Retagliptin as add-on therapy to metformin in Chinese patients with type 2 diabetes inadequately controlled with metformin: A multicentre, randomized, double-blind, placebo-controlled, phase 3 trial.

AIM: To evaluate the efficacy and safety of retagliptin in Chinese patients with type 2 diabetes (T2D) inadequately controlled with metformin. MATERIALS AND METHODS: This multicentre, phase 3 trial consisted of a 16-week, randomized, double-blind, placebo-controlled period, where patients with HbA1c levels between 7.5% and 11.0% were randomized to receive either once-daily (QD) retagliptin 100 mg (n = 87) or placebo (n = 87), both as an add-on to metformin. The primary endpoint was the change in HbA1c from baseline to week 16. RESULTS: At week 16, the least squares mean change in HbA1c from baseline, compared with placebo, was -0.82% (95% CI, -1.05% to -0.58%) for the retagliptin 100 mg QD group (P < .0001) per treatment policy estimand. Significantly higher proportions of patients in the retagliptin 100 mg QD group achieved HbA1c levels of less than 6.5% (11.5%) and less than 7.0% (26.4%) compared with those receiving placebo (0% and 4.6%; P = .0016 and P < .0001, respectively) at week 16. Retagliptin 100 mg QD also lowered fasting plasma glucose and 2-hour postprandial plasma glucose levels. The incidence of adverse events (AEs) during the treatment period was similar between the two groups. However, slightly higher proportions of increased lipase and increased amylase in the retagliptin 100 mg QD group were observed. No patients discontinued treatment permanently because of AEs, and no episodes of severe hypoglycaemia were reported. CONCLUSIONS: Retagliptin 100 mg QD as an add-on therapy to metformin offers a new therapeutic option for treating Chinese patients with T2D inadequately controlled by metformin alone, and is generally well tolerated.

Add-on testing: stability assessment of 63 biochemical analytes in centrifuged and capped samples stored at 16 °C.

OBJECTIVES: Integration of add-on testing in high-scale automated clinical laboratories constitute a valuable instrument not only for the clinicians and the general patient care, but also for the laboratory itself. Knowledge on sample quality and analytical stability upon storage is necessary to be able to offer add-on testing. The objectives of this study were to examine the analytical stability of 63 biochemical analytes in plasma and urine samples stored at 16 °C. METHODS: Samples were collected by professional laboratory technicians, analyzed at automated analyzers and stored in their primary, capped tube without separator for 10, 12, 16, 20 or 24 h at 16 °C. Stability was assessed by inspecting mean concentration of samples at baseline and examining if (A) mean concentration over time violated limits of bias, or if (B) individual sample concentrations violated limits of total error. RESULTS: The majority of the 63 analytes were stable for up to 24 h of storage. Few of the analytes were only suitable for add-on testing for 4, 6, 10, 12, 16 or 20 h of storage. One analyte, P-lactate dehydrogenase, was not found suitable for add-on testing when stored at 16 °C. CONCLUSIONS: Due to the increasing number of intelligent solutions for high-scale clinical laboratories, add-on testing has come to stay. Loss of stability could not be demonstrated for the majority of analytes after 10, 12, 16, 20 or 24 h of storage. This feature of analytical stability suggests that add-on testing is an acceptable tool for these analytes.

Brivaracetam use in clinical practice: a Delphi consensus on its role as first add-on therapy in focal epilepsy and beyond.

BACKGROUND: Antiseizure medications remain the cornerstone of treatment for epilepsy, although a proportion of individuals with the condition will continue to experience seizures despite appropriate therapy. Treatment choices for epilepsy are based on variables related to both the individual patient and the available medications. Brivaracetam is a third-generation agent antiseizure medication. METHODS: We carried out a Delphi consensus exercise to define the role of brivaracetam in clinical practice and to provide guidance about its use as first add-on ASM and in selected clinical scenarios. A total of 15 consensus statements were drafted by an expert panel following review of the literature and all were approved in the first round of voting by panelists. The consensus indicated different clinical scenarios for which brivaracetam can be a good candidate for treatment, including first add-on use. RESULTS: Overall, brivaracetam was considered to have many advantageous characteristics that render it a suitable option for patients with focal epilepsy, including a fast onset of action, favorable pharmacokinetic profile with few drug-drug interactions, broad-spectrum activity, and being well tolerated across a range of doses. Brivaracetam is also associated with sustained clinical response and good tolerability in the long term. CONCLUSIONS: These characteristics also make it suitable as an early add-on for the elderly and for patients with post-stroke epilepsy or status epilepticus as highlighted by the present Delphi consensus.

