Clinical Trials Register

Summary
EudraCT Number:	2018-003524-36
Sponsor's Protocol Code Number:	6746101818
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2018-11-19
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

Netherlands - Competent Authority

A.2

EudraCT number

2018-003524-36

A.3

Full title of the trial

Randomized, Multicenter Study to Investigate the Efficacy of Dashboard Driven Individualized Dosing of Infliximab Compared To Standard Dosing During the Induction in Patients with Acute Severe Ulcerative Colitis

A.3.1

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

Randomized, mulitcenter study to investigate how infliximab dosing calculated by a computer compares to the standard dosing during the induction of infliximab in patients with severe colitis ulcerosa.

Gerandomiseerd, multicenter onderzoek om computer-berekend gepersonaliseerde inductie-doseringen van infliximab te vergelijken met standaard inductie- doseringen bij patiënten met acute colitis ulcerosa.

A.3.2

Name or abbreviated title of the trial where available

TITRATE

A.4.1

Sponsor's protocol code number

6746101818

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	UMC Amsterdam location AMC
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	Pfizer
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	UMC Amsterdam location AMC
B.5.2	Functional name of contact point	IBD trial office
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	0031205651125
B.5.5	Fax number	0031205669285
B.5.6	E-mail	ibdstudies@amc.uva.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	Remicade
D.2.1.1.2	Name of the Marketing Authorisation holder	Janssens Biologics B.V.
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.3.4	Pharmaceutical form	Powder for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
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	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.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	Yes
D.2.1.1.1	Trade name	Metoject
D.2.1.1.2	Name of the Marketing Authorisation holder	Medac
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.3.4	Pharmaceutical form
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
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.IMP: 3
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	Puri-Nethol
D.2.1.1.2	Name of the Marketing Authorisation holder	Aspen pharma
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.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
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

Ulcerative colitis

colitis ulcerosa

E.1.1.1

Medical condition in easily understood language

ulcerative colitis

colitis ulcerosa

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	20.1
E.1.2	Level	LLT
E.1.2	Classification code	10045365
E.1.2	Term	Ulcerative colitis
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

The objective of this study is to investigate whether intensive, personalized IFX dosing by using a pharmacokinetics driven dashboard system during the induction phase in patients with acute severe UC leads to increased treatment success (as defined by sustained clinical response and endoscopic response at week 6) as compared to the standard dosing.

E.2.2

Secondary objectives of the trial

-Proportion of patients in remission at week 6 and 26 as measured by the Mayo score
-Proportion of patients with response at week 6 and 26 as measured by the Mayo score
-Proportion of patients in clinical remission at week 6 and 26 as measured by the Simple Clinical Colitis Activity Index
-Proportion of patients in corticosteroid-free remission at week 26 as measured by the Simple Clinical Colitis Activity Index
-Proportion of patients with clinical remission measured by the Lichtiger scale at week 6 and 26
-Proportion of patients in biochemical remission at week 6 and 26
-Proportion of patients with endoscopic response as measured by the Mayo endoscopic subscore
-Proportion of patients with endoscopic remission at week 6 and 26 as measured by the UCEIS
-Proportion of patients with mucosal healing at week 6 and 26 as measured by the Mayo endoscopic subscore
-Proportion of patients with complete mucosal healing at week 6 and 26

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Adult UC patients (≥18 years)
2. Admission with acute severe UC (defined patients with bloody diarrhoea ≥ 6/day and any signs of systemic toxicity (pulse > 90/min, temperature > 37.8°C, haemoglobin < 105 g/l, erythrocyte sedimentation rate [ESR] > 30 mm/h, or C-reactive protein [CRP] > 30 mg/l)
3. Failure to intravenous steroid treatment as defined by the Oxford criteria (more than 8 stools/d or 3-8 stools/d and CRP≥45 on day 3 after starting iv steroid treatment)
4. Patients going through baseline endoscopy and biopsy sampling (including CMV) before starting on IFX treatment
5. In the opinion of the investigator, the subject is capable of understanding and complying with protocol requirements.
6. The subject signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures.
7. Male or non-pregnant, non-lactating females. Females of child bearing potential must have a negative serum pregnancy test prior to randomization, and must use a hormonal (oral, implantable or injectable) or barrier method of birth control throughout the study. Females unable to bear children must have documentation of such in the source records (i.e., tubal ligation, hysterectomy, or post-menopausal [defined as a minimum of one year since the last menstrual period]).

