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Lengthening Adalimumab Dosing Interval in quiescent Crohn’s disease patients


- candidate number27329
- NTR NumberNTR6417
- ISRCTNISRCTN no longer applicable
- Date ISRCTN created
- date ISRCTN requested
- Date Registered NTR29-mei-2017
- Secondary IDsNL58948.091.16 EudraCT 2016-003321-42, ZonMW project 848015002
- Public TitleLengthening Adalimumab Dosing Interval in quiescent Crohn’s disease patients
- Scientific TitleLengthening Adalimumab Dosing Interval in quiescent Crohn’s disease patients
- ACRONYMThe LADI study
- hypothesisAdalimumab 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.

Our objective is to assess non-inferiority of extending the adalimumab dosing interval, under strict disease monitoring in CD patients in sustained (>12 months) clinical remission, compared to standard care.
- Healt Condition(s) or Problem(s) studiedCrohn's disease (CD), Chronic inflammatory bowel disease, TNF-alpha, Adalimumab
- Inclusion criteria Age 18 or older
 Diagnosis of colonic and/or distal ileal CD
 Sustained steroid-free clinical remission for >12 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 CRP <5 mg/L
- Harvey Bradshaw Index (HBI) <5
- Exclusion criteria Absence of written informed consent
 Concomitant corticosteroid usage
 Need for IBD-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
- mec approval receivedyes
- multicenter trialyes
- randomisedyes
- masking/blindingNone
- controlActive
- groupParallel
- Type2 or more arms, randomized
- Studytypeintervention
- planned startdate 3-mei-2017
- planned closingdate1-jan-2020
- Target number of participants174
- InterventionsIntervention 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 treatment following their usual dose and schedule. Treatment decisions are made at the discretion of the treating physician who will be blinded for the results of additional assessments beyond standard of care.
- Primary outcomeThe difference in cumulative incidence of pre-defined persistent flares between the dose reduction and usual care groups at 48-week follow-up.
- A persistent flare is defined as increased inflammatory markers (fecal calprotectin >250 μg/g and/or CRP >5 mg/L) combined with patient-reported symptoms (Harvey-Bradshaw Index ≥ 5), persisting for >8 weeks despite dose escalation of adalimumab.
- Secondary outcome Cumulative incidence of patients with transient flare (duration ≤8 weeks)
 Disease activity measured by HBI
 PROM: PRO-2 (abdominal pain and stool frequency).
 Adalimumab trough levels
 Anti-adalimumab antibody levels
 Adverse event rates (including injection site reactions and infections)
 Quality of life (SIBDQ) and QALY estimate based on EQ-5D utility
 Medical consumption (Medical Consumption Questionnaire (iMTA MCQ))
 Work productivity: absenteeism from labor (Productivity Cost Questionnaire (iMTA PCQ))
- TimepointsAt week 0, 12, 24, 36 and 48, following endpoints are measured:
- Disease activity (fecal calprotectin, CRP, Harvey Bradshaw Index, PRO-2)
- Pharmacokinetics/ immunogenicity (antidrug antibodies to adalimumab, trough levels)
- Adverse events
- Quality of life (SIBDQ, EQ-5D)
- Cost-effectiveness (iMTA MCQ, iMTA PCQ)

At week 6, 18, 30 and 42, following endpoints are measured:
- Harvey Bradshaw Index, PRO-2
- SIBDQ, EQ-5D
- Adverse events
- Trial web site
- statusopen: patient inclusion
- CONTACT FOR PUBLIC QUERIESDrs. Lisa J.T. Smits
- CONTACT for SCIENTIFIC QUERIESDrs. Frank Hoentjen
- Sponsor/Initiator Radboud University Medical Center Nijmegen
- Funding
(Source(s) of Monetary or Material Support)
ZonMw
- Publications
- Brief summaryRationale
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 of extending the adalimumab dosing interval, under strict disease monitoring in CD patients in sustained (>12 months) clinical remission, compared to standard care.

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 treatment following their usual dose and schedule. Treatment decisions are made at the discretion of the treating physician who will be blinded for the results of additional assessments beyond standard of care.

Main study parameters/endpoints
Primary outcome
The difference in cumulative incidence of pre-defined persistent flares between the dose reduction and usual care groups at 48-week follow-up.
A persistent flare is defined as increased inflammatory markers (FC >250 μg/g and/or CRP >10 mg/L) combined with patient-reported symptoms (HBI ≥ 5), persisting for >8 weeks despite dose escalation of adalimumab.

Secondary outcomes
 Cumulative incidence of patients with transient flare (duration ≤8 weeks)
 Disease activity measured by HBI
 PROM: PRO-2 (abdominal pain and stool frequency).
 Adalimumab trough levels
 Anti-adalimumab antibody levels
 Adverse event rates (including injection site reactions and infections)
 Quality of life (SIBDQ) and QALY estimate based on EQ-5D utility
 Medical consumption (Medical Consumption Questionnaire (iMTA MCQ))
 Work productivity: absenteeism from labor (Productivity Cost Questionnaire (iMTA PCQ))

Nature and extent of the burden and risks associated with participation, benefit and group relatedness:
In this study patients will have to visit the site every 12 weeks which is slightly more than the usual 2-3 times per year. This will allow strict monitoring of disease control and timely intervention in case of flares. In terms of diagnostics, blood tests/ faecal tests and questionnaires will be performed 4 times per year. Additionally, patients in both arms will be interviewed via telephone every 6 weeks in between clinical visits to assess for symptoms and potential disease activity. The consequence of a confirmed disease relapse includes switching back to the prior injection interval. Risk of interval extension includes a higher risk of disease flare. It is anticipated that most patients will enter remission upon subsequent adjusting of injection interval. Study patients may benefit from reduced exposure to adalimumab, the benefits include reduced risk of injection reactions, and potentially less side effects including risk of infectious complications.
- Main changes (audit trail)27-aug-2017: Wijzigingen -MT
Explanation: “In order to prevent incorrect exclusion of patients in clinical remission, we decided to change the maximum CRP levels to 10 mg/l as part of the clinical remission definition, according to the most recent ECCO guideline (Gomollón F et al, JCC 2017;11:3-25).”

Inclusion criterium:
- Fecal calprotectin (FC) < 150 μg/g and CRP <5 mg/L
Replaced by - Fecal calprotectin (FC) < 150 μg/g and CRP <10 mg/L

Primary outcome:
- A persistent flare is defined as increased inflammatory markers (fecal calprotectin >250 μg/g and/or CRP >5 mg/L) combined with patient-reported symptoms (Harvey-Bradshaw Index ≥ 5), persisting for >8 weeks despite dose escalation of adalimumab.
Replaced by
- A persistent flare is defined as increased inflammatory markers (fecal calprotectin >250 μg/g and/or CRP >10 mg/L) combined with patient-reported symptoms (Harvey-Bradshaw Index ≥ 5), persisting for >8 weeks despite dose escalation of adalimumab.
- RECORD29-mei-2017 - 3-sep-2017


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