Reporting reimbursement price decisions for onco-hematology drugs in Spain.

Introduction: Even using well-established technology assessment processes, the basis of the decisions on drug price and reimbursement are sometimes perceived as poorly informed and sometimes may be seen as disconnected from value. The literature remains inconclusive about how Health Technology Assessment Bodies (HTAb) should report the determinants of their decisions. This study evaluates the relationship between oncology and hematology drug list prices and structured value parameters at the time of reimbursement decision in Spain. Methods: The study includes all new onco-hematological products (22), with a first indication authorized between January 2017 and December 2019 in Spain and pricing decisions published up until October 2022. For each product, 56 contextual and non-contextual indicators reflecting the structured multiple criteria decision analysis (MCDA) - Evidence-based Decision-Making (EVIDEM) framework were measured. The relationship between prices and the MCDA-EVIDEM framework was explored using univariate statistical analyses. Results: Higher prices were observed when the standard of care included for combinations, if there were references to long-lasting responses, for fixed-duration treatment compared to treatment until progression and treatment with lower frequencies of administration; lower prices were observed for oral administration compared to other routes of administration. Statistically significant associations were observed between prices and the median duration of treatment, the impact on patient autonomy, the ease of use of the drug, and the recommendations of experts. Discussion: The study suggests that indicators related to the type of standard of care, references to long-lasting responders, the convenience of the use of the drug, and the impact of treatment on patient autonomy, as well as contextual indicators such as the existence of previous clinical consensus, are factors in setting oncology drug prices in Spain. The implementation of MCDA-EVIDEM methodologies may be useful to capture the influence on pricing decisions of additional factors not included in legislation or consolidated assessment frameworks such as the European Network for Health Technology Assessment (EunetHTA) core model. It may be opportune to consider this in the upcoming revision of the Spanish regulation for health technology assessments and pricing and reimbursement procedures.

Effectiveness and safety of oral anticoagulants for non-valvular atrial fibrillation: a population-based cohort study in primary healthcare in Catalonia.

Objectives: Our objective was to analyse effectiveness and safety of oral anticoagulants (OAC) for stroke prevention in non-valvular atrial fibrillation. Material and methods: Population-based cohort study including adults initiating oral anticoagulants, either direct oral anticoagulants (DOAC) or vitamin K antagonists (VKA), during 2011-2020. Data source: SIDIAP, capturing information from the electronic health records of Primary Health Care in Catalonia, Spain. Study outcomes: stroke, cerebral and gastrointestinal (GI) haemorrhage, assessed by patients' subgroups according to different clinical characteristics. Results: We included 90,773 patients. Male sex, older than 75, previous event, peripheral artery disease, deep vein thrombosis, or receiving antiplatelets, antidiabetics or proton pump inhibitors (PPI) was associated with higher stroke risk. For DOAC-treated, treatment switch increased stroke risk, while being adherent had a protective effect. Men, antidiabetic treatment or a previous event increased the risk of cerebral bleeding. Receiving direct oral anticoagulants had a protective effect in comparison to vitamin K antagonists. For DOAC-treated, treatment switch increased, and adherence decreased the bleeding risk. Men, people with chronic kidney disease or a previous event posed an increased risk of gastrointestinal bleeding, whereas receiving PPI had a protective effect. For DOAC-treated, switch was associated with a higher bleeding risk. Conclusion: Being men, a previous event and DOAC-switch posed a higher risk for all study outcomes. direct oral anticoagulants had a protective effect against cerebral bleeding in comparison to vitamin K antagonists. Adherence to direct oral anticoagulants resulted in lower risk of stroke and cerebral bleeding. We found no differences in the risk of stroke and gastrointestinal bleeding when we compared direct oral anticoagulants vs. vitamin K antagonists.

Single-dose intravenous ferric carboxymaltose infusion versus multiple fractionated doses of intravenous iron sucrose in the treatment of post-operative anaemia in colorectal cancer patients: a randomised controlled trial.

