Clinical trial NCT03937609: TITRATE (inducTIon for acuTe ulceRATivE Colitis)
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
Overall status: TERMINATED
Phase: PHASE4
Conditions: Colitis, Ulcerative
Keywords: infliximab
Lead sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Sponsor class: OTHER
Collaborators: name: Pfizer
First posted: 2019-05-06
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized, Open-label, Multicenter Study
Primary purpose: TREATMENT

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.

Eligibility 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

Primary outcomes:
measure: Increased treatment success
timeFrame: week 6
Secondary outcomes:
measure: Endoscopic Remission
timeFrame: week 6 and week 26
measure: Endoscopic Reponse
timeFrame: week 6 and week 26
measure: Clinical Remission
timeFrame: Week 6 and week 26
measure: Corticosteroid-free remission
timeFrame: week 26
Other outcomes:
Locations:
city: Dublin
country: Ireland
facility: St Vincent's University Hospital
city: Amsterdam
country: Netherlands
facility: Academic Medical Center
city: Amsterdam
country: Netherlands
facility: OLVG Oost
city: Nijmegen
country: Netherlands
facility: Radboud UMC
city: Bærums Verk
country: Norway
facility: Klinikk Baerum Sykehus
city: Lørenskog
country: Norway
facility: Akerhus University Hospital
city: Stavanger
country: Norway
facility: Helse Stavanger
Study officials:
affiliation: Amsterdamumc location AMC
name: Geert DHaens
role: PRINCIPAL_INVESTIGATOR
References: