Lengthening Adalimumab Dosing Interval in Quiescent Crohn's Disease Patients (LADI)

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Crohn Disease; Crohn Disease in Remission
• Intervention / Treatment: Other: Lengthening adalimumab dosing 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.

• Study Type: Interventional
• Enrollment (Anticipated): 174
• Phase: Phase 4

Contacts and Locations

Study Locations

• Netherlands
  • Almere, Netherlands
    • Flevoziekenhuis
  • Amsterdam, Netherlands
    • Onze Lieve Vrouwe Gasthuis (OLVG)
  • Amsterdam, Netherlands
    • AmsterdamUMC - location AMC
  • Delft, Netherlands
    • Reinier de Graaf
  • Eindhoven, Netherlands
    • Maxima Medisch Centrum
  • Enschede, Netherlands
    • Medisch Spectrum Twente
  • Geleen, Netherlands
    • Zuyderland ziekenhuis
  • Haarlem, Netherlands
    • Spaarne Gasthuis
  • Leiden, Netherlands
    • Leids Universitair Medisch Centrum
  • Maastricht, Netherlands
    • Maastricht UMC+
  • Nijmegen, Netherlands
    • Canisius Wilhelmina Ziekenhuis
  • Tilburg, Netherlands
    • Elisabeth-TweeSteden Ziekenhuis
  • Utrecht, Netherlands, PO box 85500, 3508 GA
    • UMC Utrecht
  • Gelderland
    • Nijmegen, Gelderland, Netherlands, 6500 HB
      • Radboudumc University Nijmegen Medical Centre
  • Noord-Brabant
    • 's Hertogenbosch, Noord-Brabant, Netherlands, PO box 90153, 5200 ME
      • Jeroen Bosch Ziekenhuis
    • Breda, Noord-Brabant, Netherlands, PO box 90157, 4800 RL
      • Amphia Ziekenhuis
    • Uden, Noord-Brabant, Netherlands, PO box 707, 5400 AS
      • Bernhoven
  • Noord-Holland
    • Amsterdam, Noord-Holland, Netherlands
      • VU Medisch Centrum
  • Zuid-Holland
    • Dordrecht, Zuid-Holland, Netherlands, PO box 444, 3300 AK
      • Albert Schweitzer Ziekenhuis
    • Rotterdam, Zuid-Holland, Netherlands, PO box 10900, 3004 BA
      • Franciscus Gasthuis & Vlietland
    • Rotterdam, Zuid-Holland, Netherlands, PO box 2040, 3000 CA
      • Erasmus Medical Center
    • Rotterdam, Zuid-Holland, Netherlands, PO box 5009, 3008 AA
      • Ikazia Ziekenhuis

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Intervention group; 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; Lengthening adalimumab dosing interval from 2 weeks to 3 weeks and -later- to 4 weeks.; Other Names: Lengthening Humira dosing interval; Longer adalimumab interval; Longer Humira interval; Adalimumab dose reduction; Humira dose reduction
NO_INTERVENTION: Control group; 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?

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.

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Collaborators: Erasmus Medical Center
• Investigators: Principal Investigator: Dr. Hoentjen, MD, PhD, Radboud University Medical Center; Principal Investigator: Prof. dr. van der Woude, MD, PhD, Erasmus Medical Center

Publications and helpful links

General Publications

• 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.

Helpful Links

• Dutch organisation for healthcare research and innovation (ZonMW)

Study record dates

Study Major Dates

• Study Start (ACTUAL): May 3, 2017
• Primary Completion (ANTICIPATED): October 1, 2022
• Study Completion (ANTICIPATED): October 1, 2022

Study Registration Dates

• First Submitted: May 29, 2017
• First Submitted That Met QC Criteria: May 29, 2017
• First Posted (ACTUAL): June 1, 2017

Study Record Updates

• Last Update Posted (ACTUAL): October 14, 2022
• Last Update Submitted That Met QC Criteria: October 13, 2022
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Keywords: pharmacokinetics; immunogenicity; adalimumab; cost-effectiveness; anti-TNF; dose reduction; inflammatory bowel disease; Humira; anti-tumor necrosis factor; interval lengthening; dosing interval; antidrug antibodies; trough levels
• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Gastroenteritis; Intestinal Diseases; Inflammatory Bowel Diseases; Crohn Disease; Anti-Inflammatory Agents; Antirheumatic Agents; Adalimumab
• Other Study ID Numbers: NL58948.091.16; 848015002 (OTHER_GRANT: ZonMW); 2016-003321-42 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No