BACKGROUND: Recent clinical guidelines suggest that treatment of postoperative anaemia in colorectal cancer surgery with intravenous iron reduces transfusion requirements and improves outcomes. The study aimed at comparing two intravenous iron regimens in anaemic patients after colorectal cancer surgery. MATERIALS AND METHODS: This was a single-centre, open-label, randomised, controlled trial in patients undergoing elective colorectal cancer surgery. Patients with moderate to severe anaemia (haemoglobin [Hb] <11 g/dL) after surgery were randomly assigned 1:1 to receive ferric carboxymaltose (FC; 1,000 mg, single dose) or iron sucrose (IS; 200 mg every 48 hours until covering the total iron deficit or discharge). Randomisation was stratified by Hb level: <10 g/dL (Group A) or ≥10-10.9 (Group B). The primary endpoint was the change in Hb concentration at postoperative day 30. Secondary endpoints included iron status parameters, transfusion requirements, complications, and length of hospital stay. RESULTS: From September 2015 to May 2018, 104 patients were randomised (FC 50, IS 54). The median intravenous iron dose was 1,000 mg and 600 mg in the FC and IS groups, respectively. There were no between-group differences in mean change in Hb from postoperative day 1 to postoperative day 30 (FC: 2.5 g/dL, 95% CI: 2.1-2.9; IS: 2.4 g/dL, 95% CI: 2.0-2.8; p=0.52), in transfusion requirements or length of stay. The infection rate was lower in the FC group compared with the IS group (9.8% vs 37.2%, respectively). DISCUSSION: The administration of approximately 500 mg of IS resulted in an increase in Hb at postoperative day 30 similar to that of 1,000 mg of FC, but it was associated with a higher infection rate. Future research will be needed to confirm the results, and to choose the best regime in terms of effectiveness and side effects to treat postoperative anaemia in colorectal cancer patients.

Financial impact of the hospital pharmacy's participation in clinical trials.

OBJECTIVES: To estimate the cost of the hospital pharmacy's participation in clinical trials (CTs) and to compare it to the amount received in compensation from sponsors.To analyse the financial impact of CTs that end without recruiting any patients and without any financial compensation from promoters. METHODS: This retrospective observational study analysed data from 5 years (2014-2018) at a tertiary university hospital.We established an allocation formula taking into account direct costs related to the pharmacy department's CT area's activity (reception, safekeeping, preparation, devolution, and destruction of medication, as well as patient monitoring) and indirect costs (facilities, resources, support staff). We calculated the costs to the department and the compensation received both overall and based on the type of promoter, clinical department involved in the trial, and the number of patients included. RESULTS: We included 134 trials. Costs added up to €207 372.95 and the compensation to €149 128.93 (€58 244.02 loss for the department). Trials ending without recruiting patients (33.6%) and without compensation accounted for 57.45% of the deficit. The mean cost of trials ending without recruiting patients was €875. We plan to charge a reimbursable setup fee for opening CTs to safeguard against these losses (€875 for trials in all departments except oncology; €1100 for oncology because 38% of their trials end without recruiting patients) and to compensate for the costs incurred in participating in trials for cooperative groups without financial compensation (20%). CONCLUSIONS: Billing sponsors based on costs incurred for each trial would be a fairer system than the current approach based on the number of patients included. Establishing an initial fee would make up for losses from trials that fail to recruit any patients.

Effects of selective serotonin reuptake inhibitors and other antidepressant drugs on the risk of hip fracture: a case-control study in an elderly Mediterranean population.

OBJECTIVES: To describe the association between exposure to different antidepressant drugs and hip fracture in an elderly Mediterranean population. METHODS: Cases were all patients aged 50-95 years admitted to the emergency room of our hospital with hip fracture not related to a high intensity trauma during 2010. For each case, four controls were identified from primary care electronic medical records matched by age (±3 years), gender, date of consultation at the primary care centre (±1 month) and primary care centre. Pharmacological treatments received within the previous 5 years were retrieved from the prescription records. Crude and adjusted risks associated with exposures were calculated by conditional logistic regression. ORs were adjusted by matching variables and by significant risk factors identified in the bivariate analysis (prescription of ≥4 drugs, osteoporosis, diabetes mellitus and previous fracture). RESULTS: 136 cases and 544 controls were analysed. Adjusted OR (95% CI) for hip fracture associated with exposure to any antidepressants was 2.42 (1.24 to 4.73); for selective serotonin reuptake inhibitors (SSRIs) it was 3.52 (1.67 to 7.41), for non-selective monoamine reuptake inhibitors 1.07 (0.18 to 6.46) and for other antidepressants 0.82 (0.27 to 2.48). Sertraline (OR 3.88 (1.15 to 13.09)) was the only active principle with significant adjusted risk. When only exposures >6 months were considered, significant risks persisted for SSRIs (OR 2.64 (1.10 to 6.37)). CONCLUSIONS: The results of this study are coincident with other studies in which SSRIs, but not other types of antidepressants, are associated with an increased risk of hip fracture in our setting.

