Vedolizumab Is Associated With a Lower Risk of Serious Infections Than Anti-Tumor Necrosis Factor Agents in Older Adults.

BACKGROUND & AIMS: Despite the increased numbers of older adults with inflammatory bowel diseases (IBDs), there are few studies regarding the safety and effectiveness of IBD treatments in older adults. The aim of this study was to compare the safety and effectiveness of anti-tumor necrosis factor (TNF)-α agents and vedolizumab in older adults with IBD. METHODS: We conducted a retrospective cohort study using an active comparator, new-user design for adults age 65 years and older with IBD initiating anti-TNF-α agents and vedolizumab in the Medicare claims database from 2014 to 2017. The primary safety outcome was infection-related hospitalization (excluding intra-abdominal and perianal abscesses). Co-primary outcomes to estimate effectiveness were IBD-related hospitalization, IBD-related surgery, and new corticosteroid use 60 days or more after biologic initiation. We performed propensity score weighting to control for confounding and estimated adjusted hazard ratios and 95% confidence intervals using standardized morbidity ratio-weighted variables. RESULTS: We identified 1152 anti-TNF-α new users and 480 vedolizumab new users. The median age was 71 years in both cohorts and 11% were age 80 years or older. Crohn's disease patients comprised 54% of the anti-TNF-α cohort and 57% of the vedolizumab cohort. There was no significant difference in demographics, health care utilization, or frailty in both cohorts. More than half of both cohorts had a Charlson comorbidity index of 2 or higher. Vedolizumab users had a decreased risk of infection-related hospitalization (adjusted hazard ratio, 0.47; 95% confidence interval, 0.25-0.86). There was no significant difference in the outcomes approximating effectiveness. CONCLUSIONS: Older IBD patients treated with vedolizumab had a lower risk of infection-related hospitalization compared with those initiating anti-TNFs. We observed no difference in effectiveness defined by hospitalizations, surgery, or new corticosteroid use.

Preoperative Management of Gastrointestinal and Pulmonary Medications: Society for Perioperative Assessment and Quality Improvement (SPAQI) Consensus Statement.

Perioperative medication management is integral to preoperative optimization but remains challenging because of a paucity of literature guidance. Published recommendations are based on the expert opinion of a small number of authors without collaboration from multiple specialties. The Society for Perioperative Assessment and Quality Improvement (SPAQI) recognized the need for consensus recommendations in this area as well as the unique opportunity for its multidisciplinary membership to fill this void. In a series of articles within this journal, SPAQI provides preoperative medication management guidance based on available literature and expert multidisciplinary consensus. The aim of this consensus statement is to provide practical guidance on the preoperative management of gastrointestinal and pulmonary medications. A panel of experts with anesthesiology, perioperative medicine, hospital medicine, general internal medicine, and medical specialty experience was drawn together and identified the common medications in each of these categories. The authors then used a modified Delphi approach to review the literature and to generate consensus recommendations.

More Adverse Events with Home Infusions.

According to this study: Patients with immune-mediated disease who received biologic infusions at home were more likely to be admitted to the ED or hospital that day or the next compared with patients who received infusions at a facility.The safety implications of biologic home infusions need to be further evaluated.

Prevalence and real-world management of vedolizumab-associated enthesitis in successfully treated IBD patients.

BACKGROUND: Some studies have reported the development of moderate and severe de novo SpA-associated disease under vedolizumab (VDZ) treatment for IBD. Herein, we report a case series who developed severe enthesitis under VDZ therapy from a cohort of 90 treated cases. METHODS: In a single Italian IBD Unit in which 90 cases were on VDZ therapy, we identified 11 cases who developed severe enthesitis. The onset of disease in relationship to VDZ initiation, clinical and sonographic imaging features, and outcomes (including therapy switches) was described. RESULTS: A total of 11 cases, including 8 prior anti-TNF failures, with new-onset entheseal pathology were identified: multifocal (n = 4), unifocal (n = 6), and enthesitis/synovitis/dactylitis (n = 1). The mean duration of symptoms was 46 weeks (range 6-119), the mean CRP was 5.1 mg/dl, and the majority were HLA-B27 negative and showed good clinical response for gut disease. Clinical features and US showed severe enthesitis, including power Doppler change in 7 patients. All patients were initially treated with NSAIDs, and 5 patients underwent local steroid injections. At 12 months, 5/7 cases continued VDZ and 2 were switched to ustekinumab. At 12 months follow-up of 7 cases, 5 patients were in clinical remission and 2 patients had mild enthesitis with minimal increase of power Doppler signal. In addition, 4/7 severe patients developed marked post-inflammatory entheseal calcifications. CONCLUSIONS: A predominant isolated severe enthesitis pattern of SpA may develop under VDZ therapy with severe disease in 8% of cases. Most cases continued VDZ therapy.

