Clinical Trials Register

Summary
EudraCT Number:	2015-000555-24
Sponsor's Protocol Code Number:	100752
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:	2021-06-18
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

2015-000555-24

A.3

Full title of the trial

Randomized, Placebo-Controlled, Double-Blind, Multicenter Study to Determine the Efficacy and Safety of Vedolizumab in Prevention of Endoscopic Recurrence of Crohn's Disease in Patients with Ileo-colonic Surgical Resection and Ileocolonic Anastamosis : REPREVIO (recurrence prevention with Entyvio)

Studio multicentrico, randomizzato, controllato verso placebo, in doppio cieco, per determinare l’efficacia e sicurezza di vedolizumab nella prevenzione della recidiva endoscopica di malattia di Crohn in pazienti sottoposti a resezione ileo-colica e anastomosi ileo-colica. REPREVIO (recurrence prevention with Entyvio)

A.3.1

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

Randomized, Placebo-Controlled, Double-Blind, Multicenter Study to Determine the Effectiveness and Safety of Vedolizumab in Prevention of Recurrence of Crohn's Disease of the mucosa in Patients with Surgical Removel of the area between the small and the large bowel.

A.3.2

Name or abbreviated title of the trial where available

REPREVIO

A.4.1

Sponsor's protocol code number

100752

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	AMC MEDICAL RESEARCH B.V.
B.1.3.4	Country	Netherlands
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	Academic Medical Center
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Academic Medical Center
B.5.2	Functional name of contact point	Amsterdam UMC, location AMC A3-254
B.5.3	Address:
B.5.3.1	Street Address	Meibergdreef 9
B.5.3.2	Town/ city	Amsterdam
B.5.3.3	Post code	1105 AZ
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	0031205661125
B.5.5	Fax number	0031205669285
B.5.6	E-mail	e.clasquin@amsterdamumc.nl

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	Entyvio
D.2.1.1.2	Name of the Marketing Authorisation holder	Takeda Pharma A/S
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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	Vedolizumab IV
D.3.2	Product code	[MLN0002]
D.3.4	Pharmaceutical form	Powder for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	vedolizumab
D.3.9.1	CAS number	943609-66-3
D.3.9.2	Current sponsor code	MLN0002
D.3.9.4	EV Substance Code	SUB30452
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	60
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	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)	Yes
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for injection
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Crohn's disease

Malattia di Crohn

E.1.1.1

Medical condition in easily understood language

Crohn's disease

Malattia di Crohn

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	10013099
E.1.2	Term	Disease Crohns
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

Prevent postoperative endoscopic recurrence of Crohn’s disease in the neoterminal ileum.

Prevenzione della recidiva post-operativa endoscopica della Malattia di Crohn nell'ileo neoterminale.

E.2.2

Secondary objectives of the trial

Prevention of clinical recurrence of Crohn’s disease

Prevenzione della recidiva della Malattia di Crohn

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- In the opinion of the investigator, the subject is capable of understanding and complying with protocol requirements.
- The subject signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures. Consent must be documented.
- Established Crohn’s disease as the indication for ileocolonic resection. Only patients treated with either conventional therapy or anti-TNF antagonist before surgery and with documented inadequate response, loss of response or intolerance to such treatments can be enrolled
- Age > 18
- Ileocolonic resection with ileocolonic anastomosis and removal of all tissue macroscopically affected by CD according to the surgeon
- Presence of at least 1 risk factor for recurrence:
o Active smoking > 10 cigarettes/day
o 2nd, 3rd or later resection
o Surgery for perforating complication (abscess, fistula)
o Previous exposure to anti-TNF antibodies
- Females of childbearing potential will be included if they are either sexually inactive (sexually abstinent for 14 days prior to the first study drug dose continuing through 6 months after the last study drug dose, or, in case of sexually active women, using one of the following highly effective contraceptive methods (i.e.results in < 1 % failure rate when used consistently and correctly) in this trial:
a) intrauterine device(IUD)
b) surgical sterilization of the partner (vasectomy for 6 months minimum)
c) combined (estrogen or progestogen containing) hormonal contraception associated with the inhibition of ovulation (either oral, intravaginal, or transdermal);
d) progestogen only hormonal contraception associated with the inhibition of ovulation (either oral, injectable, or implantable);
e) intrauterine hormone releasing system (IUS)
f) bilateral tubal occlusion
- Females of childbearing potential agree to remain sexually inactive or to keep the same birth control method for at least 6 months following the last dose.
- A female of non-childbearing potential must have undergone one of the following sterilization procedures at least 6 months prior to the first study dose:
a) hysteroscopic sterilization;
b) bilateral tubal ligation or bilateral salpingectomy;
c) hysterectomy;
d) bilateral oophorectomy;
or be postmenopausal with amenorrhea for at least 1-year prior to the first study drug dose and follicle stimulating hormone (FSH) serum levels consistent with postmenopausal status i.e. FSH > 40 IU/L.
- A non-vasectomized male subject agrees to use a condom with spermicide during the study until 180 days beyond the last dose of study medication and the female partner agrees to comply with inclusion 7 or 9. For a vasectomized male who has had his vasectomy 6 months or more prior to study start, it is required that they use a condom during sexual intercourse. A male who has been vasectomized less than 6 months prior to study start must follow the same restrictions as a non-vasectomized male. If male, agrees not to donate sperm from the first study drug dose until 180 days after dosing.
- Anti-TNF discontinued for at least 6 weeks prior to screening

