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TITRATE (inducTIon for acuTe ulceRATivE Colitis) (TITRATE)

Primary Purpose

Colitis, Ulcerative

Status

Recruiting

Phase

Phase 4

Locations

International

Study Type

Interventional

Intervention

Infliximab

About this trial

This is an interventional treatment trial for Colitis, Ulcerative focused on measuring infliximab

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

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)
Failure to intravenous steroid treatment as defined by the Oxford criteria (more than 8 stools/d or 3-8 stools/d and CRP≥45) and a Lichtiger score ≥ 10 on day 3 after starting iv steroid treatment
Patients going through baseline endoscopy and biopsy sampling (including CMV) before starting on IFX treatment
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.
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 week 26. 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]).

Exclusion Criteria:

Patients at imminent need of surgery as judged by the treating clinician
Previous use of IFX
Enteric pathogens (such as Salmonella, Shigella, Yershinia, Campylobacter and C. difficile) detected by stool analysis within 2 weeks prior to enrollment or at screening
Active participation in another interventional trial
Patients with Crohn's disease or IBD-U
Patients with abdominal abscess
Patients with colonic stricture
Patients with a history of colon cancer or colonic dysplasia, unless sporadic adenoma, which has been removed
Active or latent tuberculosis (screening according to national guidelines)
Cardiac failure in NYHA stage III-IV
History of demyelinating disease
Recent live vaccination
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
History of cancer in the last 5 years with the exception of non-melanoma skin 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
Patients who received any investigational drug in the past 30 days or 5 half-lives, whichever is longer
Patients who received cyclosporine in the previous 14 days
Pregnancy and lactation

Sites / Locations

St Vincent's University HospitalRecruiting
Academic Medical CenterRecruiting
OLVG OostRecruiting
Radboud UMCRecruiting
Klinikk Baerum SykehusRecruiting
Akerhus University HospitalRecruiting
Helse StavangerRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Other

Experimental

Arm Label

Standard dosing

Intervention group

Arm Description

All eligible patients will receive an intravenous infusion of IFX at 5 mg/kg IFX at week 0. The control group will continue with 5 mg/kg IFX at week 2 and 6, followed by every 8 weeks.

All eligible patients will receive an intravenous infusion of IFX at 5 mg/kg IFX at week 0. The intervention group will receive model based dosing of infliximab with 5mg/kg at various timepoints based on the dashboard model.

Outcomes

Primary Outcome Measures

Increased treatment success

Defined by clinical and endoscopic reponse. Clinical response defined as a Lichtiger score of less than 10 points with a decrease of at least 3 points compared to baseline. Endoscopic response is defined as a decrease of at least 2 points in the UCEIS at week 6 endoscopy compared to baseline

Secondary Outcome Measures

Endoscopic Remission

Mayo score 2 or less with no individual subscore less than 1

Endoscopic Reponse

Decrease in Mayo score of 3 or more points and a 30% or more from baseline and a decrease in rectal bleeding score of 1 or more or an absolute rectal bleeding score of 0 or 1

Clinical Remission

Measured by the Simple Clinical Colitis Activity Index (SCCAI score ≤ 2)

Corticosteroid-free remission

Measured by the Simple Clinical Colitis Activity Index (SCCAI score ≤ 2)

Full Information

NCT ID

NCT03937609

First Posted

April 30, 2019

Last Updated

December 2, 2022

Sponsor

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Collaborators

Pfizer

1. Study Identification

Unique Protocol Identification Number

NCT03937609

Brief Title

TITRATE (inducTIon for acuTe ulceRATivE Colitis)

Acronym

TITRATE

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

December 2022

Overall Recruitment Status

Recruiting

Study Start Date

September 4, 2019 (Actual)

Primary Completion Date

December 31, 2023 (Anticipated)

Study Completion Date

December 31, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Collaborators

Pfizer

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The aim 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 clinical and endoscopic response at week 6) as compared to the standard dosing.

Detailed Description

Previous studies performed in the AMC demonstrated that the patients with acute severe UC receiving IFX are different from patients receiving IFX while in remission.(5) The clearance of IFX is not only determined by demographic parameters (gender, body weight), blood chemistry (CRP, albumin) and anti-drug antibodies, but also disease related variables play an important role. Among others, we have demonstrated that faecal loss of IFX in ASUC patients increases IFX clearance during the induction phase (3). Furthermore, increased expression of TNF-α, the target of IFX, influences the clearance of IFX due to target mediated drug disposition (TMDD). Active IBD with high tissue concentrations of TNF-α thereby acts as a sink for anti-TNF-α antibodies (4). The PK of IFX has been mainly characterized during maintenance therapy. Evaluation of factors that influence the clearance of IFX during induction therapy will allow further optimization an individualization of IFX therapy in ASUC patients. At present, determination of IFX concentrations in the serum with an enzyme-linked immunosorbent assay (ELISA) is time consuming; physicians often receive the results after as many as 10-20 days. To allow for proactive adjustments in dosing, faster laboratory results are required, preferably in a point-of-care setting. This test is now made available by Bühlmann Laboratories (Switzerland). The study hypothesis is that in patients with acute severe UC an intensified and personalized IFX dosing regimen using individual PK data from point of care tests as a rapid input to the dashboard system during the induction phase will lead to improved clinical outcomes when compared to standard dosing regimen.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Colitis, Ulcerative

