Clinical Trials Register

Summary
EudraCT Number:	2017-001226-18
Sponsor's Protocol Code Number:	M14-431
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:	2021-06-15
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

2017-001226-18

A.3

Full title of the trial

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Induction Study of the Efficacy and Safety of Upadacitinib (ABT-494) in Subjects with Moderately to Severely Active Crohn's Disease Who Have Inadequately Responded to or are Intolerant to Biologic Therapy

Sperimentazione Multicentrica, Randomizzata, in Doppio Cieco, Controllata verso Placebo e di Induzione per Valutare l’Efficacia e la Sicurezza di Upadacitinib (ABT-494) in Soggetti affetti da Malattia di Crohn in Fase Attiva e di Grado da Moderato a Grave che hanno avuto una risposta inadeguata o sono intolleranti alla terapia con biologici.

A.3.1

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

A study of the Efficacy and Safety of Upadacitinib (ABT-494) in Subjects with Moderately to Severely Active Crohn's Disease Who Have Inadequately Responded to or are Intolerant to Biologic Therapy

Studio di Efficacia e Sicurezza di Upadacitinib (ABT-494) in soggetti affetti da Malattia di Crohn in Fase Attiva e di Grado da Moderato a Grave che hanno avuto una risposta inadeguata o sono intolleranti alla terapia con biologici.

A.3.2

Name or abbreviated title of the trial where available

A.4.1

Sponsor's protocol code number

M14-431

A.5.4

Other Identifiers

Name:

Number:

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	ABBVIE DEUTSCHLAND GMBH & CO. KG
B.1.3.4	Country	Germany
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	AbbVie Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	AbbVie Ltd
B.5.2	Functional name of contact point	EU Clinical Trials Helpdesk
B.5.3	Address:
B.5.3.1	Street Address	AbbVie House, Vanwall Business Park, Vanwall Road
B.5.3.2	Town/ city	Maidenhead, Berkshire
B.5.3.3	Post code	SL6 4UB
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	441628561090
B.5.5	Fax number	441628461153
B.5.6	E-mail	eu-clinical-trials@abbvie.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	Upadacitinib
D.3.2	Product code	[ABT-494]
D.3.4	Pharmaceutical form	Film-coated 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	Upadacitinib
D.3.9.1	CAS number	1310726-60-3
D.3.9.2	Current sponsor code	na
D.3.9.4	EV Substance Code	SUB125895
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	45
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	Yes
D.3.11.13.1	Other medicinal product type	Janus Kinase (Jak) 1 inhibitor
D.IMP: 2
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	Upadacitinib
D.3.2	Product code	[ABT-494]
D.3.4	Pharmaceutical form	Film-coated 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	Upadacitinib
D.3.9.1	CAS number	1310726-60-3
D.3.9.2	Current sponsor code	na
D.3.9.4	EV Substance Code	SUB125895
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	30
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	Yes
D.3.11.13.1	Other medicinal product type	Janus Kinase (Jak) 1 inhibitor

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	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral 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 (CD)

Malattia di Crohn

E.1.1.1

Medical condition in easily understood language

CD is an inflamatory bowel disease affects the lining of the digestive tract, often spreads into the layers of affected bowel tissue, can lead to abdominal pain, severe diarrhea, fatigue, weight loss.

La Malattia di Crohn è una malattia infiammatoria che colpisce il tubo digerente,spesso si diffonde nel tessuto intestinale,può portare a dolore addominale,grave diarrea,affaticamento, perdita di peso

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	PT
E.1.2	Classification code	10011401
E.1.2	Term	Crohn's disease
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

The objective of this study is to evaluate the efficacy and safety of upadacitinib compared to placebo as induction therapy in subjects with moderately and severely active Crohn's disease (CD).

L’obiettivo di questo studio è quello di valutare l’efficacia e la sicurezza di Upadacitinib rispetto a placebo come terapia di induzione in soggetti affetti da malattia di Crohn in fase attiva e di grado da moderato a grave.

