AzTrials
AzTrials

Crohn Disease in RemissionPhase 4LADINCT03172377

Lengthening Adalimumab Dosing Interval in Quiescent Crohn's Disease Patients

A Phase 4 study testing Lengthening adalimumab dosing interval in people with Crohn Disease in Remission and Crohn Disease, run by Radboud University Medical Center at 22 sites in Netherlands.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Crohn Disease in Remission, Crohn Disease
What is being tested?
Lengthening adalimumab dosing interval
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
174 participants
Where
22 sitesNetherlands
Study dates
3 May 2017to Oct 2022
Phase
Phase 4
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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

Who cannot join

  • 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

Trial locations and contacts

22 sites in 1 country.

22 sites in 1 country

Netherlands22 sites
  • Jeroen Bosch Ziekenhuis

    's-Hertogenbosch, North Brabant, PO box 90153, 5200 ME

  • Flevoziekenhuis

    Almere Stad

  • VU Medisch Centrum

    Amsterdam, North Holland

  • AmsterdamUMC - location AMC

    Amsterdam

  • Onze Lieve Vrouwe Gasthuis (OLVG)

    Amsterdam

  • Amphia Ziekenhuis

    Breda, North Brabant, PO box 90157, 4800 RL

  • Reinier de Graaf

    Delft

  • Albert Schweitzer Ziekenhuis

    Dordrecht, South Holland, PO box 444, 3300 AK

  • Maxima Medisch Centrum

    Eindhoven

  • Medisch Spectrum Twente

    Enschede

  • Zuyderland ziekenhuis

    Geleen

  • Spaarne Gasthuis

    Haarlem

  • Leids Universitair Medisch Centrum

    Leiden

  • Maastricht UMC+

    Maastricht

  • Radboudumc University Nijmegen Medical Centre

    Nijmegen, Gelderland, 6500 HB

  • Canisius Wilhelmina Ziekenhuis

    Nijmegen

  • Franciscus Gasthuis & Vlietland

    Rotterdam, South Holland, PO box 10900, 3004 BA

  • Erasmus Medical Center

    Rotterdam, South Holland, PO box 2040, 3000 CA

  • Ikazia Ziekenhuis

    Rotterdam, South Holland, PO box 5009, 3008 AA

  • Elisabeth-TweeSteden Ziekenhuis

    Tilburg

  • Bernhoven

    Uden, North Brabant, PO box 707, 5400 AS

  • UMC Utrecht

    Utrecht, PO box 85500, 3508 GA

Other trials in Netherlands

About this study

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.

Read the 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.

Being tested
Lengthening adalimumab dosing interval
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
Medical subject headings
Crohn Disease, Inflammatory Bowel Diseases

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Lengthening adalimumab dosing intervalOther

    Also called Lengthening Humira dosing interval, Longer adalimumab interval, Longer Humira interval, Adalimumab dose reduction

    Lengthening adalimumab dosing interval from 2 weeks to 3 weeks and -later- to 4 weeks.

Study groups in NCT03172377
Study groupRoleWhat they receive
Intervention groupExperimentalLengthening 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.
Receives: Other: Lengthening adalimumab dosing interval
Control groupNo interventionStandard 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 being measured

The primary outcome is the main question the study is designed to answer.

  1. 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%.

    Measured: From the date of randomization up to week 48.

Secondary outcomes (6)
  1. 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.

    Measured: From the date of randomization up to week 48.

  2. (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.

    Measured: From the date of randomization up to week 48.

  3. Whether adalimumab drug level is associated with successful interval lengthening

    Adalimumab drug levels at baseline measured by ELISA.

    Measured: From the date of randomization up to week 48.

  4. Whether biochemic FC or CRP are associated with successful interval lengthening

    Fecal calprotectin (mg/kg) or C-reactive protein (mg/L).

    Measured: From the date of randomization up to week 48.

  5. Whether co-medication use is associated with successful interval lengthening

    Co-medication includes azathioprine, Co-medication includes azathioprine, 6-mercaptopurine, 6-thioguanine, methotrexate.

    Measured: From the date of randomization up to week 48.

  6. 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).

