De-escalation of Anti-TNF Therapy in Inflammatory Bowel Disease

Официальное название

De-escalation of Anti-TNF Therapy in Adolescents and Young Adults With IBD With Tight Faecal Calprotectin and Trough Level Monitoring

Обзор

BACKGROUND/RATIONALE: Treatment outcomes of patients with inflammatory bowel disease (IBD) have improved enormously during the past decade due to the use of anti-tumour necrosis factor (anti-TNF) therapy. As a result, 67 to 91% of paediatric patients and 66% of adult patients is still in sustained remission two years after the initiation of anti-TNF therapy. Prolonged use of anti-TNFs comes with disadvantages such as dose dependent susceptibility to infections and dermatological adverse effects. Preliminary, mostly uncontrolled studies suggest that dose reduction by dosing interval lengthening is a realistic option in a relevant proportion of patients with IBD, provided that intensive follow-up is applied. OBJECTIVE: To evaluate whether a faecal calprotectin (FC) guided strategy of anti-TNF dosing interval lengthening is non-inferior in maintaining remission in patients with IBD, compared with an unchanged dosing interval.

Подробное описание

STUDY DESIGN:

International, multi-centre, prospective, partially randomised patient-preference trial.

STUDY POPULATION:

Study population: Eligible patients are aged 12-25 years with luminal Crohn's disease (CD) or ulcerative colitis (UC), who have three consecutive faecal calprotectin (FC) results in the target range (i.e. \<250 µg/g for CD patients; \<150 µg/g for UC patients) over a period of 6 months at study entry or recently confirmed endoscopic remission.

DE-ESCALATION STRATEGY:

In patients treated with adalimumab, the dosing interval will be lengthened from 2 to 3 weeks. In patients treated with infliximab, the dosing interval will be lengthened from 8 to 12 weeks. FC rapid tests will be performed every 4 weeks and rapid tests for anti-TNF trough levels will be performed every 12 weeks.

MAIN STUDY ENDPOINTS:

The primary outcome is the cumulative incidence of out-of-range FC results at 48 weeks follow-up. Secondary endpoints include time to get out-of-range FC results, cumulative incidence of anti-TNF associated adverse effects, proportion of patients progressing from out-of-range FC to loss-of-response and identification of predictors of successful de-escalation.

ETHICAL CONSIDERATIONS:

Patients with reduced anti-TNF exposure may have a higher risk of out-of-range FC results and, on the other hand, may benefit from fewer hospital visits or injections and possibly a decrease in adverse effects of anti-TNF therapy. Tight monitoring of FC levels (i.e. 4-weekly) will allow institution of re-escalation before the patient manifests clinical signs of relapse. This study cannot be conducted without the participation of minors and young adults, who typically have a short disease duration. Early treatment with anti-TNF agents possibly modifies the course of their disease, which makes provision for safe deescalation.

Вмешательства

• Биопрепарат Infliximab
  Dosing interval lengthening from 8 to 12 weeks
• Биопрепарат Adalimumab
  Dosing interval lengthening from 2 to 3 weeks

Первичные конечные точки

• cumulative incidence of out-of-range fecal calprotectin results at 48 weeks follow-up [Срок оценки: 48 weeks]

Вторичные конечные точки (5)

• Time to get out-of-range fecal calprotectin results [Срок оценки: up to 48 weeks]
• Cumulative incidence of anti-TNF-associated respiratory infections and dermatological adverse effects at 48 weeks follow-up [Срок оценки: 48 weeks]
• Evolution of FC and anti-TNF trough levels in the first 16 weeks after reverting to previous dosing interval [Срок оценки: Up to 48+16 weeks]
• Proportion of patients developing loss-of-response in the first 16 weeks after reverting to the previous dosing interval [Срок оценки: Up to 48+16 weeks]
• Identification of predictors of successful de-escalation. [Срок оценки: 48 weeks]

Критерии участия

Критерии включения

• Aged 12-25 years
• Diagnosed with luminal Crohn's disease or ulcerative colitis
• Treated with either 8-weekly infliximab or 2-weekly adalimumab
• Current anti-TNF agent as first ever anti-TNF agent or prior anti-TNF agent discontinued for reason other than primary non-response or secondary loss-of-response
• No previous attempts to lengthen the dosing interval
• Three consecutive faecal calprotectin (FC) results in the target range (i.e. <250 μg/g for CD patients; <150 μg/g for UC patients) in the previous 6 months or confirmed endoscopic remission within 2 months before study entry (i.e. simple endoscopic score for Crohn's disease (SES-CD) <3 points for CD patients; ulcerative colitis endoscopic index of severity (UCEIS) ≤1 point for UC patients)
• Absence of symptoms associated with active IBD (judged by the local IBD-team)
• Written informed consent granted

Критерии исключения

• Perianal fistula
• Presence of ileostomy or ileoanal pouch (as FC cut-off is not validated for small bowel faeces)
• Any inflammatory comorbidity, such as rheumatoid arthritis
• Current treatment with corticosteroids (prednisone or budesonide)
• Current pregnancy

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Бельгия · 3 центра

• Universitair Ziekenhuis Gent — Ghent
• Centre hospitalier universitaire de Liège — Liège
• Centre hospitalier régional de la Citadelle — Liège

Нидерланды · 3 центра

• Rijnstate Hospital — Arnhem
• Catharina Hospital Eindhoven — Eindhoven
• University Medical Center Groningen — Groningen

Испания · 1 центр

• Hospital Universitari de Bellvitge — L'Hospitalet de Llobregat

Публикации

• Bouhuys M, Wessels MMS, de Vries W, Lambeck AJA, Touw DJ, van Rheenen PF. Lateral flow test versus enzyme-linked immunosorbent assay to measure infliximab trough concentrations: A head-to-head comparison. J Pediatr Gastroenterol Nutr. 2024 Dec;79(6):1134-1141. doi: 10.1002/jpn3.12372. Epub 2024 Oct 10. PMID 39390697
• Bouhuys M, Lexmond WS, Dijkstra G, Lobaton T, Louis E, van Biervliet S, Groen H, Guardiola J, Rheenen PV. Efficacy of anti-TNF dosing interval lengthening in adolescents and young adults with inflammatory bowel disease in sustained remission (FREE-study): protocol for a partially randomised patient preference trial. BMJ Open. 2021 Nov 3;11(11):e054154. doi: 10.1136/bmjopen-2021-054154. PMID 34732500

Идентификаторы

NCT: NCT04646187 · 202000261 · 2020-001811-26

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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