Long-term Safety and Efficacy of the Anti-MAdCAM-1 Monoclonal Antibody Ontamalimab [SHP647] for the Treatment of Ulcerative Colitis: The Open-label Study TURANDOT II.

BACKGROUND AND AIMS: Ontamalimab, a fully-human monoclonal antibody targeting MAdCAM-1, induced remission in patients with moderate-to-severe ulcerative colitis [UC] in the TURANDOT study. We aimed to assess long-term safety, tolerability, and efficacy of ontamalimab in TURANDOT II. METHODS: TURANDOT II was a phase 2, multicentre, open-label [OL] study in patients with moderate-to-severe UC who completed TURANDOT on placebo or ontamalimab (NCT01771809). Patients were randomised to 75 mg or 225 mg ontamalimab every 4 weeks for 72 weeks [OL1]. The dosage could be increased to 225 mg from Week 8 at the investigator's discretion. All patients then received 75 mg every 4 weeks for 72 weeks [OL2], followed by 6-month safety follow-up. The primary objective was safety, measured by adverse events [AEs], serious AEs [SAEs], and AEs leading to withdrawal. Mucosal healing [MH; centrally read endoscopy] was assessed. RESULTS: Of 330 patients, 180 completed OL1; 94 escalated to 225 mg; 127 completed OL2. Overall, 36.1% experienced drug-related AEs. The most common SAE [10.0%] was worsening/ongoing UC; 5.5% of patients had serious infections, the most common being gastroenteritis [0.9%]. One death and four cancers [all unrelated to ontamalimab] occurred. No PML [progressive multifocal leukoencephalopathy]/lymphoproliferative disorders occurred. Geometric mean high-sensitivity C-reactive protein [hsCRP] and faecal calprotectin decreased across OL1 in both dose groups. The proportion of patients assigned to placebo in TURANDOT achieving MH increased from 8.8% [6/68] at baseline to 35.3% at Week 16 [24/68; non-responder imputation]. The corresponding increase in the ontamalimab group was from 23.3% [61/262] to 26.7% [70/262]. CONCLUSIONS: Ontamalimab was well tolerated up to 144 weeks in patients with moderate-to-severe UC, with good safety and efficacy.

Long-term Safety and Efficacy of Etrasimod for Ulcerative Colitis: Results from the Open-label Extension of the OASIS Study.

BACKGROUND AND AIMS: Etrasimod is an oral, selective, sphingosine 1-phosphate receptor modulator. In a phase 2, randomised, double-blind, placebo-controlled trial in adults with moderately-to-severely active ulcerative colitis [OASIS], etrasimod 2 mg provided significant benefit versus placebo and was generally well tolerated. This open-label extension [OLE] evaluated safety and efficacy of etrasimod for up to 52 weeks. METHODS: In OASIS, 156 patients received etrasimod 1 mg, etrasimod 2 mg, or placebo, once daily for 12 weeks. After completing OASIS, patients could enrol in the OLE and receive etrasimod 2 mg for an additional 34-40 weeks. RESULTS: In all, 118 patients enrolled in the OLE; 112 patients received etrasimod 2 mg at any point and were evaluated for safety and efficacy. A total of 92 [82%] patients who received etrasimod 2 mg in the OLE completed the study. Treatment-emergent adverse events occurred in 60% [67/112] of patients receiving etrasimod 2 mg at any time, most commonly worsening ulcerative colitis and anaemia; 94% of adverse events were mild/moderate. At end of treatment, 64% of patients met the criteria for clinical response, 33% for clinical remission, and 43% for endoscopic improvement. Week 12 clinical response, clinical remission, or endoscopic improvement was maintained to end of treatment in 85%, 60%, or 69% of patients, respectively. Steroid-free clinical remission occurred in 22% of overall patients. CONCLUSIONS: In this long-term extension study, etrasimod 2 mg demonstrated a favourable safety profile. Most patients with clinical response, clinical remission, or endoscopic improvement at Week 12 maintained that status to end of treatment.

