TITRATE (inducTIon for acuTe ulceRATivE Colitis)

Colitis, Ulcerative Clinical Trial

— 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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03937609
• Other study ID #: 6746101818
• Status: Recruiting
• Phase: Phase 4
• Start date: September 4, 2019
• Est. completion date: December 31, 2024

Study information

• Verified date: December 2022
• Source: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Contact: Geert DHaens, PI
• Phone: 0031205663534
• Email: g.dhaens[@]amsterdamumc.nl
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 120
• Est. completion date: December 31, 2024
• Est. primary completion date: December 31, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Colitis
• Colitis, Ulcerative
• Ulcer

Intervention

Drug:
• Infliximab
infliximab iv 5mg/kg

Locations

Country	Name	City	State
Ireland	St Vincent's University Hospital	Dublin
Netherlands	Academic Medical Center	Amsterdam
Netherlands	OLVG Oost	Amsterdam
Netherlands	Radboud UMC	Nijmegen
Norway	Klinikk Baerum Sykehus	Bærums Verk
Norway	Akerhus University Hospital	Lørenskog
Norway	Helse Stavanger	Stavanger

Sponsors (2)

Lead Sponsor	Collaborator
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)	Pfizer

Countries where clinical trial is conducted

Ireland,  Netherlands,  Norway, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	week 6
Secondary	Endoscopic Remission	Mayo score 2 or less with no individual subscore less than 1	week 6 and week 26
Secondary	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	week 6 and week 26
Secondary	Clinical Remission	Measured by the Simple Clinical Colitis Activity Index (SCCAI score = 2)	Week 6 and week 26
Secondary	Corticosteroid-free remission	Measured by the Simple Clinical Colitis Activity Index (SCCAI score = 2)	week 26