E.4

Principal exclusion criteria

1. Patients at imminent need of surgery as judged by the treating clinician
2. Previous use of IFX
3. Enteric pathogens (such as Salmonella, Shigella, Yershinia, Campylobacter and C. difficile) detected by stool analysis within 2 weeks prior to enrollment or at screening
4. Active participation in another interventional trial
5. Patients with Crohn’s disease or IBD-U
6. Patients with abdominal abscess
7. Patients with colonic stricture
8. Patients with a history of colon cancer or colonic dysplasia, unless sporadic adenoma, which has been removed
9. Active or latent tuberculosis (screening according to national guidelines)
10. Cardiac failure in NYHA stage III-IV
11. History of demyelinating disease
12. Recent live vaccination
13. Patients with ongoing acute/chronic infection (including but not limited to HIV, hepatitis B and C) with the exception of chronic herpes labialis or cervical HPV
14. History of cancer in the last 5 years with the exception of non-melanoma skin cancer
15. A history of alcohol or illicit drug use that in the opinion of the principal investigator (PI) would interfere with study procedures
16. Patients with psychiatric problems that in the opinion of the PI would interfere with study procedures
17. Patients unable to attend all study visits
18. Patients with a history of non-compliance with clinical study protocols
19. Contraindication for endoscopy
20. Patients who received any investigational drug in the past 30 days or 5 half-lives, whichever is longer
21. Patients who received cyclosporine in the previous 14 days
22. Pregnancy and lactation

E.5 End points

E.5.1

Primary end point(s)

Treatment success at week 6, defined as a combination of
• clinical response (defined as a Lichtiger score of < 10 points with a decrease of at least 3 points compared to baseline) AND
• endoscopic response (defined as a decrease of at least 2 points in the UCEIS at week 6 endoscopy compared to baseline)

E.5.1.1

Timepoint(s) of evaluation of this end point

Week 6

E.5.2

Secondary end point(s)

- Proportion of patients in remission at week 6 and 26 as measured by the Mayo score (Mayo score ≤ 2 with no individual subscore >1)
- Proportion of patients with response at week 6 and 26 as measured by the Mayo score (decrease in Mayo score ≥ 3 points and ≥30% from baseline and a decrease in the rectal bleeding subscore ≥1 or an absolute rectal bleeding subscore of 0 or 1)
- Proportion of patients in clinical remission at week 6 and 26 as measured by the Simple Clinical Colitis Activity Index (SCCAI score ≤ 2)
- Proportion of patients in corticosteroid-free remission at week 26 as measured by the Simple Clinical Colitis Activity Index (SCCAI score ≤ 2)
- Proportion of patients with clinical remission measured by the Lichtiger scale at week 6 and 26 (Lichtiger score ≤ 3)
-Days in clinical response (defined as Lichtiger score of <10 points with a decrease of at least 3 points compared to baseline) and remission ( defined as Lichtiger score < 3) throughout week 0-6
- Proportion of patients in biochemical remission at week 6 and 26 (CRP ≤ 5.0 mg/L and fecal calprotectin < 250 mg/g)
- Proportion of patients with endoscopic response as measured by the Mayo endoscopic subscore (≥1 point improvement) at week 6 and 26
- Proportion of patients with endoscopic remission measured by the UCEIS (UCEIS 1 point on all descriptors)
- Proportion of patients with mucosal healing at week 6 and 26 as measured by the Mayo endoscopic subscore (eMayo 0 or 1)
- Proportion of patients with complete mucosal healing at week 6 and 26 as measured by the Mayo endoscopic subscore (eMayo 0)
- Degree of histological improvement at week 6 and 26 compared to baseline as defined by the Robarts histopathology index
- Proportion of patients reaching minimally clinically important difference in quality of life at week 6 and week 26 compared to baseline as assessed by the IBDQ and EQ-5D-5L questionnaire
- Colectomy rates at week 26
- Total IFX dosing (mg/kg) until week 26

E.5.2.1

Timepoint(s) of evaluation of this end point

Week 6 and week 26

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

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)

E.7.4

Therapeutic use (Phase IV)

Yes

E.8 Design of the trial

E.8.1

Controlled

Yes

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

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

Yes

E.8.2.3.1

Comparator description

same medicinal substance but as standard dosing

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

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)

The treatment continues as standard treatment

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

2018-11-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-04-25

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

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