Switching Australian patients with moderate to severe inflammatory bowel disease from originator to biosimilar infliximab: a multicentre, parallel cohort study.

OBJECTIVE: To examine whether non-medical switching of patients with inflammatory bowel disease (IBD) from originator infliximab to a biosimilar (CT-P13, Inflectra) is safe and clinically non-inferior to continued treatment with originator infliximab. DESIGN: Prospective, open label, multicentre, parallel cohort, non-inferiority study in seven Australian hospitals over 48 weeks, May 2017 - October 2019. PARTICIPANTS: Adults (18 years or older) with IBD receiving maintenance originator infliximab (Remicade) who had been in steroid-free clinical remission for at least 12 weeks. INTERVENTION: Managed program for switching patients in four hospitals from originator to biosimilar infliximab (CT-P13); patients in three other hospitals continued to receive originator infliximab (control). MAIN OUTCOME MEASURES: Clinical disease worsening requiring infliximab dose escalation or change in therapy. RESULTS: The switch group included 204 patients, the control group 141 patients with IBD. Ten patients in the control group (7%) and 16 patients switched to CT-P13 (8%) experienced clinical deterioration; the adjusted risk difference (control v switch group) was -1.1 percentage points (95% CI, -6.1 to 8.2 percentage points), within our pre-specified non-inferiority margin of 15 percentage points. Serious adverse events leading to infliximab discontinuation were infrequent in both the switch (six, 3%) and control (six, 4%) groups. CONCLUSION: Switching patients with IBD from originator to biosimilar infliximab is safe and non-inferior to continuing treatment with originator infliximab. Moreover, the introduction of biosimilar infliximab, by increasing market competition, has resulted in substantial cost savings for the Pharmaceutical Benefits Scheme.

Assessment of Vedolizumab Disease-Drug-Drug Interaction Potential in Patients With Inflammatory Bowel Diseases.

Disease-drug-drug interactions (DDDIs) have been identified in some inflammatory diseases in which elevated proinflammatory cytokines can downregulate the expression of cytochrome P450 (CYP) enzymes, potentially increasing systemic exposure to drugs metabolized by CYPs. Following anti-inflammatory treatments, CYP expression may return to normal, resulting in reduced drug exposure and diminished clinical efficacy. Vedolizumab has a well-established positive benefit-risk profile in patients with ulcerative colitis (UC) or Crohn's disease (CD) and has no known systemic immunosuppressive activity. A stepwise assessment was conducted to evaluate the DDDI potential of vedolizumab to impact exposure to drugs metabolized by CYP3A through cytokine modulation. First, a review of published data revealed that patients with UC or CD have elevated cytokine concentrations relative to healthy subjects; however, these concentrations remained below those reported to impact CYP expression. Exposure to drugs metabolized via CYP3A also appeared comparable between patients and healthy subjects. Second, serum samples from patients with UC or CD who received vedolizumab for 52 weeks were analyzed and compared with healthy subjects. Cytokine concentrations and the 4ß-hydroxycholesterol-to-cholesterol ratio, an endogenous CYP3A4 biomarker, were comparable between healthy subjects and patients both before and during vedolizumab treatment. Finally, a medical review of postmarketing DDDI cases related to vedolizumab from the past 6 years was conducted and did not show evidence of any true DDDIs. Our study demonstrated the lack of clinically meaningful effects of disease or vedolizumab treatment on the exposure to drugs metabolized via CYP3A through cytokine modulation in patients with UC or CD.

Assessment of Body Weight Changes in Patients with Inflammatory Bowel Diseases Initiating Biologic Therapy: A Prospective Cohort Study.