Mirabegron Add-On Tamsulosin for Men with Overactive Bladder Symptoms: A Pooled Analysis of Four Randomized Controlled Trials.

INTRODUCTION: Overactive bladder symptoms (OABSs) affect patients' quality of life (QOL) worldwide. This pooled analysis compared the efficacy and safety of mirabegron add-on tamsulosin with those of tamsulosin add-on placebo in OABS treatment. METHODS: PubMed, Embase, MEDLINE, and the Cochrane Controlled Trial Register databases were searched for randomized controlled trials (RCTs) examining the efficacy of mirabegron add-on therapy to tamsulosin in the treatment of OABS. Moreover, references from the selected studies were screened. Review Manager 5.4 was used to analyze data. RESULTS: Four RCTs involving 1,397 patients with OABS were selected. Of the total, 697 patients receiving mirabegron add-on tamsulosin constituted the experimental group, and 700 patients receiving tamsulosin add-on placebo constituted the control group. The efficacy endpoints were as follows: mean number of micturition per day (mean difference [MD] = -0.26, 95% confidence interval [CI] = -0.41 to -0.10, p = 0.0001), urgency episodes per day (MD = -0.67, 95% CI = -1.02 to -0.32, p = 0.0002), urgency urinary incontinence (UUI) episodes per day (MD = -0.42, 95% CI = -0.66 to -0.19, p = 0.0005), mean volume voided/micturition (MD = 10.84, 95% CI = 4.97-16.71, p = 0.0003), total International Prostate Symptom Score (IPSS) (MD = -2.01, 95% CI = -4.02 to -0.01, p = 0.05), and IPSS QOL index (MD = -0.65, 95% CI = -0.94 to -0.35, p < 0.0001). Mirabegron therapy, an add-on therapy to tamsulosin, was effective in treating patients with OABS. Moreover, mirabegron might reduce the total IPSS (MD = -2.01, 95% CI = -4.02 to -0.01, p = 0.05). The safety endpoint, treatment-emergent adverse events (odds ratio = 0.94, 95% CI = 0.78-1.13, p = 0.49), suggested that although mirabegron was well-tolerated, it possibly increased the post-void residual urine volume (MD = 10.28, 95% CI = 1.82-18.75, p = 0.02). CONCLUSION: Combination therapy using mirabegron and tamsulosin may be effective in treating patients with non-neurogenic OABS in terms of UUI episodes, total IPSS, and IPSS QOL index. However, its effectiveness must be verified by analyzing additional factors for OABS through further RCTs.

Good practice recommendations on add-ons in reproductive medicine†.

