Discontinuation of Infliximab Therapy in Patients With Crohn's Disease During Sustained Complete Remission

NCT ID: NCT01817426

Last Updated: 2022-03-24

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 115 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-01-31
• Study Completion Date: 2020-05-31

Brief Summary

The purpose of this study is to determine whether infliximab can favourably and safely be discontinued in patients with Crohn's disease in sustained complete clinical, biochemical, and endoscopic remission on infliximab.

Further to examine the clinical utility of measuring levels/activity of infliximab and activity of anti-infliximab Ab in patients in sustained complete remission, in order to investigate whether pharmacoimmunological data can predict the clinical outcome and rationalize therapeutic management of these patients with respect to continuation or discontinuation of infliximab therapy. Additional, to investigate the optimal time-point, out of three, to measure this activity.

Detailed Description

Recent guidelines for the management of Crohn's disease conclude that currently available data are insufficient to make firm recommendations on when and in whom to stop TNF-α antibody (TNF-α Ab) treatment after having obtained clinical remission. Further, the term "remission" is not well uniformly defined and may incorporate one or more features such as clinical remission, as assessed by CDAI, biochemical remission, endoscopical remission etc. The recently published prospective STORI study of 115 patients with luminal Crohn's disease reported that 56% of patients with Crohn's disease who had discontinued infliximab (IFX) while in clinical remission, maintained remission one year after discontinuation of therapy. Predictors of relapse included certain clinical features as well as objective biochemical and endoscopical markers of disease activity. Consistent with these data, we have recently reported that 61% of our own patients with Crohn's disease, who discontinued IFX while in complete clinical, steroid free IFX induced remission, maintained remission after one year; and half the patients were still in remission after nearly two years (median 680 days [412-948]).

A prospective randomized study of patients with Crohn's disease is necessary to confirm and extend the limited findings above, and assess whether IFX can be safely discontinued in a selected subgroup of patients with complete clinical, biochemical, and endoscopical remission.

Methods:

Study design: Prospective, double-blinded, randomized, placebo-controlled, Danish multi-center study with estimated seven Danish participating centers. Patients and treating physicians are blinded for the type of intervention.

Study population: Patients with luminal Crohn's disease in sustained complete remission on IFX.

Study treatment: Patients are randomized to either continue IFX treatment at an unchanged dosage and frequency, or alternatively to receive matching placebo. All patients will be graded for disease activity (Crohn's Disease Activity Index (CDAI), biochemical parameters, endoscopy, and/or MRI). Following screening and inclusion patients are seen after four weeks, and then every eight weeks. Endpoints are assessed at 48 weeks.

Investigators will, as explorative analyses, examine the clinical utility of measuring IFX levels and antibodies against IFX in patients with complete remission, in order to investigate whether pharmacoimmunological data can predict the clinical outcome and rationalize therapeutic management of these patients with respect to continuation or discontinuation of IFX therapy. Additional, investigators will investigate the optimal time-point out of three to measure this activity. Patients will on the day of infusion have three blood samples drawn: one just before infusion (trough), one right after the infusion (obtained from the other arm)(peak) and one an hour after infusion (C1). Samples will be measured by common solid - and fluid phase assays for this purpose, e.g. Reporter Gene Assay (RGA).

Conditions

Crohn Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

infliximab

Patients in this arm are randomized to continue IFX therapy at an unchanged dosage and frequency.

