Clinical Trials Register

Summary
EudraCT Number:	2016-004216-36
Sponsor's Protocol Code Number:	BDPCC
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:	2020-12-17
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

2016-004216-36

A.3

Full title of the trial

Pilot, open-label, spontaneous, Phase II study on the efficacy of beclomethasone dipropionate (BDP) for treatment of Collagenous colitis (CC)

Studio pilota, open-label, spontaneo, di fase II sull’efficacia del Beclometasone dipropionato (BDP) nel trattamento delle Coliti Collagene (CC)

A.3.1

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

BDP efficacy in the treatment of CC

Efficacia del BDP nel trattamento delle CC

A.3.2

Name or abbreviated title of the trial where available

BDPCC

A.4.1

Sponsor's protocol code number

BDPCC

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	I.R.C.C.S. POLICLINICO SAN DONATO
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	IRCCS Policlinico S. Donato
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	Cronos srl
B.5.2	Functional name of contact point	NA
B.5.3	Address:
B.5.3.1	Street Address	Via Tonale 22
B.5.3.2	Town/ city	Milano
B.5.3.3	Post code	20125
B.5.3.4	Country	Italy
B.5.4	Telephone number	0267382869
B.5.5	Fax number	0267382868
B.5.6	E-mail	m.cassinotti@cronosrl.net

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	CLIPPER - 5 MG COMPRESSE GASTRORESISTENTI A RILASCIO PROLUNGATO 30 COMPRESSE
D.2.1.1.2	Name of the Marketing Authorisation holder	CHIESI FARMACEUTICI S.P.A.
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	CLIPPER
D.3.2	Product code	[-]
D.3.4	Pharmaceutical form	Gastro-resistant 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	BECLOMETASONE DIPROPIONATO
D.3.9.1	CAS number	5534-09-8
D.3.9.2	Current sponsor code	BDP
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	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

collagenous colitis

Colite Collagene

E.1.1.1

Medical condition in easily understood language

collagenous colitis

Colite Collagene

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	10048928
E.1.2	Term	Colitis collagenous
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 efficacy of BDP 5 mg extended release tablets, administered once daily for 8 weeks, in inducing a clinical response, defined as a reduction of at least 50% in the frequency of bowel movements with respect to the number of evacuations to ' start of treatment (baseline), evaluated in the 7 days preceding the visit at week 8

• Valutare l’efficacia di BDP 5 mg compresse a rilascio prolungato, somministrato una volta al giorno per 8 settimane, nell’indurre una risposta clinica, definita come la riduzione di almeno il 50% della frequenza delle evacuazioni rispetto al numero di evacuazioni all’inizio del trattamento (baseline), valutata nei 7 giorni precedenti la visita alla settimana 8

E.2.2

Secondary objectives of the trial

• To assess the safety and tolerability of BDP in patients with CC
• To evaluate the efficacy of BDP in inducing a clinical response, defined as a reduction of at least 50% in the frequency of bowel movements with respect to the number of evacuations beginning of treatment (baseline) and evaluated in the 7 days preceding the visit a week 4
• To evaluate the efficacy of BDP in inducing clinical remission, defined as having a maximum of 21 evacuations (=3 on average per day), including a maximum of 6 watery stools, during the week before the visits at weeks 4 and 8.
• To evaluate the efficacy of BDP in patients with CC, at 24:24 weeks after discontinuation of BDP.
• To evaluate the efficacy of BDP in the treatment of clinical relapses in patients who have responded to previous treatment with BDP
• To evaluate the efficacy of BDP on the resolution of the histological lesions at week 8.
• Evaluate the BDP impact on the quality of life of patients

• Valutare la sicurezza e la tollerabilità di BDP nei pazienti con CC
• Valutare l’efficacia di BDP nell’indurre una risposta clinica, definita come la riduzione di almeno il 50% della frequenza delle evacuazioni rispetto al numero di evacuazioni all’inizio del trattamento (baseline) e valutata nei 7 giorni precedenti la visita alla settimana 4
• Valutare l’efficacia di BDP nell’indurre la remissione clinica, definita come la presenza al massimo di 21 evacuazioni (in media =3 al giorno), di cui al massimo 6 di feci acquose, durante la settimana precedente le visite alle settimane 4 e 8.
• Valutare l’efficacia di BDP nei pazienti affetti da CC, alle settimane 12 e 24 dopo la sospensione di BDP.
• Valutare l’efficacia di BDP nel trattamento delle recidive cliniche in pazienti che hanno risposto a un precedente trattamento con BDP
• Valutare l’efficacia di BDP sulla risoluzione delle lesioni istologiche alla settimana 8.
• Valutare l’impatto di BDP sulla qualità della vita dei pazienti

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Male or Female patients =18 and =85 years.
• History of watery diarrhea without blood for at least 12 weeks before the start of treatment (baseline) in patients with newly diagnosed CC, or history of clinical recurrence lasting more than one month prior to screening in patients with known diagnosis of CC .
• At least 21 evacuations during the 7 days preceding the start of treatment (baseline), of which at least one evacuation a day of liquid / semiformate stools during the 7 days preceding the start of treatment.
• Complete colonoscopy performed in the last 12 weeks before the start of treatment (baseline) with histological diagnosis of CC according to histopathological criteria defined by Langner et al. in 2015. Only patients with confirmed diagnosis of CC will be enrolled in the study.