• Soggetti in grado, secondo lo sperimentatore, di comprendere e seguire le procedure previste dal protocollo
• Ottenimento della firma del consenso informato e dell’autorizzazione al trattamento dei dati personali ai fini di ricerca antecedente all’avvio di qualsiasi procedura di studio. L’ottenimento del consenso deve essere documentato.
• Diagnosi definita di Malattia di Crohn come indicazione per la resezione ileo-colica
• Età >18 anni
• Resezione ileo-colica con anastomosi ileo-colica e rimozione di tutti i tessuti macroscopicamente affetti da CD, secondo l’opinione del chirurgo
• Presenza di almeno uno dei fattori di rischio di recidiva:
o Fumo attivo (>10 sigarette al giorno)
o Seconda, terza resezione o successiva
o Chirurgia per complicanze correlate a perforazione (ascesso, fistola)
o Precedente utilizzo di anticorpi anti-TNF
• Soggetti di sesso maschile o donne non in gravidanza o allattamento. Soggetti di sesso femminile in età fertile dovranno avere test di gravidanza su siero negativo prima della randomizzazione e dovranno utilizzare metodi contraccettivi ormonali (orali, impiantabili o iniettabili) o di barriera per tutta la durata dello studio. Per le donne non potenzialmente fertili, dovrà essere documentata in cartella la causa di infertilità (legatura delle tube, isterectomia o stato post-menopausale, definito come minimo un anno dall’ultima mestruazione).
• Sospensione degli anti-TNF almeno 6 mesi prima dello screening

E.4

Principal exclusion criteria

- Patients that need to continue postoperative medication for their CD as per investigator's discretion, eg for fistulizing perianal CD.
- Previous treatment with VDZ
- Clinically significant CD elsewhere in the gastrointestinal tract not removed with surgery
- Patients with clinically documented short bowel syndrome.
- Patients with a history of cancer (other than resected cutaneous basal or squamous cell carcinoma or in situ cervical cancer) with less than 2 disease-free documented years.
- Patients with the following laboratory abnormalities:
White blood count < 3 x 109/L
Lymphocyte count < 0.5 x 109/L
Hemoglobin < 8 g/dL
Platelet count < 125 x 109/L or > 800 x 109/L
ALT or AST > 3.0 times the upper limit of normal (ULN)
Alkaline Phosphatase > 2.0 times the ULN
Serum Creatinine > 2 times the ULN
Prothrombin time (INR) > 1.5 times normal
- Active participation in another trial.
- Patients with abdominal abscess, active or latent tuberculosis or cancer.
- A history of alcohol or illicit drug use that in the opinion of the principal investigator (PI) would interfere with study procedures.
- Patients with psychiatric problems that in the opinion of the PI would interfere with study procedures.
- Patients unable to attend all study visits.
- Patients with a history of non-compliance with clinical study protocols.
- Contraindication for endoscopy.
- History of colonic dysplasia and /or colonic cancer
- Received other biologics within the last 6 weeks of screening
- Known HIV, hepatitis B or C infection
- Evidence of or treatment for C. difficile infection or other intestinal pathogen within 4 weeks prior to enrollment or at screening
- Active or latent tuberculosis
- Received any investigational drug in the past 30 days or 5 half-lives, whichever is longer.
- Positive PML subjective symptom checklist before enrollment
- Patients exposed to a live vaccine in the previous 4 weeks before screening.
- Patients with a history of hypersensitivity to the active substance or to any of it excipients
-Patients with active or latent severe infections such as tuberculosis, sepsis, cytomegalovirus, listeriosis and opportunistic infections.