Group Type: ACTIVE_COMPARATOR

Infliximab

Intervention Type: DRUG

Placebo

Patients in this arm are randomized to receive matching placebo.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: OTHER

Interventions

Infliximab

Intervention Type: DRUG

Placebo

Intervention Type: OTHER

Other Intervention Names

Remicade

Eligibility Criteria

Inclusion Criteria

• Luminal Crohn's disease defined according to standardized diagnostic criteria.
• Age ≥ 18 years.
• IFX induction treatment week 0, 2, 6 followed by maintenance therapy.
• IFX treatment length minimum 12 months. Episodic therapy with IFX pause > 12 weeks is not accepted within the last year. The treatment interval in the last three months has to be of 6-10 weeks.
• Complete remission defined as:

• CDAI score < 150 and
• Biochemical remission, and
• No other signs of disease activity as evaluated by endoscopic examination or by magnetic resonance imaging (MRI).
• Stable remission, judged by the treating physician, at two consecutive treatments visits corresponding 2 scheduled IFX infusions. Thus, the first visit is during IFX maintaining therapy (screening visit). The second visit is at time of inclusion corresponding time of next scheduled IFX infusion (i.e. after ≈ 8 weeks).
• No use of oral steroids within 3 months prior to inclusion.
• Concomitant therapy with other immune suppressants, except steroids, is allowed. The dosage and frequency must have been stable three months prior to inclusion and must remain stable throughout the study period.

Exclusion Criteria

• Initial indication for IFX being predominantly fistulizing perianal disease.
• Any contraindications for continuing IFX treatment, including prior acute or delayed infusion reaction to a TNF- inhibiting agent, any active infection requiring parenteral or oral antibiotic treatment, known infection with tuberculosis, human immunodeficiency virus (HIV) or hepatitis virus.
• Any condition including physician finds incompatible with participation in the study or the patient being unwilling or unable to follow protocol requirements.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Copenhagen University Hospital at Herlev

OTHER

Sponsor Role: lead

Responsible Party

Forskningsenheden

Mark Ainsworth, MD, professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Mark Ainsworth, MD.PHD.,DMSc

Role: PRINCIPAL_INVESTIGATOR

Herlev Hospital, dep. of gastroenterology medical section.

Locations

Aarhus University Hospital

Aarhus, Aarhus C, Denmark

Bispebjerg Hospital

Copenhagen, Copenhagen NV, Denmark

Nykøbing F. Sygehus

Nykøbing Falster, Nykøbing, Denmark

Odense University hospital

Odense, Odense C, Denmark

Herlev Hospital, department of gastroenterology medical section

Herlev, , Denmark

Hospital enheden vest Herning

Herning, , Denmark

Hvidovre Hospital

Hvidovre, , Denmark

Silkeborg Regional Hospital, Diagnostic Center

Silkeborg, , Denmark

Slagelse Sygehus

Slagelse, , Denmark

Helsinki University Hospital and University of Helsinki

Helsinki, , Finland

Akerhus University Hospital

Oslo, , Norway

Skane University Hospital

Lund, , Sweden

Karolinska Institute

Stockholm, , Sweden

Countries

Denmark; Finland; Norway; Sweden

References

Buhl S, Steenholdt C, Brynskov J, Christensen KR, Dorn-Rasmussen M, Thomsen OO, Bendtzen K, Klausen TW, Dahlerup JF, Thorsgaard N, Jahnsen J, Molazahi A, Pedersen N, Kjeldsen J, Almer S, Dahl EE, Vind I, Cannon AG, Marsal J, Sipponen T, Agnholt JS, Kievit HAL, Aure SL, Martinsen L, Meisner S, Hansen JM, Ainsworth MA. Discontinuation of Infliximab Therapy in Patients with Crohn's Disease. NEJM Evid. 2022 Aug;1(8):EVIDoa2200061. doi: 10.1056/EVIDoa2200061. Epub 2022 Jun 14.

Reference Type: DERIVED

PMID: 38319804 (View on PubMed)

Buhl SS, Steenholdt C, Brynskov J, Thomsen OO, Bendtzen K, Ainsworth MA. Discontinuation of infliximab therapy in patients with Crohn's disease in sustained complete remission (the STOP IT study): protocol for a double-blind, randomised, placebo-controlled, multicentre trial. BMJ Open. 2014 Dec 18;4(12):e005887. doi: 10.1136/bmjopen-2014-005887.

Reference Type: DERIVED

PMID: 25524543 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

02MA

Identifier Type: -

Identifier Source: org_study_id