E.2.2

Secondary objectives of the trial

To evaluate improvements in several efficacy parameters, including steroid discontinuation, laboratory parameters and quality of life questionnaires.

Valutare i miglioramenti in diversi parametri di efficacia, compresa la sospensione degli steroidi, i parametri di laboratorio e i questionari sulla qualità della vita.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Confirmed diagnosis of CD for at least 3 months prior to Baseline.
- Confirmed diagnosis of moderate to severe CD as assessed by stool frequency (SF), abdominal pain (AP) score.
- Evidence of mucosal inflammation based on the Simplified Endoscopic Score for Crohn's disease (SES-CD) on an endoscopy confirmed by a central reader.
- Demonstrated an inadequate response or intolerance to any biologic therapy for infliximab, adalimumab, certolizumab, pegol, vedolizumab, and ustekinumab.
- If female, subject must meet the contraception recommendations

- Diagnosi confermata della malattia di Crohn da almeno 3 mesi prima del Baseline.
- Diagnosi confermata della Malattia di Crohn da moderata a grave come valutato dal punteggio di frequenza delle feci (SF), dolore addominale (AP).
- Evidenza di infiammazione della mucosa basata sul punteggio endoscopico semplificato per la malattia di Crohn (SES-CD) su endoscopia confermata da una valutazione centralizzata.
- Risposta inadeguata o intolleranza, confermata da evidenze, a uno o più terapia biologica per infliximab, adalimumab, certolizumab, pegol, vedolizumab e ustekinumab.
- Se donna, il soggetto deve soddisfare le raccomandazioni sulla contraccezione

E.4

Principal exclusion criteria

Participant with a current diagnosis of ulcerative colitis or indeterminate colitis.
- Participant not on stable doses of CD related antibiotics, oral aminosalicylates, corticosteroids or methotrexate (MTX).
- Participant with the following known complications of CD: abscess (abdominal or peri-anal), symptomatic bowel strictures, > 2 missing segments of the following 5 segments: terminal ileum, right colon, transverse colon, sigmoid and left colon, and rectum; fulminant colitis, toxic megacolon, or any other manifestation that might require surgery while enrolled in the study.
- Participant with ostomy or ileoanal pouch
- Participant diagnosed with short gut or short bowel syndrome
- Screening laboratory and other analyses show abnormal results.

- Soggetto con diagnosi attuale di colite ulcerosa (UC) oppure colite di natura indeterminata
- Soggetto in trattamento con antibiotici orali, aminosalicilati e corticosteroidi, somministrati per la malattia di Crohn il cui trattamento non sia stato a dose stabile.
- Soggetto con presenza nota delle seguenti complicanze associate alla malattia di Crohn: ascesso (addominale o perianale), restringimenti intestinali sintomatici, > 2 segmenti mancanti dei seguenti 5 segmenti: ileo terminale, colon destro, colon trasverso, colon sigmoideo e sinistro e retto; colite fulminante, megacolon tossico, oppure altre manifestazioni che potrebbero rendere necessario un intervento chirurgico durante il periodo di arruolamento nella sperimentazione
- Soggetto con stomia o serbatoio ileoanale
- Soggetto con la sindrome dell’intestino corto diagnosticata
- Risultati di laboratorio e altre analisi che evidenziano valori anormali.

E.5 End points

E.5.1

Primary end point(s)

Co-primary Endpoints:
1. Proportion of subjects with clinical remission per PROs at Week 12
2. Proportion of subjects with endoscopic response at Week 12

Endpoint Co-Primari:
1. Percentuale di soggetti che presentano remissione clinica per PROs alla Settimana 12
2. Percentuale di soggetti con risposta endoscopica alla Settimana 12

E.5.1.1

Timepoint(s) of evaluation of this end point

Week 12

settimana 12

E.5.2

Secondary end point(s)