STUDY QUESTION: Which add-ons are safe and effective to be used in ART treatment? SUMMARY ANSWER: Forty-two recommendations were formulated on the use of add-ons in the diagnosis of fertility problems, the IVF laboratory and clinical management of IVF treatment. WHAT IS KNOWN ALREADY: The innovative nature of ART combined with the extremely high motivation of the patients has opened the door to the wide application of what has become known as 'add-ons' in reproductive medicine. These supplementary options are available to patients in addition to standard fertility procedures, typically incurring an additional cost. A diverse array of supplementary options is made available, encompassing tests, drugs, equipment, complementary or alternative therapies, laboratory procedures, and surgical interventions. These options share the common aim of stating to enhance pregnancy or live birth rates, mitigate the risk of miscarriage, or expedite the time to achieving pregnancy. STUDY DESIGN, SIZE, DURATION: ESHRE aimed to develop clinically relevant and evidence-based recommendations focusing on the safety and efficacy of add-ons currently used in fertility procedures in order to improve the quality of care for patients with infertility. PARTICIPANTS/MATERIALS, SETTING, METHODS: ESHRE appointed a European multidisciplinary working group consisting of practising clinicians, embryologists, and researchers who have demonstrated leadership and expertise in the care and research of infertility. Patient representatives were included in the working group. To ensure that the guidelines are evidence-based, the literature identified from a systematic search was reviewed and critically appraised. In the absence of any clear scientific evidence, recommendations were based on the professional experience and consensus of the working group. The guidelines are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines were reviewed by 46 independent international reviewers. A total of 272 comments were received and incorporated where relevant. MAIN RESULTS AND THE ROLE OF CHANCE: The multidisciplinary working group formulated 42 recommendations in three sections; diagnosis and diagnostic tests, laboratory tests and interventions, and clinical management. LIMITATIONS, REASONS FOR CAUTION: Of the 42 recommendations, none could be based on high-quality evidence and only four could be based on moderate-quality evidence, implicating that 95% of the recommendations are supported only by low-quality randomized controlled trials, observational data, professional experience, or consensus of the development group. WIDER IMPLICATIONS OF THE FINDINGS: These guidelines offer valuable direction for healthcare professionals who are responsible for the care of patients undergoing ART treatment for infertility. Their purpose is to promote safe and effective ART treatment, enabling patients to make informed decisions based on realistic expectations. The guidelines aim to ensure that patients are fully informed about the various treatment options available to them and the likelihood of any additional treatment or test to improve the chance of achieving a live birth. STUDY FUNDING/COMPETING INTEREST(S): All costs relating to the development process were covered from ESHRE funds. There was no external funding of the development process or manuscript production. K.L. reports speakers fees from Merck and was part of a research study by Vitrolife (unpaid). T.E. reports consulting fees from Gynemed, speakers fees from Gynemed and is part of the scientific advisory board of Hamilton Thorne. N.P.P. reports grants from Merck Serono, Ferring Pharmaceutical, Theramex, Gedeon Richter, Organon, Roche, IBSA and Besins Healthcare, speakers fees from Merck Serono, Ferring Pharmaceutical, Theramex, Gedeon Richter, Organon, Roche, IBSA and Besins Healthcare. S.R.H. declares being managing director of Fertility Europe, a not-for-profit organization receiving financial support from ESHRE. I.S. is a scientific advisor for and has stock options from Alife Health, is co-founder of IVFvision LTD (unpaid) and received speakers' fee from the 2023 ART Young Leader Prestige workshop in China. A.P. reports grants from Gedeon Richter, Ferring Pharmaceuticals and Merck A/S, consulting fees from Preglem, Novo Nordisk, Ferring Pharmaceuticals, Gedeon Richter, Cryos and Merck A/S, speakers fees from Gedeon Richter, Ferring Pharmaceuticals, Merck A/S, Theramex and Organon, travel fees from Gedeon Richter. The other authors disclosed no conflicts of interest. DISCLAIMER: This Good Practice Recommendations (GPRs) document represents the views of ESHRE, which are the result of consensus between the relevant ESHRE stakeholders and are based on the scientific evidence available at the time of preparation.ESHRE GPRs should be used for information and educational purposes. They should not be interpreted as setting a standard of care or bedeemedinclusive of all proper methods of care, or be exclusive of other methods of care reasonably directed to obtaining the same results.Theydo not replace the need for application of clinical judgement to each individual presentation, or variations based on locality and facility type.Furthermore, ESHRE GPRs do not constitute or imply the endorsement, or favouring, of any of the included technologies by ESHRE.

Phase 2 Results Indicate Evenamide, A Selective Modulator of Glutamate Release, Is Associated With Clinically Important Long-Term Efficacy When Added to an Antipsychotic in Patients With Treatment-Resistant Schizophrenia.

