Clinical trial NCT03172377: Lengthening Adalimumab Dosing Interval in Quiescent Crohn's Disease Patients
Official title: Lengthening Adalimumab Dosing Interval in Quiescent Crohn's Disease Patients
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Crohn Disease in Remission
Crohn Disease
Keywords: adalimumab
anti-tumor necrosis factor
anti-TNF
Humira
interval lengthening
dosing interval
inflammatory bowel disease
antidrug antibodies
trough levels
pharmacokinetics
immunogenicity
cost-effectiveness
dose reduction
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
Collaborators: name: Erasmus Medical Center
First posted: 2017-06-01
Enrollment: 174
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Multicenter, randomized controlled, open label non-inferiority trial
Primary purpose: TREATMENT

Brief summary: Crohn's disease is a chronic inflammatory bowel disease. This disease can be treated with, among other things, biologicals such as adalimumab. Patients use adalimumab for a long time to maintain remission and to prevent relapse of the bowel inflammation. The disadvantages of this therapy are the high price and side effects (such as the higher risk of infection).

Currently, adalimumab is given every 2 weeks, by injection under the skin. The optimal time between two injections has never been investigated before. Prior research in patients with rheumatoid arthritis shows that disease remission can be maintained with longer injection-intervals. Our hypothesis is that this is the same for Crohn's disease patients. Our aim is to show non-inferiority of extending the adalimumab dosing interval, under strict disease monitoring in Crohn's disease patients in sustained (\>9 months) clinical remission, compared to standard care.

During the trial,174 patients with stable Crohn's disease will be divided into 2 groups. One group continues adalimumab injections with the same 2-week interval. And the other group will incrementally extend the interval to 4 weeks, under strict disease monitoring. If a step-down leads to recurrence of disease activity patients will return to the preceding effective dosing interval. Thus, we will investigate whether, and for whom, it is safe to extend the adalimumab injection interval.

Detailed description: Rationale

Adalimumab is both an effective induction and maintenance therapy for Crohn's disease (CD). Due to the risk of side effects (infections, injection reaction) and high costs, an extension of the injection interval is an attractive option. However, this strategy has not been evaluated yet in a randomized controlled trial in CD patients.

Objective

To assess non-inferiority and cost-effectiveness of disease activity guided adalimumab interval lengthening in CD patients in sustained (\>9 months) clinical remission, compared to standard dosing of every other week.

Study design

Multicenter, randomized controlled, open label non-inferiority trial, with two treatment arms.

Study population

Crohn's disease patients, in sustained clinical remission on adalimumab maintenance therapy.

Intervention

Intervention arm: The adalimumab injection interval during maintenance therapy (40 mg per 2 weeks) will be extended through a stepwise disease activity guided manner to 3 weeks and subsequently - after 24 weeks - to 4 weeks. If a step-down leads to recurrence of disease activity patients will return to the preceding effective dosing interval.

Control arm: patients will continue adalimumab maintenance treatment of 40mg per 2 weeks. Treatment decisions are made at the discretion of the treating physician.

Main study parameters/endpoints

Primary outcome: Cumulative incidence of persistent disease flares in 48 weeks of follow-up. A persistent flare is defined as two of three of the following criteria persisting for \> 8 weeks, despite dose escalation of adalimumab; FC \>250 µg/g, CRP≥10 mg/L, HBI ≥5. Non-inferiority is reached if the difference in cumulative incidence of persistent flares not exceeds the non-inferiority margin of 15%.

Secondary outcomes include cumulative incidence of transient flares, adverse events, predictors for successful dose reduction and cost-effectiveness.

