Withdrawal of infliximab or concomitant immunosuppressant therapy in patients with Crohn's disease on combination therapy (SPARE): a multicentre, open-label, randomised controlled trial.
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SUBMITTER: Louis E
PROVIDER: S-EPMC9908559 | biostudies-literature | 2023 Mar
REPOSITORIES: biostudies-literature
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Withdrawal of infliximab or concomitant immunosuppressant therapy in patients with Crohn's disease on combination therapy (SPARE): a multicentre, open-label, randomised controlled trial.
Louis Edouard E Resche-Rigon Matthieu M Laharie David D Satsangi Jack J Ding Nik N Siegmund Britta B D'Haens Geert G Picon Laurence L Bossuyt Peter P Vuitton Lucine L Irving Peter P Viennot Stephanie S Lamb Christopher A CA Pollok Richard R Baert Filip F Nachury Maria M Fumery Mathurin M Gilletta Cyrielle C Almer Sven S Ben-Horin Shomron S Bouhnik Yoram Y Colombel Jean-Frederic JF Hertervig Erik E
The lancet. Gastroenterology & hepatology 20230111 3
<h4>Background</h4>The combination of infliximab and immunosuppressant therapy is a standard management strategy for patients with Crohn's disease. Concerns regarding the implications of long-term combination therapy provided the rationale for a formal clinical trial of treatment de-escalation. Our aim was to compare the relapse rate and the time spent in remission over 2 years between patients continuing combination therapy and those stopping infliximab or immunosuppressant therapy.<h4>Methods< ...[more]
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| S-EPMC6494506 | biostudies-literature
Project description:ObjectiveIn newly diagnosed paediatric patients with moderate-to-severe Crohn's disease (CD), infliximab (IFX) is initiated once exclusive enteral nutrition (EEN), corticosteroid and immunomodulator therapies have failed. We aimed to investigate whether starting first-line IFX (FL-IFX) is more effective to achieve and maintain remission than conventional treatment.DesignIn this multicentre open-label randomised controlled trial, untreated patients with a new diagnosis of CD (3-17 years old, weighted Paediatric CD Activity Index score (wPCDAI) >40) were assigned to groups that received five infusions of 5 mg/kg IFX at weeks 0, 2, 6, 14 and 22 (FL-IFX), or EEN or oral prednisolone (1 mg/kg, maximum 40 mg) (conventional). The primary outcome was clinical remission on azathioprine, defined as a wPCDAI <12.5 at week 52, without need for treatment escalation, using intention-to-treat analysis.Results100 patients were included, 50 in the FL-IFX group and 50 in the conventional group. Four patients did not receive treatment as per protocol. At week 10, a higher proportion of patients in the FL-IFX group than in the conventional group achieved clinical (59% vs 34%, respectively, p=0.021) and endoscopic remission (59% vs 17%, respectively, p=0.001). At week 52, the proportion of patients in clinical remission was not significantly different (p=0.421). However, 19/46 (41%) patients in the FL-IFX group were in clinical remission on azathioprine monotherapy without need for treatment escalation vs 7/48 (15%) in the conventional group (p=0.004).ConclusionsFL-IFX was superior to conventional treatment in achieving short-term clinical and endoscopic remission, and had greater likelihood of maintaining clinical remission at week 52 on azathioprine monotherapy.Trial registration numberClinicalTrials.gov Registry (NCT02517684).
