psichiatrico (amoxapina, maprotilina, nefazodone, trazodone, bupropione, buspirone, vilazodone, mirtazapina) nelle 2 settimane antecedenti lo studio, trattamento precedente o concomitante con fluoxetina nelle 5 settimane antecedenti lo studio e/o trattamento precedente o concomitante con anticoagulanti o antiaggreganti che inducano un INR>1,5.

E.5 End points

E.5.1

Primary end point(s)

- To evaluate the colonic lesion staining and flagging efficacy of Methylene Blue MMX® 25 mg tablets after a total oral dose of 200 mg in association with a high volume split dose regimen or a low volume split dose regimen of bowel cleansing preparation or water.
- To evaluate the Bowel cleansing quality according to the validated Boston Bowel Preparation Scale (BBPS) after the intake of the high volume split dose regimen or the low volume split dose regimen bowel cleansing preparation and of a total dose of 200 mg of Methylene Blue MMX® 25 mg tablets administered during the intake of the bowel cleansing preparation or water.

- Valutare l'efficacia della colorazione e dell'identificazione delle lesioni del colon con compresse di blu di metilene MMX® 25mg dopo una dose totale orale di 200 mg, in associazione con un regime a dosi suddivise di preparato per la pulizia intestinale o acqua ad alto volume o a basso volume.
- Valutare la qualità della pulizia degli intestini secondo la scala convalidata di preparazione intestinale di Boston (Boston Bowel Preparation Scale, BBPS) dopo l'assunzione del preparato per la pulizia intestinale ad alto volume o a basso volume e di una dose totale di 200 mg di blu di metilene MMX® in compresse da 25mg, somministrata durante l’assunzione del preparato per la pulizia intestinale o acqua.

E.5.1.1

Timepoint(s) of evaluation of this end point

During the colonoscopy

Coincidenti con la durata della colonscopia

E.5.2

Secondary end point(s)

- To evaluate the safety and tolerability of oral Methylene Blue MMX® 25 mg tablets in association with different bowel preparations administered according to different schedules.
- To collect an endoscopic evaluation of the polyps detected after colonic mucosal staining obtained with a total dose of 200 mg of Methylene Blue MMX® 25 mg tablets, regardless of their removal: both removed polyps and polyps left in situ will be accounted for.

- Valutare la sicurezza e la tollerabilità delle compresse di blu di metilene MMX® 25mg in associazione con la somministrazione, secondo diversi schemi, di diversi preparati per la pulizia intestinale.
- Raccogliere una valutazione endoscopica dei polipi rilevati dopo la colorazione della mucosa colonica ottenuta con una dose totale di 200 mg di blu di metilene MMX® compresse da 25mg, indipendentemente dalla loro asportazione: sarà valutata la procedura sia con i polipi asportati sia con i polipi lasciati in situ.

E.5.2.1

Timepoint(s) of evaluation of this end point

Visits 1 and 2. Early termination visit if applicable

Visite 1 e 2. Visita di interruzione anticipata, se applicabile

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

Yes

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)

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

Yes

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

Yes

E.8.1.7.1

Other trial design description

Dose singola, a gruppi paralleli

Single dose, parallel groups

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

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

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.8.5.1

Number of sites anticipated in the EEA

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:

100

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

100

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.4.2

For a multinational trial

F.4.2.1

In the EEA

100

F.4.2.2

In the whole clinical trial

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)

None

Nessuno

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

2018-01-30

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-10-17

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

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