Crohn Disease (CD), Intensification
Conditions
Keywords
Crohn's disease, Intensification, Guselkumab
Brief summary
Crohn's disease (CD) is a chronic and destructive inflammatory disease of the gastrointestinal tract characterized by phases of relapse and remission. Tumor necrosis factor (TNF) antagonists, anti-integrins and anti-interleukin (IL) 12/23 are the main therapeutic agents to obtain deep remission and prevent disability. Despite the significant advances these biologics represent in treating inflammatory bowel disease (IBD), many patients experience suboptimal responses, including primary non-response or a loss of effectiveness over time, often leading to treatment discontinuation. For all these medications, a dose-response relationship has been demonstrated and an increase in dose or dosing frequency is recommended. Dose escalation is now an essential therapeutic approach necessary in 30 to 50% of CD patients treated with biologics. This strategy, supported by international guidelines, allows for long-term efficacy to be maintained without compromising safety. Guselkumab (GUS) is a monoclonal antibody targeting the p19 subunit of IL-23. In a recent phase III trial (GALAXI), GUS demonstrated superiority of both subcutaneous (SC) maintenance doses (200 mg every 4 weeks \[q4w\] and 100 mg every 8 weeks \[q8w\]) compared to placebo and ustekinumab. In the GALAXI phase III program, at least 30% of patients did not achieve clinical response after a 12-week intravenous induction, and almost 20% experienced a loss of response by week 44. In these patients, the benefit of an intensified dose of GUS (200 mg q4w) maintenance remains to be determined to guide clinicians in optimizing its use in clinical practice. The investigator aimed to evaluate the one-year effectiveness of GUS in CD in real-world settings and under optimal conditions allowing dose intensification.
Detailed description
Interventionnel, open multicenter study, the objectives are: Primary Objective To evaluate the one-year effectiveness of GUS in CD in real-world setting. Secondary Objectives * To evaluate the effectiveness of GUS intensification from 100 mg q8w to 200 mg q4w in patients with loss of response, * To evaluate the effectiveness of an intensified GUS 200 mg q4w maintenance therapy in patients who are primary non-responders to GUS SC induction at 12 weeks; * To assess the factors associated with GUS intensification effectiveness.
Interventions
DRUGGuselkumab
Guselkumab is a human monoclonal antibody targeting IL-23. In this study, patients receive guselkumab as part of a treat-to-target strategy. At week 12 (W12), patients are managed according to disease response: those with adequate response continue standard maintenance dosing, while non-responders are escalated to an intensified treatment regimen with adjusted dosing frequency.
Sponsors
Groupe d'Etude Therapeutique des Affections Inflammatoires Digestives
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Masking description
All participants receive guselkumab treatment with protocol-defined dose optimization based on clinical response after the induction period
Intervention model description
All eligible patients will receive subcutaneous guselkumab (GUS) 400 mg every 4 weeks during the induction period at Weeks 0, 4, and 8. At Week 12, treatment response will be assessed based on patient-reported outcomes (PRO2) and fecal calprotectin (FC): * Primary responders, defined as a decrease ≥ 30% in PRO2 and ≥ 25% in FC, will receive GUS 100 mg every 8 weeks as maintenance therapy. * Primary non-responders, defined as the absence of a ≥ 30% decrease in PRO2 or a ≥ 25% decrease in FC at Week 12, will directly receive GUS 200 mg every 4 weeks as maintenance therapy. In case of loss of response for the primary responders between Weeks 12 and 48 defined as an increase in FC \> 25% with a minimum cutoff of 250 µg/g, or an FC value \> 250 µg/g at Week 24, or objective disease activity confirmed by IUS, MRI, treatment will be intensified to GUS 200 mg every 4 weeks. This response-driven treatment strategy explains the need for additional visits during the maintenance period.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* \- Patients with a diagnosis of CD according to ECCO guidelines, * 18 years of age or older at the time of informed consent, * Absence of contraindication to guselkumab, * Active disease according to PRO2 (abdominal pain \> 1 or stool frequency \> 3), and faecal calprotectin \> 250 ug/g, * Objective active disease documented within ≤ 2 months by endoscopy or by MRI when not contraindicated, orby IUS), * Not currently participating in any interventional research. * Patient naïve or exposed to one or more advanced therapy, in accordance with the approved indication for guselkumab in Crohn's disease. * Females of childbearing potential must have a negative serum pregnancy test at the baseline Visit.