| S-EPMC8666701 | biostudies-literature
Project description:BackgroundEpisodic infliximab (IFX) treatment is associated with the formation of antibodies to IFX (ATIs) in the majority of patients, which can lead to infusion reactions and a shorter duration of response. Concomitant use of immunosuppressives (IS) reduces the risk of ATI formation.Aims and methodsTo investigate which of the IS-that is, methotrexate (MTX) or azathioprine (AZA)-is most effective at reducing the risk of ATI formation, a multicentre cohort of 174 patients with Crohn's disease, treated with IFX in an on-demand schedule, was prospectively studied. Three groups were studied: no IS (n = 59), concomitant MTX (n = 50) and concomitant AZA (n = 65). ATI and IFX concentrations were measured in a blinded manner at Prometheus Laboratories before and 4 weeks after each infusion.ResultsATIs were detected in 55% (96/174) of the patients. The concomitant use of IS therapy (AZA or MTX) was associated with a lower incidence of ATIs (53/115; 46%) compared with patients not taking concomitant IS therapy (43/59; 73%; p<0.001). The incidence of ATIs was not different for the MTX group (44%) compared with the AZA group (48%). Patients not taking IS therapy had lower IFX levels (median 2.42 microg/ml (interquartile range (IQR) 1-10.8), maximum 21 microg/ml) 4 weeks after any follow-up infusion than patients taking concomitant IS therapy (median 6.45 microg/ml (IQR 3-11.6), maximum 21 microg/ml; p = 0.065), but there was no difference between MTX or AZA. In patients who developed significant ATIs >8 microg/ml during follow-up, the IFX levels 4 weeks after the first infusion were retrospectively found to be significantly lower than in patients who did not develop ATIs on follow-up or had inconclusive ATIs.ConclusionConcomitant IS therapy reduces ATI formation associated with IFX treatment and improves the pharmacokinetics of IFX. There is no difference between MTX and AZA in reducing these risks. ATI profoundly influences the pharmacokinetics of IFX. The formation of ATIs >8 microg/ml is associated with lower serum levels of IFX already at 4 weeks after its first administration.
| S-EPMC1954977 | biostudies-literature
Project description:IntroductionCrohn's disease is a chronic inflammatory disease of the gastrointestinal tract with an increasing incidence and prevalence worldwide. The early use of anti--tumour necrosis factor agents, such as infliximab, in patients with an aggressive form of Crohn's disease has become part of routine practice. However, infliximab has limitations, and early surgery might benefit patients more. The objective of this study was to compare laparoscopic bowel resection with infliximab treatment in patients with moderately or severely active Crohn's disease with respect to endoscopic remission. The laparoscopic bowel resection combined with infliximab treatment trial is the first randomised controlled trial to demonstrate if early surgery can improve the outcome of patients with Crohn's disease with limited non-stricturing disease treated with infliximab.Methods and analysisThis is a randomised, open-label, controlled trial at Renji Hospital. In this study, a total of 106 adult patients aged 18-80 years with moderately or severely active and steroid-dependent or steroid-resistant Crohn's disease of the distal ileum will be randomly assigned in a 1:1 ratio to the control and surgery groups. The primary outcome is 12-month endoscopic remission measured by the Simple Endoscopic Score for Crohn's Disease in the control group and the Rutgeerts score in the surgery group. The secondary outcomes are clinical remission, surgery rate, quality of life, Crohn's disease-related medical costs and Crohn's disease-related morbidity. The patients will be followed up every 6 months after randomisation through intestinal magnetic resonance enterography and colonoscopy for either 3 years or until clinical remission.Ethics and disseminationAll participants will provide informed consent. The protocol has been approved by the Medical Ethical Committee of the Academic Medical Center in Shanghai (No KY2019-180). Results will be disseminated through peer-reviewed journals and scientific conference presentations.Trial registration numberChiCTR2000029323.
| S-EPMC7670938 | biostudies-literature
Project description:ObjectivesThe prevalence of pediatric Crohn's disease (CD) is increasing in Japan and other countries, and many patients are unresponsive to or do not tolerate current treatment options. This study aimed to investigate the efficacy, safety, and pharmacokinetic profile of infliximab (IFX) in pediatric patients with moderate-to-severe CD and inadequate response to existing treatment.Study designThis was an open-label, uncontrolled, multicenter Phase 3 study conducted at nine sites in Japan between April 2012 and March 2015. Pediatric patients (aged 6-17 years) with moderate-to-severe CD were treated with IFX 5 mg/kg at Weeks 0, 2, and 6, and at 8-week intervals thereafter until Week 46, with final evaluation at Week 54. IFX dose was increased to 10 mg/kg in patients who showed loss of response to IFX from Week 14 onwards.ResultsA total of 14 patients fulfilled eligibility criteria and were treated. Dose-escalation criteria were met by five patients who then received 10 mg/kg IFX. The remaining nine patients continued to receive an IFX dose of 5 mg/kg. IFX rapidly improved clinical symptoms and its effect was maintained for up to 54 weeks. Overall Pediatric Crohn's Disease Activity Index (PCDAI) response rate was 85.7%, and overall PCDAI remission rate was 64.3%. Three out of five patients who increased IFX dose regained PCDAI remission by retrieval of serum IFX concentration. Adverse events and serious adverse events occurred in 100.0% and 14.3% of patients, respectively. There was no substantial difference in the safety profiles of patients taking a constant dose of 5 mg/kg and those taking an increased dose of 10 mg/kg.ConclusionsThese findings support the effective use of IFX in the treatment of pediatric patients with CD where other treatments have proven ineffective.