Hypertensive crisis following the administration of tedizolid: possible serotonin syndrome.

Thiscase report concerns a 34-year-old male with a hip prosthesis infection, under treatment with antidepressant and antihypertensive drugs, who presented with an increase in blood pressure after four days of treatment with oral tedizolid. Tedizolid was discontinued, and the dose of antihypertensive was increased. The patient progressively achieved the normalisation of blood pressure values, which allowed a reduction in the antihypertensive agent dose to its usual regimen. No cases of hypertension or serotonin toxicity are described in the initial tedizolid studies, where patients treated with other serotonergic drugs were excluded. However, this does not mean that these effects may not occur in clinical practice, especially in patients under concomitant treatment with this type of medication, because of the greater risk of drug interactions. The causality of this suspected drug reaction was analysed and it was considered as possible. The case has been reported to the pharmacovigilance system.

Effects of bupivacaine or levobupivacaine on cerebral oxygenation during spinal anesthesia in elderly patients undergoing orthopedic surgery for hip fracture: a randomized controlled trial.

BACKGROUND: Bupivacaine and levobupivacaine have similar pharmacokinetic and pharmacodynamic characteristics, and are used regularly in spinal anesthesia. Whether potential differences in their hemodynamic and anesthetic profiles could determine a differential risk of complications in elderly subjects, is controversial. The main objective was to compare the effects of intrathecally administered levobupivacaine (LB) versus bupivacaine (B), on regional cerebral O2 saturation during spinal anesthesia, cognitive status and neurological complications in elderly patients undergoing surgery for hip fracture. METHODS: This was a randomized, controlled, single blind study. 58 patients aged 70 or older undergoing surgery for hip fracture with spinal anesthesia were allocated with a 1:1 ratio to receive LB or B, combined with fentanyl 15 µg, by intrathecal route. The primary outcome was the proportion of intraoperative time with regional cerebral desaturation (≥20% reduction in regional cerebral oxygen saturation from baseline), monitored by near -infrared spectroscopy. Secondary endpoints included hemodynamic parameters, level of sensory and motor block, changes in Short Portable Mental Status Questionnaire (SPMSQ), and neurological complications. RESULTS: The mean percentage of intraoperative time with desaturation in the B group was 6.1% (SD: 17.5) and 4.7% (SD: 11.9) in the left and right hemisphere respectively; in the LB group the mean was 4.8% (SD: 11.4) in the left hemisphere and 2.4% (SD: 8.3) in the right one. No statistically significant differences were found between treatment groups. The level of sensory block at the start of surgery was lower for LB than for B (Th10 vs Th8, p:0.047) and motor block at 15 min was lower for LB (2.5 vs 3, p:0.009). No differences in postoperative SPMSQ were observed. Neurological complications such as confusional state, agitation or disorientation were reported in 50% of patients in the B group and 21.4% of patients in the LB group, p = 0.05. CONCLUSIONS: No statistically significant differences in regional cerebral oxygen saturation or hemodynamic parameters were observed between both treatment groups. Bupivacaine and levobupivacaine differed in sensory and motor block achieved. While no differences were observed in cognitive impairment measured by the SPMSQ between treatment groups neurological complications reported by the physician were more frequent with bupivacaine. TRIAL REGISTRATION: European Union Clinical Trials Register ( EudraCT 2013-000846 -20 ) (April 9th, 2013). ClinicalTrials.gov ( NCT01960543 ) (September 23rd, 2013).

Single dose of intravenous ferric carboxymaltose infusion versus multiple fractionated doses of intravenous iron sucrose in the treatment of postoperative anaemia in colorectal cancer patients: study protocol for a randomised controlled trial.