Keywords

infliximab

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Parallel Assignment

Model Description

Randomized, Open-label, Multicenter Study

Masking

None (Open Label)

Allocation

Randomized

Enrollment

120 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Standard dosing

Arm Type

Other

Arm Description

All eligible patients will receive an intravenous infusion of IFX at 5 mg/kg IFX at week 0. The control group will continue with 5 mg/kg IFX at week 2 and 6, followed by every 8 weeks.

Arm Title

Intervention group

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Infliximab

Other Intervention Name(s)

Remicade, Inflectra and Remsima

Intervention Description

infliximab iv 5mg/kg

Primary Outcome Measure Information:

Title

Increased treatment success

Description

Time Frame

week 6

Secondary Outcome Measure Information:

Title

Endoscopic Remission

Description

Mayo score 2 or less with no individual subscore less than 1

Time Frame

week 6 and week 26

Title

Endoscopic Reponse

Description

Decrease in Mayo score of 3 or more points and a 30% or more from baseline and a decrease in rectal bleeding score of 1 or more or an absolute rectal bleeding score of 0 or 1

Time Frame

week 6 and week 26

Title

Clinical Remission

Description

Measured by the Simple Clinical Colitis Activity Index (SCCAI score ≤ 2)

Time Frame

Week 6 and week 26

Title

Corticosteroid-free remission

Description

Measured by the Simple Clinical Colitis Activity Index (SCCAI score ≤ 2)

Time Frame

week 26

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: 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) Failure to intravenous steroid treatment as defined by the Oxford criteria (more than 8 stools/d or 3-8 stools/d and CRP≥45) and a Lichtiger score ≥ 10 on day 3 after starting iv steroid treatment Patients going through baseline endoscopy and biopsy sampling (including CMV) before starting on IFX treatment 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. 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 week 26. 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]). Exclusion Criteria: Patients at imminent need of surgery as judged by the treating clinician Previous use of IFX Enteric pathogens (such as Salmonella, Shigella, Yershinia, Campylobacter and C. difficile) detected by stool analysis within 2 weeks prior to enrollment or at screening Active participation in another interventional trial Patients with Crohn's disease or IBD-U Patients with abdominal abscess Patients with colonic stricture Patients with a history of colon cancer or colonic dysplasia, unless sporadic adenoma, which has been removed Active or latent tuberculosis (screening according to national guidelines) Cardiac failure in NYHA stage III-IV History of demyelinating disease Recent live vaccination 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 History of cancer in the last 5 years with the exception of non-melanoma skin 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 Patients who received any investigational drug in the past 30 days or 5 half-lives, whichever is longer Patients who received cyclosporine in the previous 14 days Pregnancy and lactation

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Geert DHaens, PI

Phone

0031205663534

g.dhaens@amsterdamumc.nl

First Name & Middle Initial & Last Name or Official Title & Degree

Esmé Clasquin

Phone

0031205661125

e.clasquin@amsterdamumc.nl

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Geert DHaens

Organizational Affiliation

Amsterdamumc location AMC

Official's Role

Principal Investigator

Facility Information:

Facility Name

St Vincent's University Hospital

City

Dublin

Country

Ireland

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Glen Doherty

Facility Name

Academic Medical Center

City

Amsterdam

Country

Netherlands

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Prof G D'Haens

Facility Name

OLVG Oost

City

Amsterdam

Country

Netherlands

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Svend Rietdijk

Facility Name

Radboud UMC

City

Nijmegen

Country

Netherlands

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Marjolijn Duijvestein

Facility Name

Klinikk Baerum Sykehus

City

Bærums Verk

Country

Norway

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Svein Frigstad

Facility Name

Akerhus University Hospital

City

Lørenskog

Country

Norway

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Kristin Jorgensen

Facility Name

Helse Stavanger

City

Stavanger

Country

Norway

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Tore Bjorn Grimstad

12. IPD Sharing Statement

Plan to Share IPD

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TITRATE (inducTIon for acuTe ulceRATivE Colitis)

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