Exclusion criteria
* \- Patient under legal protection, * Previous exposure to an anti-IL23 * Combination of advanced therapy with GUS, * Patient with ostomy, * Pregnant or breastfeeding woman, * Patient with perianal CD predominant disease. * Active clinically significant infection or HIV, Hep B, Hep C, or active tuberculosis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| - Steroid free clinical remission (SFCR) associated with fecal calprotectin < 250 ug/g at Week 48 | Week 48 +/- 12Weeks for the patients who are intensified between Week 32 and Week 48 | Steroid-free clinical remission (SFCR), defined as clinical remission measured by the patient reprt outcome, PRO2 : abdominal pain ≤ 1 and stool frequency ≤ 3, without corticosteroid use at the time of assessment, combined with fecal calprotectin \< 250 µg/g. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Guselkumab persistence | Week 48 | Evaluation of the Guselkumab persistence during the study |
| - Morphological remission at Week 48 assessed using the same tool that was used for the patient's inclusion: endoscopy, MRI or IUS (major secondary endpoint), | Week 48 | Evaluation of the morphological remission at W48 by one of the morphological exams: endoscopy: SES-CD \<3 points, MRI: bowel wall thickness ≤3 mm without contrast enhancement, IUS: bowel wall thickness ≤3 mm without color doppler signal |
| SFCR associated with fecal calprotectin < 250 ug/g at Week 12, Week 24 and Week 48, | Week 12, Week 24 and Week 48 | Evaluation of the clinical remission by PRO2: abdominal pain ≤ 1 and stool frequency ≤ 3, without corticoids associates with a biological remission defined by calprotectin \< 250 ug/g |
| Clinical remission at Week 12, Week 24 and Week 48 | Week 12, Week 24 and Week 48 | Evaluation of the Clinical remission at the visits by the patient report outcome PRO2: abdominal pain ≤ 1 and stool frequency ≤ 3 |
| Biomarker remission at Week 12, Week 24 and Week 48 | Week 12, Week 24 and Week 48, | Evaluation of the biomarker remission: CRP \< 5 g/L and fecal calprotectin \<250 ug/g |
| Need for GUS dose intensification (Week 12, Week 24 and Week 48) | Week 12, Week 24 and Week 48 | Evaluation of the need of intensification at the visits if the FC increase (\> 25% with a minimal cut-off of 250 ug/g) between W12 and W48 or by a FC \> 250 µg/g at W24, or disease activity confirmed by : Endoscopy: SES-CD \> 3 points or IUS: bowel wall thickness ≥ 3 mm and/or with color doppler signal, or MRI : bowel wall thickness ≥3 mm and/or with contrast enhancement. |
| Serum levels of guselkumab (Week 12, Week 24 and Week 48) | Week 12, Week 24 and Week 48 | Analysis of the serum level of guselkumab |
| Neutralizing antibodies to guselkumab (Week 12, Week 24 and Week 48) | Week 12, Week 24 and Week 48 | Evaluation of the neutralization antibodies to guselkumab |
| -Change in the Short Inflammatory Bowel Disease Questionnaire(SIBD-Q) from baseline (Week 12, Week 24 and Week 48) | Week 12, Week 24 and Week 48 | Analysis of the change in SIBD-Q (quality of life index) during the study Score range: 10 - 70 The higher the score, the better the patient's clinical status (i.e., greater likelihood of remission). |
| Crohn's Disease-related hospitalization during study period (Week 12, Week 24 and Week 48) | Week 12, Week 24 and Week 48 | Crohn's Disease-related hospitalization during study period |
Countries
France
Contacts
CONTACTMIRA RAAD
CONTACTMarie Coisnon
PRINCIPAL_INVESTIGATORMathurin Fumery, Investigator
Hospital of Amiens, France
Outcome results
None listed