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TITRATE (inducTIon for acuTe ulceRATivE Colitis) (TITRATE)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03937609
Recruitment Status : Recruiting
First Posted : May 6, 2019
Last Update Posted : February 6, 2020
Sponsor:
Collaborator:
Pfizer
Information provided by (Responsible Party):
Geert D'Haens, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

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.

Condition or disease Intervention/treatment Phase
Colitis, Ulcerative Drug: Infliximab Phase 4

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 120 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Randomized, Open-label, Multicenter Study
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : September 4, 2019
Estimated Primary Completion Date : December 31, 2023
Estimated Study Completion Date : December 31, 2024

Resource links provided by the National Library of Medicine

Drug Information available for: Infliximab

Arm Intervention/treatment
Standard dosing
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.
Drug: Infliximab
infliximab iv 5mg/kg
Other Name: Remicade, Inflectra and Remsima

Experimental: Intervention group
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.
Drug: Infliximab
infliximab iv 5mg/kg
Other Name: Remicade, Inflectra and Remsima




Primary Outcome Measures :
  1. Increased treatment success [ Time Frame: week 6 ]
    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 :
  1. Endoscopic Remission [ Time Frame: week 6 and week 26 ]
    Mayo score 2 or less with no individual subscore less than 1

  2. Endoscopic Reponse [ Time Frame: week 6 and week 26 ]
    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

  3. Clinical Remission [ Time Frame: Week 6 and week 26 ]
    Measured by the Simple Clinical Colitis Activity Index (SCCAI score ≤ 2)

  4. Corticosteroid-free remission [ Time Frame: week 26 ]
    Measured by the Simple Clinical Colitis Activity Index (SCCAI score ≤ 2)



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. 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)
  2. 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
  3. Patients going through baseline endoscopy and biopsy sampling (including CMV) before starting on IFX treatment
  4. In the opinion of the investigator, the subject is capable of understanding and complying with protocol requirements.
  5. The subject signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures.
  6. 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:

  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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03937609


Contacts
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Contact: Geert DHaens, PI 0031205663534 g.dhaens@amsterdamumc.nl
Contact: Esmé Clasquin 0031205661125 e.clasquin@amsterdamumc.nl

Locations
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Netherlands
Academic Medical Center Recruiting
Amsterdam, Netherlands
Principal Investigator: Prof G D'Haens         
Sponsors and Collaborators
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Pfizer
Investigators
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Principal Investigator: Geert DHaens Amsterdamumc location AMC
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Responsible Party: Geert D'Haens, Professor, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
ClinicalTrials.gov Identifier: NCT03937609    
Other Study ID Numbers: 6746101818
First Posted: May 6, 2019    Key Record Dates
Last Update Posted: February 6, 2020
Last Verified: February 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Geert D'Haens, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA):
infliximab
Additional relevant MeSH terms:
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Colitis
Colitis, Ulcerative
Ulcer
Gastroenteritis
Gastrointestinal Diseases
Digestive System Diseases
Colonic Diseases
Intestinal Diseases
Pathologic Processes
Inflammatory Bowel Diseases
Infliximab
Dermatologic Agents
Gastrointestinal Agents
Antirheumatic Agents