Results from a pilot, 6-week, randomized, open-label, rater-blinded study, with 46-week extension, indicate very good tolerability with exceptional, clinically important, increasing efficacy of evenamide (7.5, 15, and 30 mg bid), a glutamate modulator, as add-on treatment to antipsychotics in 161 treatment-resistant, schizophrenia patients. Ninety-five percent of patients completed 6 weeks (1 discontinued for adverse event), and 89% continued in the extension. Results from the first 100 patients enrolled showed very low attrition over 1 year (77 completers); data pooled from all dose groups showed the Positive and Negative Syndrome Scale total score improved significantly (P < .001; paired t test; last observation carried forward [LOCF]) from baseline at 6 weeks (-9.4), 6 months (-12.7), and 1 year (-14.7); similarly, the proportion of responders (≥20% improvement) increased over time from 6 weeks (16.5%) to 6 months (39%) to 1 year (47.4%). Noteworthy improvement was also observed at each timepoint on the Clinical Global Impression - Severity scale and Clinical Global Impression of Change, indicating progressively increasing efficacy of evenamide up to 1 year.

Curalin supplement for patients with type 2 diabetes mellitus.

OBJECTIVE: To examine the efficacy and safety of Curalin supplement in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Adult patients with type 2 diabetes were randomized 1:1 to receive Curalin supplement or placebo. The primary endpoint was HbA1c decrease at 1 month. The secondary endpoint was a decrease in HbA1c by more than 0.5% and 1% and a change in 7 daily blood glucose measurements. A satisfaction questionnaire was used as an exploratory endpoint. Safety variables and adverse events were assessed. RESULTS: After 1 month of intervention, HbA1c was reduced by 0.94% in the Curalin arm versus 0.4% in the placebo arm (P = 0.008). 72% of Curalin patients had decreased HbA1c levels >0.5% versus 35% in the placebo arm (P < 0.05). The Treatment Satisfaction Questionnaire indicated that Curalin arm patients reported higher overall satisfaction. CONCLUSIONS: Curalin treatment significantly reduced HbA1c over a 1-month period and was well-tolerated.

Should substitution monotherapy or combination therapy be used after failure of the first antiseizure medication? Observations from a 30-year cohort study.

OBJECTIVES: To assess the temporal trends in the use of second antiseizure (ASM) regimens and compare the efficacy of substitution monotherapy and combination therapy after failure of initial monotherapy in people with epilepsy. METHODS: This was a longitudinal observational cohort study conducted at the Epilepsy Unit of the Western Infirmary in Glasgow, Scotland. We included patients who were newly treated for epilepsy with ASMs between July 1982, and October 2012. All patients were followed up for a minimum of 2 years. Seizure freedom was defined as no seizure for at least 1 year on unchanged medication at the last follow up. RESULTS: During the study period, 498 patients were treated with a second ASM regimen after failure of the initial ASM monotherapy, of whom 346 (69%) were prescribed combination therapy and 152 (31%) were given substitution monotherapy. The proportion of patients receiving second regimen as combination therapy increased during the study period from 46% in first epoch (1985-1994) to 78% in the last (2005-2015) (RR = 1.66, 95% CI: 1.17-2.36, corrected-p = .010). Overall, 21% (104/498) of the patients achieved seizure freedom on the second ASM regimen, which was less than half of the seizure-free rate on the initial ASM monotherapy (45%, p < .001). Patients who received substitution monotherapy had similar seizure-free rate compared with those who received combination therapy (RR = 1.17, 95% CI: 0.81-1.69, p = .41). Individual ASMs used, either alone or in combination, had similar efficacy. However, the subgroup analysis was limited by small sample sizes. SIGNIFICANCE: The choice of second regimen used based on clinical judgment was not associated with treatment outcome in patients whose initial monotherapy failed due to poor seizure control. Alternative approaches such as machine learning should be explored to aid individualized selection of the second ASM regimen.

Efficacy and safety of janagliflozin as add-on therapy to metformin in Chinese patients with type 2 diabetes inadequately controlled with metformin alone: A multicentre, randomized, double-blind, placebo-controlled, phase 3 trial.