• Pazienti che debbano continuare i trattamenti per la malattia di Crohn, secondo giudizio dello sperimentatore, ad esempio pel malattia perianale fistolizzante.
• Precedente trattamento con VDZ
• Presenza di malattia di Crohn clinicamente significativa e non rimossa chirurgicamente in altre zone del tratto gastrointestinale
• Pazienti con sindrome dell’intestino corto documentata clinicamente
• Pazienti con anamnesi positiva per neoplasie maligne (ad eccezione di carcinoma cutaneo basocellulare o cellule squamose o, in caso di pazienti femmine, carcinoma della cervice in situ, escisso chirurgicamente) con intervallo libero da malattia inferiore ai due anni
• Pazienti con le seguenti anomalie di laboratorio:
o Leucociti < 3 x 109/L
o Linfociti < 0.5 x 109/L
o Emoglobina < 8 g/dL
o Piastrine < 125 x 109/L o > 800 x 109/L
o ALT o AST >3.0 volte il limite superiore della norma
o Fosfatasi alcalina >3.0 volte il limite superiore della norma
o Creatininemia >3.0 volte il limite superiore della norma
o Tempo di protrombina (INR) >1.5 volte la norma
• Partecipazione ad altro studio clinico
• Pazienti con ascesso addominale, tubercolosi attiva o latente, cancro
• Anamnesi positiva per abuso di alcol o altre sostanze da abuso che, secondo l’opinione dello sperimentatore, possa interferire con la partecipazione allo studio
• Pazienti con problemi psichiatrici che, secondo lo sperimentatore, possano interferire con la partecipazione allo studio
• Pazienti che non siano in grado di effettuare tutte le visite di studio
• Pazienti che abbiano già mostrato scarsa compliance a procedure previste da protocolli di studio
• Controindicazioni all’esecuzione di esami endoscopici
• Anamnesi positiva per displasia o carcinoma del colon
• Trattamenti con farmaci biologici nelle 6 settimane che precedono lo screening
• Infezione da HIV, epatite B o C
• Presenza di infezione, anche trattata farmacologicamente, da C.difficile o altro patogeno intestinale nelle 4 settimane che precedono il baseline o durante lo screening
• Tubercolosi attiva o latente
• Trattamento con farmaci sperimentali nei 30 giorni o 5 emivite precedenti, considerando il periodo più lungo tra i due
• Checklist dei sintomi soggettivi per PML positiva prima dell’arruolamento
• Pazienti esposti a un vaccino vivo nelle 4 settimane precedenti allo screening
• Pazienti con una storia di ipersensibilità alla sostanza attiva o a uno qualsiasi degli eccipienti
• Pazienti con infezioni gravi attive o latenti come la tubercolosi, la sepsi, l'infezione da citomegalovirus, la listeriosi e le infezioni opportunistiche.

E.5 End points

E.5.1

Primary end point(s)

Proportion of patients with severe endoscopic postoperative recurrence of CD (Rutgeerts i2b, i3 or i4) after approximately 6 months (Week 26).

Percentuale di pazienti che mostra recidiva endoscopica severa di CD (Rutgeerts i2b, i3 o i4) 6 mesi dopo la resezione ileocolica con anastomosi (pazienti stomizzati esclusi).
Lo score endoscopico di Rutgeerts rappresenta un endpoint surrogato validato per valutare il decorso clinic successive della malattia (si veda l’appendice per il sistema di attribuzione del punteggio). Tutte le endoscopie saranno registrate per una successiva revisione e ri-lettura centralizzata.

E.5.1.1

Timepoint(s) of evaluation of this end point

Week 26

Settimana 26

E.5.2

Secondary end point(s)

The proportion of patients with any endoscopic recurrence of CD (Modified Rutgeerts Grade > i0) after 6 months; Changes in the CDAI (Crohn's disease activity index) and HBI (Harvey Bradshaw index) between week 0 and 26. ; Quality of life measure with a disease-specific instrument (IBDQ) and a generic QoL instrument (SF-36). ; Serum concentrations of vedolizumab and antibodies to vedolizumab before every infusion

La proporzione di pazienti con recidiva endoscopica di CD (Modified Rutgeerts Grade> I0) dopo 6 mesi.; Andamento del CDAI (indice di attività della Malattia di Crohn) e HBI (indice Harvey Bradshaw) tra settimana 0 e 26; Qualità di misura la vita con uno strumento specifico per la malattia (IBDQ) e uno strumento QoL generici (SF-36). ; Le concentrazioni sieriche di Vedolizumab e anticorpi anti Vedolizumab prima di ogni infusione

E.5.2.1

Timepoint(s) of evaluation of this end point

At week 26; at week 26 ; at week 26 ; at every visit

A settimana 26; a settimana 26 ; a settimana 26 ; a tutte le visite

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

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)

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

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

Yes

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:

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

Yes

F.3.3.2

Women of child-bearing potential using contraception

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)

No specific programs. Best medical standard care

Nessun programma specifico. La migliore cura standard.

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

2017-10-16

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-01-17

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

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