Lengthening Adalimumab Dosing Interval in Quiescent Crohn's Disease Patients

NCT03172377 | Unknown Phase 4 DMC

• 3 other identifiers: NL58948.091.168480150022016-003321-42
• Study Type: interventional
• Target: 174
• Locations: 1 country
• Sites: 22

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.

Conditions

Crohn Disease in Remission; Crohn Disease

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

Outcome Measures

Primary Outcomes (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%.

  From the date of randomization up to week 48.

Secondary Outcomes (6)

• Cumulative incidence of transient disease flares.

  From the date of randomization up to week 48.

• (Serious) adverse event rate

  From the date of randomization up to week 48.

• Whether adalimumab drug level is associated with successful interval lengthening

  From the date of randomization up to week 48.

• Whether biochemic FC or CRP are associated with successful interval lengthening

  From the date of randomization up to week 48.

• Whether co-medication use is associated with successful interval lengthening

  From the date of randomization up to week 48.

Study Arms (2)

Intervention group

EXPERIMENTAL

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

Control group

NO INTERVENTION

Standard care: patients will continue adalimumab maintenance treatment of 40mg per 2 weeks. Treatment decisions are made at the discretion of the treating physician.

Interventions

Lengthening adalimumab dosing interval OTHER

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

Also known as: Lengthening Humira dosing interval, Longer adalimumab interval, Longer Humira interval, Adalimumab dose reduction, Humira dose reduction

Intervention group

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Radboud University Medical Center: lead
• Erasmus Medical Center: collaborator

Study Sites (22)

Radboudumc University Nijmegen Medical Centre

Nijmegen, Gelderland, 6500 HB, Netherlands

Location

Jeroen Bosch Ziekenhuis

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

Location

Amphia Ziekenhuis

Breda, North Brabant, PO box 90157, 4800 RL, Netherlands

Location

Bernhoven

Uden, North Brabant, PO box 707, 5400 AS, Netherlands

Location

VU Medisch Centrum

Amsterdam, North Holland, Netherlands

Location

Albert Schweitzer Ziekenhuis

Dordrecht, South Holland, PO box 444, 3300 AK, Netherlands

Location

Franciscus Gasthuis & Vlietland

Rotterdam, South Holland, PO box 10900, 3004 BA, Netherlands

Location

Erasmus Medical Center

Rotterdam, South Holland, PO box 2040, 3000 CA, Netherlands

Location

Ikazia Ziekenhuis

Rotterdam, South Holland, PO box 5009, 3008 AA, Netherlands

Location

Flevoziekenhuis

Almere Stad, Netherlands

Location

AmsterdamUMC - location AMC

Amsterdam, Netherlands

Location

Onze Lieve Vrouwe Gasthuis (OLVG)

Amsterdam, Netherlands

Location

Reinier de Graaf

Delft, Netherlands

Location

Maxima Medisch Centrum

Eindhoven, Netherlands

Location

Medisch Spectrum Twente

Enschede, Netherlands

Location

Zuyderland ziekenhuis

Geleen, Netherlands

Location

Spaarne Gasthuis

Haarlem, Netherlands

Location

Leids Universitair Medisch Centrum

Leiden, Netherlands

Location

Maastricht UMC+

Maastricht, Netherlands

Location

Canisius Wilhelmina Ziekenhuis

Nijmegen, Netherlands

Location

Elisabeth-TweeSteden Ziekenhuis

Tilburg, Netherlands

Location

UMC Utrecht

Utrecht, PO box 85500, 3508 GA, Netherlands

Location

Related Publications (4)

• 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.

  PMID: 38594435 DERIVED

• 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.

  PMID: 37310877 DERIVED

• 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.

  PMID: 36736339 DERIVED

• 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.

  PMID: 32461297 DERIVED

Related Links

• Dutch organisation for healthcare research and innovation (ZonMW)

MeSH Terms

Conditions

Crohn Disease; Inflammatory Bowel Diseases

Condition Hierarchy (Ancestors)

Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Intestinal Diseases

Study Officials

• Dr. Hoentjen, MD, PhD

  Radboud University Medical Center

  PRINCIPAL INVESTIGATOR

• Prof. dr. van der Woude, MD, PhD

  Erasmus Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Multicenter, randomized controlled, open label non-inferiority trial

Study Record Dates

• First Submitted: May 29, 2017
• First Posted: June 1, 2017
• Study Start: May 3, 2017
• Primary Completion: October 1, 2022
• Study Completion: October 1, 2022
• Last Updated: October 14, 2022

Record last verified: 2021-11

Locations

NL (22)