BACKGROUND: Patients with colorectal cancer (CRC) often present with associated anaemia which is usually present at the time of diagnosis and is aggravated during the postoperative period due to blood loss during the surgery process. Several guidelines advocate for the treatment of postoperative anaemia in these patients in order to prevent complications and allogeneic blood transfusions. However, there are no publications to shed light on the effectiveness of intravenous iron (IVI) administration after CRC surgery and the optimal dose and regimen. We have started a clinical trial with the objective of comparing the effectiveness of 1000 mg of ferric carboxymaltose with fractionated iron sucrose 200 g/48 h for the treatment of postoperative anaemia, by measuring the change of haemoglobin (Hb) levels from postoperative day (POD) 1 to POD 30. METHODS: We designed an open label randomised controlled trial to compare two postoperative IVI treatment regimens. Patients aged > 18 years undergoing CRC surgery, with Hb < 11 g/dL on POD 1 are randomly assigned to receive either 1000 mg of ferric carboxymaltose (single dose) or 200 g/48 h of iron sucrose. The main study endpoint will be the change from POD 1 to POD 30 in Hb levels and the key secondary endpoint the percentage of patients with Hb levels ≥ 13 g/dL at POD 30. Other secondary endpoints include: changes in iron metabolism parameters (Fe, ferritin, transferrin, % saturated trasferrin) at POD 30; total doses of iron received; number of postoperative transfusions; compliance with oral iron treatment; number of medical and surgical complications; adverse reactions reported by the patient; use of health resources after surgery; and changes in quality of life (QoL). It has been estimated that a sample of 48 patients per group will allow detecting a difference of 0.75 g/dL in Hb in the change in Hb levels from POD 1 to POD 30. DISCUSSION: The results of this study will confirm if the single dose of 1000 mg ferric carboxymaltose should be preferred in front of the fractionated doses and in which type of patients this regimen should be used preferably. TRIAL REGISTRATION: European Union Clinical Trials Register, EudraCT 2015-001005-13 . Registered on 6 January 2015.

Evidence supporting regulatory-decision making on orphan medicinal products authorisation in Europe: methodological uncertainties.

BACKGROUND: To assess uncertainty in regulatory decision-making for orphan medicinal products (OMP), a summary of the current basis for approval is required; a systematic grouping of medical conditions may be useful in summarizing information and issuing recommendations for practice. METHODS: A grouping of medical conditions with similar characteristics regarding the potential applicability of methods and designs was created using a consensus approach. The 125 dossiers for authorised OMP published between 1999 and 2014 on the EMA webpage were grouped accordingly and data was extracted from European Public Assessment Reports (EPARs) to assess the extent and robustness of the pivotal evidence supporting regulatory decisions. RESULTS: 88% (110/125) of OMP authorizations were based on clinical trials, with 35% (38/110) including replicated pivotal trials. The mean (SD) number of pivotal trials per indication was 1.4 (0.7), and the EPARs included a median of three additional non-pivotal supportive studies. 10% of OMPs (13/125) were authorised despite only negative pivotal trials. One-third of trials (53/159) did not include a control arm, one-third (50/159) did not use randomisation, half the trials (75/159) were open-label and 75% (119/159) used intermediate or surrogate variables as the main outcome. Chronic progressive conditions led by multiple system/organs, conditions with single acute episodes and progressive conditions led by one organ/system were the groups where the evidence deviated most from conventional standards. Conditions with recurrent acute episodes had the most robust datasets. The overall size of the exposed population at the time of authorisation of OMP - mean(SD) 190.5 (202.5) - was lower than that required for the qualification of clinically-relevant adverse reactions. CONCLUSIONS: The regulatory evidence supporting OMP authorization showed substantial uncertainties, including weak protection against errors, substantial use of designs unsuited for conclusions on causality, use of intermediate variables, lack of a priorism and insufficient safety data to quantify risks of relevant magnitude. Grouping medical conditions based on clinical features and their methodological requirements may facilitate specific methodological and regulatory recommendations for the study of OMP to strengthen the evidence base.

Applicability and added value of novel methods to improve drug development in rare diseases.