    Measured: From the date of randomization up to week 48.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted1 Jun 2017
  2. Study start3 May 2017
  3. Primary completionOct 2022 (estimated)
  4. Study completionOct 2022 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
Multicenter, randomized controlled, open label non-inferiority trial
Masking
None (open label)
Enrolment
174 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03172377
Sponsor's protocol ID
NL58948.091.16
Other IDs
848015002, 2016-003321-42, 2016
Acronym
LADI
Status last verified
Nov 2021
First submitted
29 May 2017
Last updated
14 Oct 2022
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Undecided

Publications

  • van Linschoten RCA, Jansen FM, Pauwels RWM, Smits LJT, Atsma F, Kievit W, de Jong DJ, de Vries AC, Boekema PJ, West RL, Bodelier AGL, Gisbertz IAM, Wolfhagen FHJ, Romkens TEH, Lutgens MWMD, van Bodegraven AA, Oldenburg B, Pierik MJ, Russel MGVM, de Boer NK, Mallant-Hent RC, Ter Borg PCJ, van der Meulen-de Jong AE, Jansen JM, Jansen SV, Tan ACITL, van der Woude CJ, Hoentjen F; LADI study group, the Dutch Initiative on Crohn, Colitis (ICC). A Prediction Model for Successful Increase of Adalimumab Dose Intervals in Patients with Crohn's Disease: Secondary Analysis of the Pragmatic Open-Label Randomised Controlled Non-inferiority LADI Trial. Dig Dis Sci. 2024 Jun;69(6):2165-2174. doi: 10.1007/s10620-024-08410-z. Epub 2024 Apr 9.

    PubMed 38594435
  • Jansen FM, van Linschoten RCA, Kievit W, Smits LJT, Pauwels RWM, de Jong DJ, de Vries AC, Boekema PJ, West RL, Bodelier AGL, Gisbertz IAM, Wolfhagen FHJ, Romkens TEH, Lutgens MWMD, van Bodegraven AA, Oldenburg B, Pierik MJ, Russel MGVM, de Boer NK, Mallant-Hent RC, Ter Borg PCJ, van der Meulen-de Jong AE, Jansen JM, Jansen SV, Tan ACITL, Hoentjen F, van der Woude CJ; LADI study group. Cost-Effectiveness Analysis of Increased Adalimumab Dose Intervals in Crohn's Disease Patients in Stable Remission: The Randomized Controlled LADI Trial. J Crohns Colitis. 2023 Nov 24;17(11):1771-1780. doi: 10.1093/ecco-jcc/jjad101.

    PubMed 37310877
  • van Linschoten RCA, Jansen FM, Pauwels RWM, Smits LJT, Atsma F, Kievit W, de Jong DJ, de Vries AC, Boekema PJ, West RL, Bodelier AGL, Gisbertz IAM, Wolfhagen FHJ, Romkens TEH, Lutgens MWMD, van Bodegraven AA, Oldenburg B, Pierik MJ, Russel MGVM, de Boer NK, Mallant-Hent RC, Ter Borg PCJ, van der Meulen-de Jong AE, Jansen JM, Jansen SV, Tan ACITL, van der Woude CJ, Hoentjen F; LADI study group and the Dutch Initiative on Crohn and Colitis. Increased versus conventional adalimumab dose interval for patients with Crohn's disease in stable remission (LADI): a pragmatic, open-label, non-inferiority, randomised controlled trial. Lancet Gastroenterol Hepatol. 2023 Apr;8(4):343-355. doi: 10.1016/S2468-1253(22)00434-4. Epub 2023 Jan 31.

    PubMed 36736339
  • 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.

    PubMed 32461297

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Lengthening adalimumab dosing interval in people with Crohn Disease in Remission and Crohn Disease, run by Radboud University Medical Center at 22 sites in Netherlands.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 14 Oct 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 22 sites in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Cumulative incidence of persistent disease flares. (time frame: From the date of randomization up to week 48.). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03172377, which also lists 4 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Oct 2022.

Free account

Log in to keep searching

You’ve used your 3 free searches. AzTrials is free: log in or create a free account to keep searching clinical trials and save the ones you want to follow.

Create a free accountLog in