Lengthening Adalimumab Dosing Interval in Quiescent Crohn's Disease Patients

Study Overview
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Brief Summary
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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
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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.

Official Title
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Lengthening Adalimumab Dosing Interval in Quiescent Crohn's Disease Patients

Conditions
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Crohn Disease in Remission, Crohn Disease

Intervention / Treatment
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* Other: Lengthening adalimumab dosing interval


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Multicenter, randomized controlled, open label non-inferiority trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention group<br>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. | Other: Lengthening adalimumab dosing interval<br>* Lengthening adalimumab dosing interval from 2 weeks to 3 weeks and -later- to 4 weeks.<br>* Other names: Humira dose reduction;|
| No Intervention: Control group<br>Standard care: patients will continue adalimumab maintenance treatment of 40mg per 2 weeks. Treatment decisions are made at the discretion of the treating physician. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative incidence of persistent disease flares. | 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%. | From the date of randomization up to week 48. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative incidence of transient disease flares. | 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. | From the date of randomization up to week 48. | 
| (Serious) adverse event rate | (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. | From the date of randomization up to week 48. | 
| Whether adalimumab drug level is associated with successful interval lengthening | Adalimumab drug levels at baseline measured by ELISA. | From the date of randomization up to week 48. | 
| Whether biochemic FC or CRP are associated with successful interval lengthening | Fecal calprotectin (mg/kg) or C-reactive protein (mg/L). | From the date of randomization up to week 48. | 
| Whether co-medication use is associated with successful interval lengthening | Co-medication includes azathioprine, Co-medication includes azathioprine, 6-mercaptopurine, 6-thioguanine, methotrexate. | From the date of randomization up to week 48. | 
| The decremental cost effectiveness ratio of this interval lengthening strategy | 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). | From the date of randomization up to week 48. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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