BACKGROUND: The ASTERIX project developed a number of novel methods suited to study small populations. The objective of this exercise was to evaluate the applicability and added value of novel methods to improve drug development in small populations, using real world drug development programmes as reported in European Public Assessment Reports. METHODS: The applicability and added value of thirteen novel methods developed within ASTERIX were evaluated using data from 26 European Public Assessment Reports (EPARs) for orphan medicinal products, representative of rare medical conditions as predefined through six clusters. The novel methods included were 'innovative trial designs' (six methods), 'level of evidence' (one method), 'study endpoints and statistical analysis' (four methods), and 'meta-analysis' (two methods) and they were selected from the methods developed within ASTERIX based on their novelty; methods that discussed already available and applied strategies were not included for the purpose of this validation exercise. Pre-requisites for application in a study were systematized for each method, and for each main study in the selected EPARs it was assessed if all pre-requisites were met. This direct applicability using the actual study design was firstly assessed. Secondary, applicability and added value were explored allowing changes to study objectives and design, but without deviating from the context of the drug development plan. We evaluated whether differences in applicability and added value could be observed between the six predefined condition clusters. RESULTS AND DISCUSSION: Direct applicability of novel methods appeared to be limited to specific selected cases. The applicability and added value of novel methods increased substantially when changes to the study setting within the context of drug development were allowed. In this setting, novel methods for extrapolation, sample size re-assessment, multi-armed trials, optimal sequential design for small sample sizes, Bayesian sample size re-estimation, dynamic borrowing through power priors and fall-back tests for co-primary endpoints showed most promise - applicable in more than 40% of evaluated EPARs in all clusters. Most of the novel methods were applicable to conditions in the cluster of chronic and progressive conditions, involving multiple systems/organs. Relatively fewer methods were applicable to acute conditions with single episodes. For the chronic clusters, Goal Attainment Scaling was found to be particularly applicable as opposed to other (non-chronic) clusters. CONCLUSION: Novel methods as developed in ASTERIX can improve drug development programs. Achieving optimal added value of these novel methods often requires consideration of the entire drug development program, rather than reconsideration of methods for a specific trial. The novel methods tested were mostly applicable in chronic conditions, and acute conditions with recurrent episodes.

Rare disease registries: potential applications towards impact on development of new drug treatments.

BACKGROUND: Low prevalence, lack of knowledge about the disease course, and phenotype heterogeneity hamper the development of drugs for rare diseases. Rare disease registries (RDRs) can be helpful by playing a role in understanding the course of the disease, and providing information necessary for clinical trial design, if designed and maintained properly. We describe the potential applications of a RDR and what type of information should be incorporated to support the design of clinical trials in the process of drug development, based on a broad inventory of registry experience. We evaluated two existing RDRs in more detail to check the completeness of these RDRs for trial design. RESULTS: Before and during the application for regulatory approval a RDR can improve the efficiency and quality in clinical trial design by informing the sample size calculation and expected disease course. In exceptional circumstances information from RDRs has been used as historical controls for a one-armed clinical trial, and high quality RDRs may be used for registry-based randomized controlled trials. In the post marketing phase of (conditional) drug approval a disease-specific RDR is likely to provide more relevant information than a product-specific registry. CONCLUSIONS: A RDR can be very helpful to improve the efficiency and quality of clinical trial design in several ways. To enable the applicability and optimal use of a RDR longitudinal data collection is indispensable, and specific data collection, prepared for repeated measurement, is needed. The developed checklist can help to define the appropriate variables to include. Attention should be paid to the inclusion of patient-relevant outcome measures in the RDR from the start. More research and experience is needed on the possibilities and limitations of combining RDR information with clinical trial data to maximize the availability of relevant evidence for regulatory decisions in rare diseases.

Open-label randomized controlled trial to compare wound dressings for patients undergoing hip and knee arthroplasty: study protocol for a randomized controlled trial.