AIM: To evaluate the efficacy and safety of janagliflozin in Chinese patients with type 2 diabetes (T2D) inadequately controlled with metformin monotherapy. MATERIALS AND METHODS: This multicentre phase 3 trial included a 24-week, randomized, double-blind, placebo-controlled period, followed by a 28-week extension period. Patients (N = 421) with HbA1c of 7.0% or higher and 10.5% or less were randomized (1:1:1) to receive once-daily placebo, janagliflozin 25 or 50 mg. After the 24-week treatment period, patients on placebo were re-randomized (1:1) to janagliflozin 25 or 50 mg for the additional 28-week treatment, whereas patients on janagliflozin maintained the same therapy. The primary endpoint was the change from baseline in HbA1c to week 24. RESULTS: At week 24, the placebo-adjusted least squares mean changes of HbA1c were -0.58% and -0.58% with janagliflozin 25 and 50 mg, respectively (P < .0001 for both). The proportion of patients achieving HbA1c less than 7.0% was higher with janagliflozin 25 and 50 mg compared with placebo (41.8%, 41.7% and 28.0%, respectively). Both janagliflozin doses provided significant reductions in fasting plasma glucose, 2-hour postprandial glucose, body weight and systolic blood pressure, and improvements in high-density lipoprotein cholesterol and insulin sensitivity compared with placebo (P < .05 for all). The trends in improvement of these variables were retained during the 28-week extension period. No severe hypoglycaemia occurred throughout the whole 52-week treatment. CONCLUSIONS: Janagliflozin 25 or 50 mg once-daily added to metformin therapy significantly improved glycaemic control, reduced body weight and systolic blood pressure, improved high-density lipoprotein cholesterol and insulin sensitivity, and was generally well-tolerated by Chinese T2D patients who had poor glycaemic control with metformin monotherapy.

Batoclimab as an add-on therapy in neuromyelitis optica spectrum disorder patients with acute attacks.

BACKGROUND AND PURPOSE: Neuromyelitis optica spectrum disorder (NMOSD) is a severe neurological inflammatory disease mainly caused by pathogenic aquaporin-4 antibodies (AQP4-IgG). The safety and efficacy of the neonatal Fc receptor antagonist batoclimab addition to conventional intravenous methylprednisolone pulse (IVMP) therapy in patients with NMOSD acute attacks was assessed. METHODS: In an open-label, dose-escalation phase 1b study, NMOSD patients with acute myelitis and/or optic neuritis received four doses of weekly subcutaneous injections of either 340 mg or 680 mg batoclimab with concurrent IVMP and were followed up for 27 weeks. The primary end-points were safety and tolerability. Secondary end-points included pharmacodynamics and efficacy, with key efficacy assessment at week 4. RESULTS: In total nine NMOSD patients were enrolled, including two and seven in the 340 and 680 mg groups. Five patients had acute myelitis, while the remaining four had unilateral optic neuritis. Batoclimab add-on therapy had an overall good safety profile without serious adverse events. In the 680 mg group, mean immunoglobulin G (IgG) reached its maximum reduction at the last dose (day 22). In the meantime, AQP4-IgG was undetectable in six of seven subjects whose baseline AQP4-IgG titers ranged from 1:32 to 1:320. Expanded Disability Status Scale score was reduced by 1.3 ± 0.4 at week 4 (2.7 ± 1.3) compared with baseline (4.0 ± 1.0). CONCLUSIONS: Batoclimab add-on therapy to IVMP is safe and tolerated in patients with NMOSD. Preliminary evidence suggests a beneficial neurological effect. A randomized controlled trial would be needed to prove the efficacy.

The real-world effectiveness of intravenous brivaracetam as a second-line treatment in status epilepticus.