BACKGROUND: Prior studies have inconsistently suggested that biologic therapy may be associated with weight gain in inflammatory bowel disease patients (IBD). Our aim was to compare weight gain across different biologic therapy classes with distinct mechanisms of action. METHODS: This prospective cohort study recruited patients with moderate to severe IBD initiating outpatient biologic therapy with anti-TNF (infliximab, adalimumab), vedolizumab, or ustekinumab. Weight measurements were performed at weeks 0, 14, 30, and 54. Changes in weight between baseline and each of the follow-up visits were modeled as a continuous variable, and multivariate regression assessed the independent effect of therapeutic class on this outcome. RESULTS: Our study enrolled 269 patients (163 CD, 106 UC) initiating biologic therapy [99 anti-TNF (37%), 122 vedolizumab (45%), 48 ustekinumab (18%)]. From baseline, the weight significantly increased at week 14 with a mean of 0.36 kg (± 3.8 kg, p = 0.004) and continued to increase compared to baseline with 0.96 kg (± 3.9 kg, p < 0.001) and 1.29 kg (± 4.2 kg, p < 0.001) at week 30 and 54, respectively. On univariate and multivariable analysis, no significant differences between any of the biologic therapies for weight gain were seen at any time point (weight gain anti-TNF: 0.31 kg, 1.06 kg, 1.33 kg; VDZ: 0.30 kg, 0.83 kg, 1.10 kg; UST: 0.63 kg, 1.21 kg, 2.31 kg at wk 14, wk 30, and wk 54, respectively). None of the disease activity parameters showed any statistical association with weight gain. CONCLUSION: There was no difference in weight gain among the different biologic therapeutic classes.

An update on efficacy and safety considerations for the latest drugs used to treat irritable bowel syndrome.

INTRODUCTION: Irritable bowel syndrome (IBS), globally affecting 11.2% of the population and imposing a direct annual cost of $1.7bn-$10bn in the US, is one of the today's major therapeutic challenges. Therefore, there is urgent need to address this issue through reviewing the tolerability and efficacy of available medications. AREAS COVERED: Over the past decade, related experiments were cited through Clinicaltrials.gov, PubMed, WHO ICTRP, and Cochrane library. Pharmacological parameters of approved medications available in the USFDA, EMA, TGA and PMDA were also stated. EXPERT OPINION: Anti-spasmodics are used as the first-line treatment in pain-predominant IBS and IBS-D, among which calcium channel blockers and neurokinin-type 2 receptor antagonists seem to replace anti-cholinergic drugs. As second-line treatments, rifaximin is considered to be the best for IBS-D though it has lower efficacy than alosetron and eluxadoline. For IBS-C, linaclotide is the most effective and the safest second-line therapy, following laxatives/fibers, which may be replaced by tenapanor, in the future. When moderate to severe IBS is associated with severe pain or comorbid psychological disorders, gut-brain neuromodulators could also be prescribed. Regarding all this, there is still a paramount need to conduct careful clinical studies on efficacy, safety and cost-effectiveness of current approved and non-approved treatments.

Value Assessment and Quantitative Benefit-Risk Modelling of Biosimilar Infliximab for Crohn's Disease.

BACKGROUND AND OBJECTIVE: Regulatory approval of biosimilars often depends on extrapolating evidence from one clinical indication to all of those of the originator biologic. We aimed to develop a quantitative benefit-risk analysis to assess whether the resulting increase in the uncertainty in the clinical performance of biosimilars (i.e. risk) may be countered by their lower pricing (benefit). METHODS: A 1-year decision-analytic model was developed for the biosimilar infliximab (Inflectra®) for Crohn's disease. The perspective was that of the National Health Service in the UK and costs were valued to 2015/16. A hypothetical cohort of biologic-naïve patients with moderate-to-severe Crohn's disease was simulated through the model. Immunogenicity to infliximab was a key modifier, influencing rates of non-response and infusion reactions. Net health benefit was estimated based on quality-adjusted life-years. A range of sensitivity analyses tested the robustness of the results and explored how the biosimilar price must respond to varying immunogenicity to remain the preferred option. RESULTS: The base-case analysis predicted a positive incremental net health benefit of 0.04 (95% central range 0.00-0.09) favouring the biosimilar, based on 0.803 quality-adjusted life-years, and costs of £18,087 and £19,176 for the biosimilar and originator, respectively. Two-way sensitivity analyses suggested that if 50% of patients developed antibodies, the value-based price of £410 per vial must be lower than that of the originator (£420), but remain higher than the actual market price (£378). CONCLUSIONS: The model supports the use of Inflecta® for Crohn's disease in the UK, and provides a framework for the quantitative evaluation of biosimilars in the context of a health technology assessment. Value-based pricing using this methodology could protect health systems from the potential risks of biosimilars where they are untested in the approved populations.