BACKGROUND: Surgical wounds are covered to prevent bleeding, absorb the exudates, and provide a barrier against external contamination. Currently, in our hospital, after orthopedic surgery, traditional occlusive dressing of sterile gauze and non-woven hypoallergenic adhesive tape is placed. Some of the newest dressings have been shown to reduce the incidence of blisters compared with traditional dressing or colloid adhesive dressings. However, there are no comparative evaluations between the different types of dressings and their contribution to the overall results of the healing process. METHODS/DESIGN: This is a randomized, controlled, open-label trial to compare five types of dressings used in total knee and hip arthroplasty surgical wounds. A total of 550 patients will be randomly allocated to one of the following dressings: (1) traditional occlusive dressing, (2) Aquacel Surgical®, (3) Mepilex® Border Post-Op, (4) OpSite Post-Op Visible, or (5) UrgoTul® Absorb Border. The dressing assigned is placed right after surgery. Patients will be followed up to 14 days after surgery when the dressing is definitively removed and will be tracked up to 3 months to record any late complications. During the immediate postoperative period and patient hospitalization and at the ambulatory visits after discharge, every time that the dressing is changed, nurses perform the study assessments. The main study outcome will be the percentage of patients with skin integrity at all times when the dressing has been changed. Skin integrity is a composite of the absence of blisters, erosion, erythema, maceration, swelling, wound dehiscence, and purulent exudates. Secondary outcomes include time to first change of dressing; percentage of patients with presence/absence of blisters, erosion, erythema, maceration, swelling, wound dehiscence, and purulent exudates; number of dressing changes needed; days of hospital stay; and nurse and patient satisfaction. Differences in the main variable between each treatment group and group 1 will be tested by means of a chi-squared test or Fisher's exact test. Subgroup analyses of diabetic and non-diabetic patients, patients with a body mass index of more than 30 or not more than 30, and type of surgery (hip or knee) are planned. DISCUSSION: The results of this study will be useful for clinical decision making by giving information on the contribution of the dressings studied to the outcome of the wound and may also show which dressing offers better results depending on the characteristics of patients. TRIAL REGISTRATION: This trial has been registered at ClinicalTrials.gov ( NCT03190447 ). Retrospectively registered on 16 June 2017.

Intravenous iron administration for post-operative anaemia management after colorectal cancer surgery in clinical practice: a single-centre, retrospective study.

BACKGROUND: Evidence on the role of intravenous iron (IVI) supplementation after colorectal cancer (CRC) surgery is rather scant. This study was aimed at assessing the benefit of post-operative IVI administration after elective CRC surgery at our institution. MATERIALS AND METHODS: This was a single-centre, retrospective observational study including all patients who underwent CRC surgery during 2014. Anaemia was defined as a haemoglobin (Hb) <13 g/dL, regardless of gender. Anaemic patients received 200 mg IVI up to three times a week to cover iron deficiency (IVI group). Those who did not receive IVI were placed on standard care (NIVI group). The primary outcome was the proportion of anaemic patients on post-operative day (POD)1 and POD30. Secondary outcomes included Hb changes from POD1 to POD30, transfusion requirements and complication rates. RESULTS: Of the 159 patients studied, 139 (87%) presented with anaemia: 47 (34%) of these received post-operative IVI and 92 (66%) did not. Patients in the IVI group had lower POD1 Hb levels compared to those in the NIVI group (p=0.001). On POD30, only 103 had their Hb measured (34 IVI, 69 NIVI). Anaemia was more prevalent and more severe among the patients in the IVI group (p=0.027), despite their greater increment in Hb (2.0±1.5 g/dL vs 1.1±1.2 g/dL; p=0.001). Eleven patients needed post-operative transfusions (7 IVI, 4 NIVI; p=0.044). There were no differences in post-operative complication rates between the groups. No IVI-related adverse events were recorded DISCUSSION: Compared with standard care, post-operative IVI administration to anaemic patients improved the recovery of Hb levels at POD30, without increasing post-operative complications.

Outpatient multimodal intravenous analgesia in patients undergoing day-case surgery: description of a three year experience.

BACKGROUND: The use of elastomeric devices for ambulatory intravenous pain treatment in Major Ambulatory Surgery (MAS) has been described to improve postoperative pain management. The objective of the study was to describe the first 3 years experience of the use of elastomeric devices for ambulatory intravenous pain treatment in MAS implemented at our site since 2010. METHODS: Data were retrieved from the medical records for all patients who, between January 2010 and March 2014, underwent surgical procedures at the ambulatory surgical centre at our hospital and were prescribed a home-based continuous intravenous analgesia. RESULTS: Data were retrieved from the medical records of 1128 patients. The most frequent surgical interventions included orthopedic and proctology surgeries. 80 % of patients were discharged home without pain; during the first 48 h after discharge roughly 40 % of subjects were completely free of pain, 50 % reported mild pain (VAS 1 to 3) and 9 % reported higher pain scores (4 and above). Peripheral nerve block was associated to better pain control in the immediate postoperative period. Vomiting in the first 24 h was 4.6 % before introducing haloperidol into the drug schemes, and 2.6 % thereafter. Complications related with the intravenous route required treatment withdrawal in 1.1 % cases. Only 3.5 % of patients returned to the hospital in the first 72 h, mainly for non-pain related reasons. Overall, 99.5 % of patients were satisfied with the treatment received at home. CONCLUSION: Our initial experience suggest that outpatient multimodal intravenous analgesia in patients undergoing day-case surgery is a feasible alternative in our setting, that allows an effective management of postoperative pain with a small rate of adverse events and complications requiring readmission.