PURPOSE: Status epilepticus (SE) is defined by abnormally prolonged seizures that may lead to brain damage and death. Our aim was to evaluate the efficacy and tolerability (effectiveness) of intravenous brivaracetam (BRV) as a second-line treatment. METHODS: Twenty-one patients (median age 68 years ± 17.28) were prospectively recruited between June 2019 and December 2022. Patients were treated with BRV (50-200 mg) as a second-line add-on therapy for SE. We evaluated the response of SE to the administration of BRV in terms of SE termination and recurrence of epileptic seizures at 6, 12, and 24 h, also monitoring safety. The first-line therapy was represented by intravenous benzodiazepines (mainly diazepam). RESULTS: Almost a quarter of patients had generalized seizures, whereas the vast majority (76.2%) presented focal seizures. In 52.4% of patients, the underlying cause was cerebrovascular. Fourteen (66.7%) patients displayed a good early response in the subsequent 6 h. At 12 and 24 h, 8 (38%) and 11 (52.4%) patients, respectively, did not present seizures. CONCLUSION: The present study highlights the potential of BRV when used as an early add-on therapy in SE, further confirming its good safety profile.

The burden of chronic drug-refractory focal onset epilepsy: Can it be prevented?

Despite the many therapeutic options for epilepsy available today, a third of patients still have poorly controlled epilepsy. Over the years, their transition through lines of treatment exposes them to increased risk of disease progression, mortality, morbidity, mental distress, and not least significantly impaired quality of life (QoL). The present review explores the multiple factors contributing to the impairment of health-related QoL in PWE-including both seizure-related and non seizure-related. The analysis aims to identify potential areas of intervention and strategies for a more holistic approach to epilepsy care and inform policy-makers and healthcare providers in their approach to this condition.

Tolerability of clobazam as add-on therapy in patients aged 50 years and older with drug-resistant epilepsy.

OBJECTIVE: To evaluate the tolerability of clobazam in patients with drug-resistant epilepsy aged 50 years and older. METHODS: We performed a single center, retrospective chart review of patients at least 50 years of age with drug resistant epilepsy of any type who started clobazam as an add on therapy. Retention rate, safety, and tolerability at 6 and 12 months and last follow-up, and the discontinuation rate due to side effects were analyzed. RESULTS: A total of 26 patients met inclusion criteria. Mean age was 62 ± 7.1 years, and 69.2% of patients were female. The mean baseline seizure frequency before initiation of clobazam was 2 (range 1-30) seizures per month. The mean total daily dose of clobazam administered was 13 (range 5 to 30) mg/day. At the 12-month follow-up visit after clobazam initiation, 40% of patients were seizure-free and an additional 45% of patients had > 50% reduction in seizure frequency. The mean seizure frequency at 12-month follow-up was 1.5 (range 0-24) seizures per month. The mean total dose of clobazam at 12-month follow-up was 14.25 (range 5 to 25) mg/day. The mean duration of clobazam at last follow was 55.2 ± 27.02 (mean ± SD months) and 18 (69.2%) patients remained on clobazam. Twenty out of 26 (76.9%) patients reported at least one side effect and 6/26 (23%) discontinued the medication within a month of initiation. At last follow-up, 40% remained seizure free on stable dosing. CONCLUSION: Clobazam can be a safe and tolerable, add-on treatment older adults with drug-resistant epilepsy. Those who responded tolerated the medication well. Discontinuation due to side effects occurred soon after initiation of therapy.

Comparison of add-on medications for persistent storage symptoms after α-blocker treatment in BPH patients - a network meta-analysis.

BACKGROUND: Patients with benign prostatic hyperplasia (BPH) receive α-blockers as first-line therapy to treat lower urinary tract symptoms; however, some individuals still experience residual storage symptoms. Antimuscarinics, ß3-agonists, and desmopressin are effective add-on medications. Nevertheless, there is currently no evidence for the appropriate choice of the first add-on medication. This systematic review aimed to investigate the clinical benefits of antimuscarinics, ß3-agonists, and desmopressin, in addition to α-blockers, for persistent storage symptoms in BPH patients. METHODS: A comprehensive literature search of randomized controlled trials (RCTs) comparing the efficacy of different add-on medications in BPH patients with persistent storage symptoms despite α-blocker treatment was conducted. Clinical outcomes included the International Prostate Symptom Score (IPSS), IPSS storage subscore, nocturia, micturition, and urgency. A network meta-analysis was performed to estimate the effect size. Surface under cumulative ranking curves (SUCRAs) were used to rank the included treatments for each outcome. RESULTS: A total of 15 RCTs were identified. Add-on imidafenacin and mirabegron resulted in significant improvement in all outcomes assessed. Other add-on medications such as desmopressin, tolterodine, solifenacin, fesoterodine, and propiverine showed positive benefits for most, but not all, outcomes. Based on the SUCRA rankings, add-on desmopressin was the best-ranked treatment for IPSS and nocturia, and add-on imidafenacin was the best for the IPSS storage subscore and micturition. CONCLUSIONS: BPH patients presenting with persistent storage symptoms despite α-blocker administration are recommended to include additional treatment. Desmopressin and imidafenacin may be considered high-priority add-on treatments because of their superior efficacy compared with other medications.

