Lengthening Adalimumab Dosing Interval in Quiescent Crohn's Disease Patients
- Conditions
- Crohn Disease in RemissionCrohn Disease
- Interventions
- Other: Lengthening adalimumab dosing interval
- Registration Number
- NCT03172377
- Lead Sponsor
- Radboud University Medical Center
- 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.
Recruitment & Eligibility
- Status
- UNKNOWN
- Sex
- All
- Target Recruitment
- 174
-
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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Intervention group Lengthening adalimumab dosing interval Lengthening adalimumab dosing interval: The adalimumab injection interval during maintenance therapy (40 mg sc / 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.
- Primary Outcome Measures
Name Time Method Cumulative incidence of persistent disease flares. From the date of randomization up to week 48. 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 Outcome Measures
Name Time Method Cumulative incidence of transient disease flares. From the date of randomization up to week 48. A transient flare is defined as two of three of the following criteria persisting for ≤ 8 weeks; FC \>250 µg/g, CRP≥10 mg/L, HBI ≥5.
Whether adalimumab drug level is associated with successful interval lengthening From the date of randomization up to week 48. Adalimumab drug levels at baseline measured by ELISA.
Whether biochemic FC or CRP are associated with successful interval lengthening From the date of randomization up to week 48. Fecal calprotectin (mg/kg) or C-reactive protein (mg/L).
The decremental cost effectiveness ratio of this interval lengthening strategy From the date of randomization up to week 48. Dividing the difference in costs (based on medical consumption (by medical consumption questionnaire(MCQ)) and work productivity (by productivity cost questionnaire(PCQ))) by the difference in quality-adjusted life years (based on EuroQol-5D questionnaire).
(Serious) adverse event rate From the date of randomization up to week 48. (Serious) adverse events that are (possibly) related to adalimumab and the (Serious) adverse events that are (possibly) related to adalimumab interval lengthening in the intervention and control group, expressed as events/ 100 patient-years of follow-up.
Whether co-medication use is associated with successful interval lengthening From the date of randomization up to week 48. Co-medication includes azathioprine, Co-medication includes azathioprine, 6-mercaptopurine, 6-thioguanine, methotrexate.
Trial Locations
- Locations (22)
Radboudumc University Nijmegen Medical Centre
🇳🇱Nijmegen, Gelderland, Netherlands
Jeroen Bosch Ziekenhuis
🇳🇱's Hertogenbosch, Noord-Brabant, Netherlands
Amphia Ziekenhuis
🇳🇱Breda, Noord-Brabant, Netherlands
Bernhoven
🇳🇱Uden, Noord-Brabant, Netherlands
Franciscus Gasthuis & Vlietland
🇳🇱Rotterdam, Zuid-Holland, Netherlands
Ikazia Ziekenhuis
🇳🇱Rotterdam, Zuid-Holland, Netherlands
AmsterdamUMC - location AMC
🇳🇱Amsterdam, Netherlands
Onze Lieve Vrouwe Gasthuis (OLVG)
🇳🇱Amsterdam, Netherlands
Medisch Spectrum Twente
🇳🇱Enschede, Netherlands
Spaarne Gasthuis
🇳🇱Haarlem, Netherlands
Leids Universitair Medisch Centrum
🇳🇱Leiden, Netherlands
Maastricht UMC+
🇳🇱Maastricht, Netherlands
Canisius Wilhelmina Ziekenhuis
🇳🇱Nijmegen, Netherlands
Elisabeth-TweeSteden Ziekenhuis
🇳🇱Tilburg, Netherlands
UMC Utrecht
🇳🇱Utrecht, Netherlands
Maxima Medisch Centrum
🇳🇱Eindhoven, Netherlands
VU Medisch Centrum
🇳🇱Amsterdam, Noord-Holland, Netherlands
Albert Schweitzer Ziekenhuis
🇳🇱Dordrecht, Zuid-Holland, Netherlands
Erasmus Medical Center
🇳🇱Rotterdam, Zuid-Holland, Netherlands
Reinier de Graaf
🇳🇱Delft, Netherlands
Flevoziekenhuis
🇳🇱Almere, Netherlands
Zuyderland ziekenhuis
🇳🇱Geleen, Netherlands