An economic evaluation of tofacitinib for the treatment of moderately-to-severely active ulcerative colitis: modeling the cost of treatment strategies in the United States.

Aims: To evaluate the cost differences between a treatment strategy including tofacitinib (TOFA) vs treatment strategies including adalimumab (ADA), golimumab (GOL), infliximab (IFX), and vedolizumab (VEDO) among all patients with moderate-to-severe ulcerative colitis (UC) (further stratified by patients naïve/exposed to tumor necrosis factor inhibitors [TNFis]). Materials and methods: An Excel-based decision-analytic model was developed to evaluate costs from the perspective of a third-party US payer over 2 years. Efficacy and safety parameters were taken from prescribing information and published trials. All patients started induction therapy on the first treatment in the strategy and continued if efficacy criteria were met and no major adverse event occurred (in which cases they proceeded to the next treatment in the strategy). Results: The cost per member per month (PMPM) of the TOFA->IFX->VEDO->GOL strategy ($1.11) was lower than that of the ADA->IFX->VEDO->GOL strategy ($1.34; Δ = $-0.23) among the TNFi-naïve population (n = 204 patients out of a plan of one million members). Similarly, the use of TOFA before ADA (i.e. TOFA->ADA->IFX-> VEDO) was also associated with lower PMPM costs than the use of ADA before TOFA (i.e. ADA->TOFA->IFX->VEDO): $1.15 vs $1.25 (Δ = $-0.10). Similar, and often larger, differences were observed in both the overall moderate-to-severe population and the TNFi-exposed population. Sensitivity analyses resulted in the same conclusions. Limitations: Our model relied on efficacy data from prescribing information and published trials, which were not head-to-head and slightly differed with respect to methods. Additionally, our model used representative minor and major ADRs (and the associated costs) to represent toxicity management, which was a simplifying assumption. Conclusions: This analysis, the first of its kind to evaluate TOFA vis-à-vis other advanced therapies in the US, suggests the early use of TOFA among both TNFi-naïve and TNFi-failure patients results in lower PMPM costs compared with other treatment alternatives.

Benefit-Risk Assessment of Vedolizumab in the Treatment of Crohn's Disease and Ulcerative Colitis.

Vedolizumab, a humanized monoclonal antibody to the α4ß7 integrin, reduces lymphocyte trafficking to the intestine. This gut-selective mechanism of action offers a safer alternative to other biologics used to treat ulcerative colitis (UC) and Crohn's disease (CD). We reviewed efficacy and safety data from randomized controlled trials (RCTs), open-label extension (OLE) and observational studies, and pooled analyses of vedolizumab therapy. In UC, RCTs demonstrate that vedolizumab is effective for induction and maintenance of remission, regardless of prior tumor necrosis factor (TNF) antagonist exposure. In CD, vedolizumab is moderately effective as an induction therapy and demonstrates efficacy as a maintenance agent. Secondary analyses indicate that prolonged induction therapy may result in greater efficacy, particularly in TNF antagonist-exposed patients. Comparative efficacy studies and network meta-analyses show similar efficacy to other biologic therapies. OLE studies in UC and CD demonstrate the durability of maintenance efficacy and low serious adverse event (SAE) rates. In an integrated safety analysis of controlled data, there was no significant difference in adverse event, SAE, infection and serious infection rates between vedolizumab and placebo. No drug-specific safety signals were identified. Immunogenicity rates were low and no cases of progressive multifocal leukoencephalopathy directly attributable to vedolizumab are reported in the literature. Vedolizumab is effective for induction and maintenance of inflammatory bowel disease with low treatment-related risks. Given the high therapeutic index of this gut-specific agent, it can be used as either a first- or second-line biologic therapy for UC and CD.

Benefit-Risk Assessment of Plecanatide in the Treatment of Chronic Idiopathic Constipation.