Patient informed choice in the age of evidence-based medicine: IVF patients' approaches to biomedical evidence and fertility treatment add-ons.

With the increasing offer of fertility treatment by a largely privatised sector, which has involved the proliferation of treatment add-ons lacking evidence of effectiveness, In-Vitro Fertilisation (IVF) patients are expected to make informed choices on what to include in their treatment. Drawing on interviews with 51 individuals undergoing fertility treatment, this article explores patients' approaches to medical evidence interpretation and its role in their decisions to include add-ons. While most IVF patients share understandings of what counts as medical evidence, our findings show how their approaches also differ. Our analysis focuses on how patients negotiate the notion of medical evidence and its relation to other forms of experience or knowledge. We present four different approaches to evidence in IVF: (1) delegating evaluations of evidence to experts; (2) critically assessing available evidence; (3) acknowledging the process of making evidence; and (4) contextualising evidence in their lived experience of infertility. We suggest that patients' choice to include add-ons is not due to a lack of information on or understanding of evidence, but rather should be interpreted as part of the complexity of patients' experiences of infertility.

Effectiveness and safety of perampanel as adjunctive therapy among Chinese patients with focal-onset epilepsy: A real-world prospective observational study.

OBJECTIVE: Perampanel (PER) has previously been shown to be effective and tolerable when used as an adjunctive therapy for patients with focal-onset seizures (FOS). This study aimed to evaluate the effect of PER as adjunctive therapy for patients with FOS in the Chinese population under real-world conditions for 1 year. METHODS: A prospective, single-center, 1-year observational study was conducted at Huashan Hospital, enrolling both under age (≥4 years old) and adult patients with FOS. Response to PER was assessed at 3-, 6-, and 12-month checkpoints by analyzing the 50 % responder rate, the seizure-free rate, and reduction in seizure frequency. RESULTS: One hundred and eight patients (mean age: 26.6 years, 56.5 % males) with FOS were included, with seventy-six patients finishing the 1-year follow-up (retention rate: 70.4 %, mean PER dose: 4.3 mg/day). The seizure frequency was reduced significantly at 3, 6, and 12 months relative to baseline (p < 0.001 for each seizure type). At 12 months, the responder rate was 65.8 %, and the seizure-free rate was 39.5 %. A significantly higher responder rate was found in patients with focal to bilateral tonic-clonic seizures (p = 0.024), among which the percentage of patients with sleep-related epilepsy was significantly high (p = 0.045). Responders had a lower number of concomitant anti-seizure medications (ASMs) than the non-responders (p = 0.009). Drug-related adverse events (AEs) were reported in 37 % of patients, mostly mild or moderate, and the patients who experienced AEs had a higher daily dose of PER than those who did not (p = 0.026). CONCLUSION: Perampanel, an add-on therapy for focal-onset seizures, was found to be effective and tolerable in Chinese patients at 12 months.

Evaluation of persistence and healthcare utilization in patients treated with anti-seizure medications as add-on therapy: A nationwide cohort study in South Korea.