• Uomini o donne =18 e =85 anni.
• Storia di diarrea acquosa non ematica da almeno 12 settimane prima dell’inizio del trattamento (baseline) in pazienti con nuova diagnosi di CC, o storia di recidiva clinica della durata di più di 1 mese prima dello screening in pazienti con diagnosi nota di CC.
• Almeno 21 evacuazioni durante i 7 giorni precedenti l’inizio del trattamento (baseline), di cui almeno 1 evacuazione al giorno di feci liquide/semiformate durante i 7 giorni precedenti l’inizio del trattamento.
• Aver eseguito una colonscopia completa nelle ultime 12 settimane prima dell’inizio del trattamento (baseline) con diagnosi istologica di CC secondo i criteri istopatologici definiti da Langner et al. nel 2015. Potranno essere arruolati nello studio solo i pazienti con diagnosi di CC confermata dall’anatomopatologo.

E.4

Principal exclusion criteria

• Infectious chronic diarrhea (ie detection of bacterial pathogens / parasites in stool or rectal biopsies).
• Diarrhoea caused by other symptomatic organic diseases of the gastrointestinal tract or traceable to defined endoscopic-histological findings (ie ulcerative colitis, ischemic colitis, post-actinic colitis, Crohn's disease, tumors, polyps> 2 cm).
• Celiac disease (serological tests, eg. Total IgA and anti-transglutaminase IgA must be performed) or active hyperthyroidism when the effectiveness of the treatment is not optimal ( blood tests, for example. TSH-r must be performed).
• Suspected drug-induced CM or drug-induced diarrhea (eg. Olmesartan, metformin) [Verhaegh 2016].
• Previous extended colon resections.
• Previous radiation therapy directed to the abdominal and pelvic region.
• diverticular disease in acute or complicated phase (eg. post-diverticulitis stenosis).
• Known hereditary forms of intolerance to lactose or fructose, of glucose-galactose impaired absorption, of sucrase-isomaltase insufficiency, , of Lapp lactase deficiency or congenital deficiency of lactase.
• History of invasive cancer in the last five years.
• Severe comorbidities that substantially reduce life expectancy.
• Abnormal liver function (ALT or ALP> 2.5 x ULN), liver cirrhosis or portal hypertension; impaired renal function.
• Known cataracts.
• Hemorrhagic diathesis.
• Peptic disease in the active phase.
• Asthma, diabetes, infections, osteoporosis, glaucoma, tuberculosis or uncontrolled hypertension despite the specific therapy.
• cardiovascular, renal, endocrine or severe psychiatric disorders.
• Known intolerance / hypersensitivity to the IMP or to drugs with similar chemical structure or pharmacological profile.
• Treatment with anti-diarrheal drugs (eg. Loperamide), Boswellia serrata extract, cholestyramine or bulking agents within 14 days before the start of treatment (baseline).
• Treatment with immunomodulators (eg, Thiopurines or methotrexate) or anti-TNF in the 3 months preceding the start of treatment (baseline).
• Treatment with budesonide, BDP, mesalazine, steroids or oral antibiotics within 4 weeks before the start of treatment (baseline).
• treatment with ketoconazole or other CYP3A -inhibitors within 3 weeks before the start of treatment (baseline).
• Addiction to alcohol or drugs in the previous years.
• Pregnant or breast-feeding.
• Participation in another clinical trial within 30 days prior or previous participation in this same trial.
• reduction of surrenal function
• Concomitant infections with Mycobacterium tubercolosis, mycotic or viral.