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Project description:[This corrects the article DOI: 10.1371/journal.pone.0201956.].
| S-EPMC9017882 | biostudies-literature
Project description:BackgroundMycophenolate mofetil is an immunosuppressant commonly used to treat systemic lupus erythematosus (SLE) and lupus nephritis. It is a known teratogen associated with significant toxicities, including an increased risk of infections and malignancies. Mycophenolate mofetil withdrawal is desirable once disease quiescence is reached, but the timing of when to do so and whether it provides a benefit has not been well-studied. We aimed to determine the effects of mycophenolate mofetil withdrawal on the risk of clinically significant disease reactivation in patients with quiescent SLE on long-term mycophenolate mofetil therapy.MethodsThis multicenter, open-label, randomised trial was conducted in 19 centres in the USA. Eligible patients were aged between 18 and 70 years old, met the American College of Rheumatology (ACR) 1997 SLE criteria, and had a clinical SLEDAI score of less than 4 at screening. Mycophenolate mofetil therapy was required to be stable or decreasing for 2 years or more if initiated for renal indications, or for 1 year or more for non-renal indications. Participants were randomly allocated in a 1:1 ratio to a withdrawal group, who tapered off mycophenolate mofetil over 12 weeks, or a maintenance group who maintained their baseline dose (1-3g per day) for 60 weeks. Adaptive random allocation ensured groups were balanced for study site, renal versus non-renal disease, and baseline mycophenolate mofetil dose (≥2 g per day vs <2 g per day). Clinically significant disease reactivation by week 60 following random allocation, requiring increased doses or new immunosuppressive therapy was the primary endpoint, in the modified intention-to-treat population (all randomly allocated participants who began study-provided mycophenolate mofetil). Non-inferiority was evaluated using an estimation-based approach. The trial was registered at ClinicalTrials.gov (NCT01946880) and is completed.FindingsBetween Nov 6, 2013, and April 27, 2018, 123 participants were screened, of whom 102 were randomly allocated to the maintenance group (n=50) or the withdrawal group (n=52). Of the 100 participants included in the modified intention-to-treat analysis (49 maintenance, 51 withdrawal), 84 (84%) were women, 16 (16%) were men, 40 (40%) were White, 41 (41%) were Black, and 76 (76%) had a history of lupus nephritis. The average age was 42 (SD 12·7). By week 60, nine (18%) of 51 participants in the withdrawal group had clinically significant disease reactivation, compared to five (10%) of 49 participants in the maintenance group. The risk of clinically significant disease reactivation was 11% (95% CI 5-24) in the maintenance group and 18% (10-32) in the withdrawal group. The estimated increase in the risk of clinically significant disease reactivation with mycophenolate mofetil withdrawal was 7% (one-sided upper 85% confidence limit 15%). Similar rates of adverse events were observed in the maintenance group (45 [90%] of 50 participants) and the withdrawal group (46 [88%] of 52 participants). Infections were more frequent in the mycophenolate mofetil maintenance group (32 [64%]) compared with the withdrawal group (24 [46%]).InterpretationsMycophenolate mofetil withdrawal is not significantly inferior to mycophenolate mofetil maintenance. Estimates for the rates of disease reactivation and increases in risk with withdrawal can assist clinicians in making informed decisions on withdrawing mycophenolate mofetil in patients with stable SLE.FundingThe National Institute of Allergy and Infectious Diseases and the National Institute of Arthritis and Musculoskeletal and Skin Diseases.