Safety and Activity of UR-1505 in Atopic Dermatitis: A Randomized, Double-blind Phase II Exploratory Trial.

PURPOSE: UR-1505 is a new small molecule with immune modulator properties intended for the topical treatment of inflammatory skin diseases that has shown anti-inflammatory effects in models of skin inflammation. We compared the activity of UR-1505 ointment against its vehicle in the treatment of atopic dermatitis. Secondary objectives included exploring dose response, safety, and local tolerability of UR-1505. METHODS: Patients with AD lesions on 2 symmetrical topographic areas (arms, leg, or trunk) were included in this unicenter randomized, double-blind, within-patient, controlled Phase II exploratory trial and received simultaneously 2 different treatments (0.5%, 1%, or 2% UR-1505 and vehicle or 0.1% tacrolimus ointment) once daily during 28 days. The primary efficacy end point was the change from baseline in the Investigator Global Assessment score at Day 28. Secondary end points were percentage of area clearance, local Eczema Area Severity Index (local EASI), and local tolerability. A linear mixed model was used, fitting treatment, body side, and group (treatment at the contralateral side) as fixed factors and the patient as a random effect. FINDINGS: Twenty-eight patients were randomized and 25 patients were included in the per protocol analysis, with 50 evaluable lesions (n = 13 for vehicle, n = 8 for UR-1505 0.5%, n = 9 for 1% UR-1505, n=8 for 2% UR-1505, and n=12 for tacrolimus). The mean Investigator Global Assessment score change from baseline at Day 28 was -1.7 for vehicle, -1.0, -1.2, and -1.5 for 0.5%, 1%, and 2% UR-1505, respectively, and -2.6% for tacrolimus (P = 0.002). No serious nor causal adverse reactions were reported in this study, but patients reported numerous local symptoms after product applications, especially itching, tingling, tightness, and heat/burning sensations at frequencies that were similar for vehicle, 1% UR-1505, and 2% UR-1505; more frequent with 0.5% UR-1505; and lowest for tacrolimus. IMPLICATIONS: This study found that UR-1505 may not be a suitable option for the treatment of atopic dermatitis due to its lack of clinically relevant effect compared with its vehicle and 0.1% tacrolimus ointment.

Safety and activity of dersalazine sodium in patients with mild-to-moderate active colitis: double-blind randomized proof of concept study.

BACKGROUND: Dersalazine sodium is an inhibitor of platelet activator factor with potential efficacy in patients with ulcerative colitis through an alternative mechanism of action. The study was a first proof of clinical safety and activity of dersalazine sodium in patients with ulcerative colitis. METHODS: A double-blind study of randomized patients with ulcerative colitis (Mayo score ≥ 5 and ≤ 10, including a sigmoidoscopy subscore ≥ 2) to dersalazine sodium 1200 mg/12 h, mesalazine 1200 mg/12 h, or placebo for 4 weeks. Mayo scores were calculated on week 2 (partial Mayo) and week 4 (full Mayo). All patients received open-label mesalazine for 4 additional weeks, and a final visit was done at week 8. RESULTS: The study included 34 patients (13 dersalazine sodium, 10 mesalazine, and 11 placebo). Clinical remission was observed in 46.2% patients treated with dersalazine sodium versus 12.5% in mesalazine and 10% in placebo after 4 weeks of treatment. Colon biopsies showed significantly decreased expression of inflammatory genes in dersalazine sodium patients. Adverse events at least possibly related to treatment were observed in 23%, 12.5%, and 7.6% of patients receiving dersalazine sodium, mesalazine, and placebo, respectively; no serious adverse reactions were reported. Increased liver enzymes were reported in 2/13 patients receiving dersalazine sodium, with normal bilirubin levels; both returned to normal values on treatment interruption. CONCLUSIONS: Studies in wider populations are needed to confirm the clinical activity of dersalazine sodium. Weekly measurements of liver function tests may be necessary for early detection of adverse events.