Plecanatide, a uroguanylin analog, activates the guanylate cyclase C receptors in the epithelial lining of the gastrointestinal tract in a pH-dependent fashion initiating (1) the conversion of intracellular guanosine triphosphate to cyclic guanosine monophosphate, which increases the activity of the cystic fibrosis transmembrane conductance regulator to increase chloride and bicarbonate secretion into the intestinal lumen and (2) a decrease in activity of the sodium-hydrogen ion exchanger. The resulting ionic shifts cause an increase in lumenal fluid to facilitate digestion. Plecanatide has been approved by the FDA for use in chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation. This manuscript is a critical assessment of the therapeutic efficacy and potential risks associated with the use of plecanatide in CIC. The discussion of CIC as a clinical and investigative disorder focuses on the importance of this problem as well and the difficulties involved in clinical management and scholarly investigation of a symptom arising from multiple pathophysiologic mechanisms. Clinical data from studies of recently approved drugs for CIC are utilized to construct a platform for thoughtful understanding of CIC and of how changes in investigation guidelines influence the interpretation of study data and guide symptom management. Plecanatide is a safe and effective medication for the management of adults with CIC.

Baseline risk assessment of patients with ulcerative colitis: does initial treatment selection influence outcomes?

BACKGROUND AND AIMS: Treatment of ulcerative colitis (UC) typically follows a step-up approach and targets colonic mucosal healing. Although mucosal healing reduces the risk of colectomy, whether or not early treatment of patients with 'high-risk' features using tumor necrosis factor (TNF) antagonists reduces the risk of colectomy is not clear. Accordingly, we aim to evaluate the effect of baseline treatment selection according to the risk profile on 5-year outcomes and identify predictors of poor outcomes. PATIENTS AND METHODS: Adult patients with confirmed UC were retrospectively identified. Baseline clinical and endoscopic data were collected. Patients were assigned a risk profile on the basis of the presence or absence of 'high-risk' features within the first 6 months of diagnosis including moderate to severe endoscopic disease, frequent need for steroids, steroid dependency, and disease involving the entire colon according to endoscopy. Treatment discordance was defined as treating 'high-risk' patients with medications other than anti-TNF therapy during the first 6 months after diagnosis or treating 'low-risk' patients with anti-TNF therapy within 6 months of diagnosis. The associations between discordance and 5-year colectomy and hospitalization rates were statistically calculated through regression analysis, as were predictors of outcomes. RESULTS: A total of 108 patients were identified and studied. The median age was 36 years (interquartile range=27-50) and the average duration of disease was 6.6 (±3.1) years. Females comprised 62% of the cohort and 30% reported cigarette smoking. Seventy three percent of the patients were placed in the 'high-risk' category. The 5-year risk of colectomy was not statistically significantly higher in patients identified as 'high-risk' compared with those who were 'low-risk' (risk ratio=0.86, 95% confidence interval=0.24-3.1, P=0.81), nor was the 5-year risk of hospitalizations (risk ratio=1.63, 95% confidence interval=0.81-3.30, P=0.15). On the basis of stepwise model selection, colectomy was significantly predicted by discordance (P=0.039), arthritis (P=0.007), baseline stool frequency (P=0.019), Adalimumab use within the first 6 months of diagnosis (P=0.006), and pyoderma gangrenosum (P=0.049); hospitalization was predicted by discordance (P=0.018), baseline albumin concentrations (P=0.005), thromboembolism (P<0.005), thiopurine use within the first 6 months of diagnosis (P<0.005), Adalimumab use within the first 6 months of diagnosis (P=0.003), nationality (P=0.016), endoscopic severity (P=0.007), arthritis (P=0.005), and pyoderma gangrenosum (P=0.025). CONCLUSION: Among other clinical parameters, discordance between baseline risk and treatment selection appears to be a significant predictor of outcomes in UC.

Cost savings using a test-based de-escalation strategy for patients with Crohn's disease in remission on optimized infliximab: A discrete event model study.