• Diarrea cronica infettiva (ovvero riscontro di batteri patogeni/parassiti nelle feci o nelle biopsie rettali).
• Diarrea causata da altre patologie organiche sintomatiche del tratto gastroenterico o riferibile a definiti reperti endoscopico-istologici (ovvero colite ulcerosa, colite ischemica, colite post-attinica, malattia di Crohn, tumori, polipi >2 cm).
• Malattia celiaca (devono essere stati eseguiti i test sierologici, per es. IgA totali e anti-transglutaminasi IgA) o ipertiroidismo attivo quando l’efficacia del trattamento non è ottimale (devono essere stati eseguiti gli esami ematici; per es. TSH-r).
• Sospetto di CM indotta da farmaci o di diarrea indotta da farmaci (per es. olmesartan, metformina) [Verhaegh 2016].
• Pregresse resezioni estese del colon.
• Pregressa radioterapia diretta alla regione addominale o pelvica.
• Malattia diverticolare in fase acuta o complicata (es. stenosi post-diverticolite).
• Note forme ereditarie d’intolleranza al lattosio o al fruttosio, di malassorbimento di glucosio-galattosio, di insufficienza di saccarasi-isomaltasi, di deficit di Lapp lattasi o di deficit congenito di lattasi.
• Storia di tumore invasivo negli ultimi 5 anni.
• Comorbidità severe che riducono sostanzialmente l’aspettativa di vita.
• Funzione epatica alterata (ALT o ALP >2,5 x ULN), cirrosi epatica o ipertensione portale; funzione renale alterata.
• Nota cataratta.
• Diatesi emorragica.
• Malattia peptica in fase attiva.
• Asma, diabete mellito, infezioni, osteoporosi, glaucoma, tubercolosi o ipertensione non controllata nonostante la terapia specifica.
• Patologie cardiovascolari, renali, endocrine o psichiatriche severe.
• Nota intolleranza/ipersensibilità al farmaco in sperimentazione o ai farmaci che presentano una struttura chimica o un profilo farmacologico simile.
• Trattamento con anti-diarroici (per es. loperamide), estratti di Boswellia serrata, colestiramina o agenti formanti massa (bulking agents), assunti nei 14 giorni precedenti l’inizio del trattamento (baseline).
• Trattamento con immunomodulatori (es, tiopurine o metotrexate) o anti-TNF nei 3 mesi precedenti l’inizio del trattamento (baseline).
• Trattamento con Budesonide, BDP, mesalazina, steroidi o antibiotici orali nelle 4 settimane precedenti l’inizio del trattamento (baseline).
• Trattamento con ketoconazolo o altri CYP3A-inibitori nelle 3 settimane precedenti l’inizio del trattamento (baseline).
• Dipendenza da alcool o droghe negli anni precedenti.
• Gravidanza o allattamento.
• Partecipazione ad altro studio clinico nei 30 giorni precedenti o pregressa partecipazione a questo stesso trial.
• iposurrenalismo
• Concomitanti infezioni da Mycobacterium tubercolosis, micotiche o virali.

E.5 End points

E.5.1

Primary end point(s)

At least 50% reduction of evacuation frequency compared to the start of treatment (baseline)

Riduzione della frequenza delle evacuazioni di almeno il 50% dall’inizio del trattamento

E.5.1.1

Timepoint(s) of evaluation of this end point

In the 7 days preceding week 8

Nei 7 giorni precedenti la visita alla settimana 8

E.5.2

Secondary end point(s)

At least 50% reduction of evacuation frequency compared to the start of treatment (baseline); Clinical remission rate, defined as a maximum of 21 evacuations including no more than 6 evacuations of watery stools ; Time to symptoms resolution (the first of seven consecutive days with no more than 3 evacuations per day or less than 1 evacuation of watery stools per day or no more than 3 evacuations per day of which less than 1 evacuation of watery stools per day ); Impact on stools consistency (watery, half-watery/solid) as per Bristol stool scale; Impact on quality of life as per Short Health Scale (SHS); Rate of patients with hystologic remission; Rate of patients with hystologic improvement ; primary non-responders rate; Rate of primary responders in clinical remission and rate of primary responders in clinical relapse; Rate of clinical remission and clinical response in primary responders having a clinical relapse, and time to relapse; Impact on the Physician’s Global Assessment (PGA); Impact on abdominal pain

Riduzione della frequenza delle evacuazioni di almeno il 50% dall’inizio del trattamento; Tasso di remissione clinica, definita come un numero massimo di 21 evacuazioni, di cui non più di 6 evacuazioni di feci acquose; Tempo di risoluzione dei sintomi, definito come il primo di 7 giorni consecutivi con: non più di 3 evacuazioni al giorno in media o <1 evacuazione di feci acquose al giorno in media o non più di 3 evacuazioni al giorno in media, di cui <1 evacuazione di feci acquose al giorno in media; Impatto sulla consistenza delle feci (liquide/ semi-formate/ formate), definito dalla scala di Bristol; Impatto sulla qualità della vita in base alla Short Health Scale (SHS); Quota di pazienti in remissione istologica; Proporzione di pazienti con miglioramento del quadro istologico; Tasso di non-responder primari ; Tasso di responder primari in remissione clinica e tasso di responder primari che sono andati incontro a una recidiva clinica

; Tasso di remissione clinica e di risposta clinica nei responder primari che sono andati incontro a una recidiva clinica, e il tempo di recidiva ; Impatto sul Physician’s Global Assessment (PGA); Impatto sul dolore addominale

E.5.2.1

Timepoint(s) of evaluation of this end point

In the 7 days preceding week 4; At weeks 4 and 8; All study duration;
All study duration; Weeks 4 and 8; Week 8; Week 8; Weeks 4 and 8; Weeks 12 and 24; All study duration; Study end; All study duration

Nei 7 giorni precedenti la visita alla settimana 4; Alle settimane 4 e 8; Durante tutto lo studio; Durante tutto lo studio; Settimane 4 e 8; Settimana 8; Settimana 8; Settimane 4 e 8; Settimane 12 e 24.; Durante tutto lo studio; Al termine dello studio; Durante tutto lo studio

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

E.8.1.1

Randomised

E.8.1.2

Open

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)

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

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:

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

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

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)

Routinary clinical practice

Come da 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

2017-01-31

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-03-09

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

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