Salvage Therapy With High/Low Methotrexate for Loss of Response to Infliximab Dose Escalation
Phase 4, Open Lable Non Randomized un Controlled Study. Salvage Therapy With High/Low Methotrexate for Loss of Response to Infliximab Dose Escalation
The goal of the present study is to evaluate if addition of methotrexate can restore remission after loss of response to infliximab after dose escalation.
another goal is to evaluate if low dose methotrexate can maintain remission achieved by regular dose methotrexate by 6 months.
Aperçu de l'étude
Statut
Les conditions
Intervention / Traitement
Description détaillée
Background: IFX mono-therapy became the method of choice for treatment in pediatric CD, though this strategy has been called into question due to frequent loss of response to IFX requiring dose escalation of IFX or decreased intervals of IFX( up to 40% during the first year) (1). This loss of response has been attributed to development of ATIs and low trough levels of IFX, which can develop after the first infusions. This loss of response will often occur in patients with prior azathioprine exposure (2,3,4).
Currently , the first step during loss of response to infliximab in children is dose escalation either by decreasing the interval between infusions or doubling the dose. However, patients with persistent antibodies or high titers are likely to fail even with dose escalation. The Sonic trial clearly demonstrated that combination therapy with a thiopurine may be more effective than Anti TNF alpha monotherapy (2). Ben Horin et al demonstrated that antidrug antibodies can be reversed and improved anti TNF trough levels obtained by adding an immunomodulator to failed monotherapy due to an antidrug antibody (3).
We have previously shown that in patients with a previous loss of response to two biologics leading to cessation of both biologics can respond to reinduction with adalimumab and methotrexate . Among 12 patients (10 children and two adults) , 6 obtained complete remission. We subsequently lowered the does in several patients without loss of response, and tried stopping methotrexate in 3 patients. All 3 patients relapsed within months of complete cessation of methorexate.In this previous study we took two separate actions that restored response, re-induction and methotrexate therapy. In the current proposal we will take patients that are on escalated therapy and just add methotrexate, in order to evaluate if adding methotrexate once weekly can restore response after loss of response to infliximab after failed dose escalation.It is important to note that methotrexate does not increase the risk of malignancy as co-therapy as far as we know.
Methods: It is a prospective open label phase 4, non randomized uncontrolled study in a small cohort of patients to evaluate if addition of methotrexate can restore remission after loss of response to infliximab after dose escalation in paediatric patients.
Type d'étude
Inscription (Réel)
Phase
- Phase 4
Contacts et emplacements
Lieux d'étude
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Holon, Israël, 58100
- The E. Wolfson.Medical Center
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Critères de participation
Critère d'éligibilité
Âges éligibles pour étudier
Accepte les volontaires sains
Sexes éligibles pour l'étude
La description
Inclusion Criteria:
- Informed consent
- Established diagnosis of Crohns disease.
- Age: 8 - 18 years ( inclusive)
- Active disease PCDAI >10 at least two weeks after infusion.
- On Infliximab with at least 3 prior infusions, and still active despite a decreased dose interval ( ≤ 6 weeks) or increased dose of infliximab (≥7.5 mg/kg /dose q 8 weeks).
Comment: Patients who are on combination therapy with a stable thiopurine>8 weeks can also be included ( thiopurine will be stopped at enrollment).
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Exclusion Criteria:
1. Patients who are primary non responders after first two doses 2. Patients who have had to stop infliximab due to side effects. 3. Patients with known intolerance to methotrexate. 4. Elevated ALT >1.5 normal. 5. Pregnancy. 6. Patients who have insulin-dependent diabetes 7. Patients who have significantly impaired renal function 8. Current bacterial infection/ inflammation including Hepatitis B or C and Pneumonia.
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Plan d'étude
Comment l'étude est-elle conçue ?
Détails de conception
- Objectif principal: Traitement
- Répartition: N / A
- Modèle interventionnel: Affectation à un seul groupe
- Masquage: Aucun (étiquette ouverte)
Armes et Interventions
Groupe de participants / Bras |
Intervention / Traitement |
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Expérimental: Addition of methotrexate
Addition SC methotrexate at 15 mg/m2, not to exceed 25 mg/m2 .
Patients in remission after 4 weeks will reduce their dose by halve.
patients not in remission will continue the full dose until 12 weeks.
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Infliximab therapy after escalation.
SC methotrexate at 15 mg/m2 , not to exceed 25 mg/m2 per week for 4 weeks.
Patients in remission after 4 weeks reduce their dose by halve.
patients not in remission will continue the full dose until 12 weeks.
Autres noms:
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Que mesure l'étude ?
Principaux critères de jugement
Mesure des résultats |
Description de la mesure |
Délai |
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remission
Délai: at 12 weeks
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remission without additional therapy.
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at 12 weeks
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Mesures de résultats secondaires
Mesure des résultats |
Délai |
|---|---|
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Remission
Délai: 6 months
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6 months
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Trough levels
Délai: week 12
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week 12
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ATIs
Délai: week 12
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week 12
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Collaborateurs et enquêteurs
Parrainer
Les enquêteurs
- Chaise d'étude: Arie Levine, MD, Pediatric Gastroenterology and Nutrition Unit, The E. Wolfson MC, Tel-Aviv University, Holon, Israel
Dates d'enregistrement des études
Dates principales de l'étude
Début de l'étude
Achèvement primaire (Réel)
Achèvement de l'étude (Réel)
Dates d'inscription aux études
Première soumission
Première soumission répondant aux critères de contrôle qualité
Première publication (Estimation)
Mises à jour des dossiers d'étude
Dernière mise à jour publiée (Réel)
Dernière mise à jour soumise répondant aux critères de contrôle qualité
Dernière vérification
Plus d'information
Termes liés à cette étude
Termes MeSH pertinents supplémentaires
- Maladies du système digestif
- Maladies gastro-intestinales
- Gastro-entérite
- Maladies intestinales
- Maladies intestinales inflammatoires
- Maladie de Crohn
- Effets physiologiques des médicaments
- Mécanismes moléculaires de l'action pharmacologique
- Inhibiteurs de la synthèse des acides nucléiques
- Inhibiteurs d'enzymes
- Agents antirhumatismaux
- Antimétabolites, Antinéoplasique
- Antimétabolites
- Agents antinéoplasiques
- Agents immunosuppresseurs
- Facteurs immunologiques
- Agents dermatologiques
- Agents de contrôle de la reproduction
- Agents abortifs, non stéroïdiens
- Agents abortifs
- Antagonistes de l'acide folique
- Méthotrexate
Autres numéros d'identification d'étude
- 0143-14-WOMC
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