| S-EPMC10922882 | biostudies-literature
Project description:IntroductionThe only biologic therapy currently approved to treat moderate to severe Crohn's disease in children (<18 years old) are those that antagonise tumour necrosis factor-alpha (anti-TNF). Therefore, it is critically important to develop novel strategies that maximise treatment effectiveness in this population. There is growing evidence that rates of sustained corticosteroid-free clinical remission, endoscopic healing and drug durability considerably improve when patients receive early anti-TNF dose optimisations guided by reactive or proactive therapeutic drug monitoring and pharmacodynamic monitoring. In response, our team has developed a personalised and scalable infliximab dosing intervention that starts with dose selection and continues throughout maintenance to optimise drug exposure. We hypothesise that a precision dosing strategy starting from induction and targeting dose-specific pharmacokinetic and pharmacodynamic endpoints throughout therapy will significantly improve outcomes compared with a conventional dosing strategy.Methods and analysisConduct a clinical trial to assess rates of deep remission between Crohn's disease patients receiving infliximab with precision dosing (n=90) versus conventional care (n=90). Patients (age 6-22 years) will be recruited from 10 medical centres in the USA. Each centre has been selected to provide either precision dosing or conventional care dosing. Precision dosing includes the use of a clinical decision support tool (RoadMAB) from the start of infliximab to achieve specific (personalised) trough concentrations and specific pharmacodynamic targets (at doses 3, 4 and 6). Conventional care includes the use of a modified infliximab starting dose (5 or 7.5 mg/kg based on the pretreatment serum albumin) with a goal to achieve maintenance trough concentrations of 5-10 µg/mL. The primary endpoint is year 1 deep remission defined as a combination of clinical remission (paediatric Crohn's disease activity index<10 (child) or a Crohn's disease activity index<150 (adults)), off prednisone>8 weeks and endoscopic remission (simple endoscopic severity-Crohn's disease≤2).Ethics and dissemination). The study protocol has been approved by the Cincinnati Children's Hospital Medical Centre Institutional Review Board. Study results will be disseminated in peer-reviewed journals and presented at scientific meetings.Trial registration numberNCT05660746.
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Project description:About 40% IBD patients treated with anti-TNF antibodies do not respond to therapy. Baseline biomarkers of response are therefore of interest. By combining computational deconvolution of gene expression and meta-analysis approaches we identified cellular biomarkers in tissue (validated in 2 cohorts by IHC of biopsies), and investigated associated gene biomarkers in blood. This dataset provides data from the validation cohort III (blood).
2018-02-01 | GSE107865 | GEO
Project description:Most glioblastoma tumours exhibit intrinsic phosphatidylinositol 3-kinase (PI3K) pathway activation. Preclinical in vitro and in vivo models suggest that buparlisib (an oral pan-PI3K inhibitor) can have an effect on glioblastoma directly and by enhancing the activity of radiation and of temozolomide. This was a phase I, two-stage, multicentre, open-label, dose-escalation study of buparlisib in combination with temozolomide and radiotherapy in patients with newly diagnosed glioblastoma. In stage I, patients who completed the concomitant phase of combination of temozolomide and radiation prior to study entry received buparlisib in combination with temozolomide. In stage II, patients received buparlisib in combination with temozolomide and radiotherapy in the concomitant phase and temozolomide in the adjuvant treatment phase. The primary objective was to estimate the maximum tolerated dose (MTD) of buparlisib when combined with the approved first-line treatment of temozolomide and radiotherapy. The MTD of buparlisib in combination with temozolomide at stage I (adjuvant phase only) was 80 mg/day, which was used as the starting dose in stage II. The MTD of buparlisib in combination with temozolomide and radiotherapy in stage II (concomitant + adjuvant phase) was not determined due to the observed dose-limiting toxicities and treatment discontinuations due to adverse events (AEs). In stage I, the most commonly reported AEs were nausea (72.7%) and fatigue (59.1%). In stage II, the most commonly reported AEs were fatigue and nausea (56.3% each). No on-treatment deaths were reported during the study. Considering that the primary objective of estimating the MTD was not achieved in addition to the observed challenging safety profile of buparlisib in combination with radiotherapy and temozolomide, Novartis decided not to pursue the development of buparlisib in newly diagnosed glioblastoma.Trial registration numberClinicalTrials.gov identifier: NCT01473901.
| S-EPMC7359189 | biostudies-literature