1. Proportion of subjects with clinical remission per CDAI (CDAI < 150) in subjects with a Baseline CDAI of 220 to 450 at Week 12
2. Proportion of subjects with clinical remission at Week 4
3. Proportion of subjects with enhanced clinical response at Week 2
4. Proportion of subjects with endoscopic remission at Week 12
5. Proportion of subjects who discontinue corticosteroid use for CD and achieve clinical remission at Week 12, in subjects taking corticosteroids for CD at Baseline
6. Change from Baseline in Inflammatory Bowel Disease Questionnaire
(IBDQ) at Week 12
7. Proportion of subjects achieving CR-100 at Week 2
8. Proportion of subjects achieving CR-100 at Week 12
9. Proportion of subjects with hospitalizations due to CD at during the 12
week double-blind induction period
10. Proportion of subjects with resolution of extra-intestinal
manifestation (EIM) at Week 12, in subjects with EIM at Baseline

1. Percentuale di soggetti con remissione clinica in base al punteggio CDAI (CDAI < 150) alla Settimana
12 in soggetti con punteggio CDAI al Baseline compreso fra 220 e 450
2. Percentuale di soggetti con remissione clinica alla Settimana 4
3. Percentuale di soggetti con miglioramento della risposta clinica alla Settimana 2
4. Percentuale di soggetti con remissione endoscopica alla Settimana 12
5. Percentuale di soggetti che interrompono l’utilizzo di corticosteroidi assunti per la malattia di Crohn e ottengono la remissione clinica alla Settimana 12, fra i soggetti che al Baseline erano in trattamento con corticosteroidi per la malattia di Crohn
6. Cambiamento rispetto al Baseline nel questionario sulle malattie infiammatorie intestinali
(IBDQ) alla settimana 12
7. Percentuale di soggetti che hanno raggiunto il CR-100 alla settimana 2
8. Percentuale di soggetti che hanno raggiunto il CR-100 alla settimana 12
9. Proporzione di soggetti con ospedalizzazioni a causa di CD durante l'induzione in doppio cieco di 12 settimane periodo
10.Proporzione di soggetti con risoluzione extra-intestinale
manifestazione (MIO) alla settimana 12, in soggetti con MIO al Baseline

E.5.2.1

Timepoint(s) of evaluation of this end point

1. week 12
2. week 4
3. week 12
4. week 12
5. week 12
6. week 12
7. week 2
8. week 12
9. week 12
10. week 12

1. alla settimana 12
2. alla settimana 4
3. alla settimana 12
4. alla settimana 12
5. alla settimana 12
6. alla settimana 12
7. alla settimana 2
8. alla settimana 12
9. alla settimana 12
10. alla settimana 12

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

Yes

E.6.7

Pharmacodynamic

Yes

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

Yes

E.8.1.7.1

Other trial design description

1)Randomizzato,doppio cieco,2bracci
2)aperto,1braccio
3)periodo di estensione trattamento,3bracci

Part 1 Randomized, double-blind 2arm
Part 2 Open Label 1arm
Part 3 Extension Treatment Period 3arm

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

146

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Australia

Belarus

Bosnia and Herzegovina

Brazil

Canada

Chile

China

Colombia

Egypt

Hong Kong

Israel

Japan

Korea, Democratic People's Republic of

Malaysia

Mexico

New Zealand

Russian Federation

Serbia

Singapore

South Africa

Taiwan

Turkey

Ukraine

United States

Switzerland

Argentina

E.8.7

Trial has a data monitoring committee

Yes

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:

815

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

311

F.4.2.2

In the whole clinical trial

855

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)

Subjects who achieve clinical response at week 12 or 24 may be enroll in the maintenance/long-term extension study M14-430 with upadacitinib. Subjects who do not achieve clinical response to upadacitinib at week 24 will receive standard of care treatment, per the investigator’s decision.

I soggetti che ottengono una risposta clinica alla settimana 12 o 24 possono essere arruolati nello studio di estensione di mantenimento/a lungo termine M14-430 con upadacitinib. I soggetti che non ottengono una risposta clinica all'upadacitinib alla settimana 24 interromperanno il trattamento e riceveranno un trattamento standard di cura, secondo la decisione dello sperimentatore.

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

2018-04-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-04-12

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

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IMP with orphan designation in the indication
Orphan Designation Number:
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