Eligibility criteria: Inclusion Criteria:

* Diagnosis of colonic and/or distal ileal CD
* Sustained steroid-free clinical remission for \>9 months whilst being treated with adalimumab at a stable dose
* Adalimumab dosed at 40 mg sc every 2 weeks
* Full clinical response and disease control, all three criteria below need to be fulfilled prior to enrollment:

  * Absence of active inflammatory intestinal or extra-intestinal symptoms, as judged by both patient and physician
  * Fecal calprotectin (FC) \< 150 μg/g and C reactive protein (CRP) \<10 mg/L
  * Harvey Bradshaw Index (HBI) \<5

Exclusion Criteria:

* Absence of written informed consent
* Concomitant corticosteroid usage
* Need for CD-related surgery
* Actively draining peri-anal fistula
* Pregnancy or lactation
* Other significant medical conditions that might interfere with this study (such as current/recent malignancy, immunodeficiency syndromes and psychiatric illness)
* Impossibility to measure outcomes, e.g. planned relocation, language issues, short life expectancy

Primary outcomes:
measure: Cumulative incidence of persistent disease flares.
timeFrame: From the date of randomization up to week 48.
Secondary outcomes:
measure: Cumulative incidence of transient disease flares.
timeFrame: From the date of randomization up to week 48.
measure: (Serious) adverse event rate
timeFrame: From the date of randomization up to week 48.
measure: Whether adalimumab drug level is associated with successful interval lengthening
timeFrame: From the date of randomization up to week 48.
measure: Whether biochemic FC or CRP are associated with successful interval lengthening
timeFrame: From the date of randomization up to week 48.
measure: Whether co-medication use is associated with successful interval lengthening
timeFrame: From the date of randomization up to week 48.
measure: The decremental cost effectiveness ratio of this interval lengthening strategy
timeFrame: From the date of randomization up to week 48.
Other outcomes:
Locations:
city: Nijmegen
country: Netherlands
facility: Radboudumc University Nijmegen Medical Centre
state: Gelderland
city: 's Hertogenbosch
country: Netherlands
facility: Jeroen Bosch Ziekenhuis
state: Noord-Brabant
city: Breda
country: Netherlands
facility: Amphia Ziekenhuis
state: Noord-Brabant
city: Uden
country: Netherlands
facility: Bernhoven
state: Noord-Brabant
city: Amsterdam
country: Netherlands
facility: VU Medisch Centrum
state: Noord-Holland
city: Dordrecht
country: Netherlands
facility: Albert Schweitzer Ziekenhuis
state: Zuid-Holland
city: Rotterdam
country: Netherlands
facility: Franciscus Gasthuis & Vlietland
state: Zuid-Holland
city: Rotterdam
country: Netherlands
facility: Erasmus Medical Center
state: Zuid-Holland
city: Rotterdam
country: Netherlands
facility: Ikazia Ziekenhuis
state: Zuid-Holland
city: Almere
country: Netherlands
facility: Flevoziekenhuis
city: Amsterdam
country: Netherlands
facility: AmsterdamUMC - location AMC
city: Amsterdam
country: Netherlands
facility: Onze Lieve Vrouwe Gasthuis (OLVG)
city: Delft
country: Netherlands
facility: Reinier de Graaf
city: Eindhoven
country: Netherlands
facility: Maxima Medisch Centrum
city: Enschede
country: Netherlands
facility: Medisch Spectrum Twente
city: Geleen
country: Netherlands
facility: Zuyderland ziekenhuis
city: Haarlem
country: Netherlands
facility: Spaarne Gasthuis
city: Leiden
country: Netherlands
facility: Leids Universitair Medisch Centrum
city: Maastricht
country: Netherlands
facility: Maastricht UMC+
city: Nijmegen
country: Netherlands
facility: Canisius Wilhelmina Ziekenhuis
city: Tilburg
country: Netherlands
facility: Elisabeth-TweeSteden Ziekenhuis
city: Utrecht
country: Netherlands
facility: UMC Utrecht
Study officials:
affiliation: Radboud University Medical Center
name: Dr. Hoentjen, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Erasmus Medical Center
name: Prof. dr. van der Woude, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Smits LJT, Pauwels RWM, Kievit W, de Jong DJ, de Vries AC, Hoentjen F, van der Woude CJ; LADI study group. Lengthening adalimumab dosing interval in quiescent Crohn's disease patients: protocol for the pragmatic randomised non-inferiority LADI study. BMJ Open. 2020 May 26;10(5):e035326. doi: 10.1136/bmjopen-2019-035326.