BACKGROUND: Drug de-escalation is considered in Crohn's disease patients in sustained remission on optimized infliximab treatment. AIM: We built a model to evaluate the magnitude of cost savings in patients' disease course with or without drug de-escalation guided by infliximab trough levels. METHODS: We designed 4 virtual cohorts (P1-P4) of 10,000 patients in clinical remission on optimized infliximab treatment followed for 2 years. P1: no drug de-escalation - 10 mg/kg/8 weeks; P2: drug de-escalation from 10 mg/kg/8 weeks to 5 mg/kg/8 weeks according to trough levels; P3: no drug de-escalation - 10 mg/kg/6 weeks; and P4: drug de-escalation from 10 mg/kg/6 weeks to 10 mg/kg/8 weeks according to trough levels. For P2 and P4 cohorts, drug de-escalation was decided if trough levels were ≥7 µg/mL and no de-escalation if trough levels were <7 µg/mL. Only costs related to drug administration were considered. RESULTS: The cost differences when comparing P1 versus P2 and P3 versus P4 were 7.6% and 4.6%, respectively, corresponding to costs savings of €30.5 millions and €20.3 million for 10,000 patients. CONCLUSION: Over a 2-year period, infliximab de-escalation according to trough levels led to cost saving of about 6%, corresponding to around €25.4 million.

Patient-Reported Experiences with a Relicensed Generic: Thioguanine for the Treatment of Inflammatory Bowel Diseases.

BACKGROUND AND AIM: Patient-reported outcomes and experiences are indicative of the impact and the quality of care. Thioguanine, a generic drug initially developed for leukemia, has been explored and relicensed as a certified treatment for patients with inflammatory bowel diseases (IBD). The patients' perception of this treatment has not been evaluated before. In this study, we aimed to assess self-reported experiences with thioguanine for IBD. METHODS: Questionnaires were sent out to members of the Dutch National Crohn's and Colitis patient organization. The Treatment Satisfaction with Medicines Questionnaire (SATMED-Q) was used to address questions regarding the satisfaction and impact of thioguanine therapy on the disease and their daily life. Furthermore, data on demographics, disease and (historical) treatment characteristics were collected. Open-ended questions were used for additional comments to the questionnaire. RESULTS: A total of 173 organization members (73% female) reported to be previous or current users of thioguanine. A total of 74% were satisfied with the effectiveness of thioguanine, whereas 5% were not. Eighty percent of the respondents were satisfied with the quality of care. A good or excellent impact on daily life was reported by 54%. A neutral or bad impact on daily life was reported by 40% and 6%, respectively. Improvement of disease activity was reported by 58%. This remained stable or worsened in 39% and 3%, respectively. CONCLUSION: In this self-report survey, among thioguanine treated patients with IBD who had failed with traditional therapies, 80% reported satisfaction with medical care and 74% with the effectiveness of the therapy. In the evaluation of new or rediscovered therapies, patient-reported outcomes and experiences should be considered as a key instrument.

A Programme for Risk Assessment and Minimisation of Progressive Multifocal Leukoencephalopathy Developed for Vedolizumab Clinical Trials.

INTRODUCTION: Over the past decade, the potential for drug-associated progressive multifocal leukoencephalopathy (PML) has become an increasingly important consideration in certain drug development programmes, particularly those of immunomodulatory biologics. Whether the risk of PML with an investigational agent is proven (e.g. extrapolated from relevant experience, such as a class effect) or merely theoretical, the serious consequences of acquiring PML require careful risk minimisation and assessment. No single standard for such risk minimisation exists. Vedolizumab is a recently developed monoclonal antibody to α4ß7 integrin. Its clinical development necessitated a dedicated PML risk minimisation assessment as part of a global preapproval regulatory requirement. OBJECTIVE: The aim of this study was to describe the multiple risk minimisation elements that were incorporated in vedolizumab clinical trials in inflammatory bowel disease patients as part of the risk assessment and minimisation of PML programme for vedolizumab. METHODS: A case evaluation algorithm was developed for sequential screening and diagnostic evaluation of subjects who met criteria that indicated a clinical suspicion of PML. An Independent Adjudication Committee provided an independent, unbiased opinion regarding the likelihood of PML. RESULTS: Although no cases were detected, all suspected PML events were thoroughly reviewed and successfully adjudicated, making it unlikely that cases were missed. CONCLUSION: We suggest that this programme could serve as a model for pragmatic screening for PML during the clinical development of new drugs.