OBJECTIVE: To compare medication adherence and healthcare utilization among patients who were treated with anti-seizure medications (ASMs) as first add-on to monotherapy for epilepsy using the national health insurance claims data. METHODS: A retrospective observational cohort study was conducted using the Korean National Health Insurance claims data. Patients who received ASM as first add-on to monotherapy during January 2017 to February 2018 were included. The selected patients were followed up for 12 months to evaluate persistence, adherence, and healthcare resource utilization. RESULTS: In total, 4277 patients who received ASM as first add-on to monotherapy for epilepsy were enrolled. The mean treatment duration of add-on ASM was 296.6 ±â€¯108.6 days during the 1-year follow-up period and 64.3% of the total population were persistent on the add-on ASM at 365 days from the index date. The mean medication possession ratio (MPR) was 90.3 ±â€¯23.7 and the proportion of adherent patients with ≥80% MPR was 79.3%. Lamotrigine (LTG), levetiracetam (LEV), oxcarbazepine (OXC), and perampanel (PER) groups showed significantly higher persistence and adherence than carbamazepine (CBZ), topiramate (TPM), and valproate (VAL) groups during the 1-year follow-up period. Significant differences in length of stays, total hospitalization cost, outpatient visit cost, and emergency cost were shown between ASM groups and LTG, LEV, OXC, and PER showed relatively low utilization and cost. CONCLUSIONS: Better adherence was observed in LTG, LEV, OXC, and PER groups than in CBZ, TPM, and VAL groups. Healthcare utilization and related costs showed significant difference between ASM groups.

Scientific and ethical issues in add-on designs for antidiabetic drugs.

This editorial describes the clinical trials related to antidiabetic drugs, most of them following an "add-on" design of where the new drug is added to metformin and the comparative arm is metformin plus placebo. Many drugs are already approved for therapy following this design; the authors believe that it is unethical to continue this trend because it makes it impossible to stratify the many antidiabetic drugs according to their efficacy and toxicity.

The use of uncertain exposure-A method to define switching and add-on in pharmacoepidemiology.

PURPOSE: When defining exposure to pharmacological treatments in pharmacoepidemiology, register data often do not provide information regarding if a pharmacological treatment is a switch or an add-on. This study aims to compare two methods defining switching and add-on therapies and their impact on exposure-outcome associations. Additionally, to guide bias reduction, it aims to describe how the methods relate to immortal time bias and selection bias. METHODS: Cohort study using Swedish population-based health registers to identify antidepressant (AD) prescriptions as exposures while hospitalizations for psychiatric reasons were used as an empirical outcome example. The first method for exposure definition used conditioning on future exposure (FE), the second used the concept of uncertain exposure (UE). To estimate associations between outcome and exposure categories "Use of one AD," "Use of two or more ADs", and "UE" compared to "Unexposed," hazard ratios (HRs) and 95% confidence intervals were estimated using Cox regression adjusted for age and sex. RESULTS: Using the UE method, 7.2% of time periods were classified as "UE" with a notable proportion of psychiatric hospitalizations (7.7%) occurring during this time, while when using the FE method these hospitalizations were distributed over unexposed time and AD use time. The FE method resulted in slightly higher associations than the UE method. The highest HR was found during "UE": HR (95% CI) 5.54 (5.06-6.07). CONCLUSIONS: This study suggests that to reduce the potential immortal time bias, selection bias, and exposure misclassification inherent to the FE method, the UE method could be used for identifying switching and add-on therapies. If not used as a main exposure definition, the UE method may be used to investigate the impact of UE time in a sensitivity analysis.

Effectiveness and Tolerability of Dronabinol Use in Patients with Chronic Pain: A Retrospective Analysis of 12-Week Open-Label Real-World Data Provided by the German Pain e-Registry.

OBJECTIVE: To evaluate the effectiveness of Δ9-tetrahydrocannabinol (dronabinol [DRO]) as an add-on treatment in patients with refractory chronic pain (CP). METHODS: An exploratory retrospective analysis of 12-week data provided by the German Pain e-Registry on adult patients with treatment refractory CP who received DRO. RESULTS: Between March 10, 2017, and June 30, 2019, the German Pain e-Registry collected information on 89,095 patients with pain, of whom 1,145 patients (1.3%) received DRO (53.8% female, mean ± standard deviation age: 56.9 ± 10.6 years), and 70.0% documented use for the entire 12-week evaluation period. The average DRO daily dose was 15.8 ± 7.5 mg, typically in three divided doses (average DRO dose of 5.3 ± 2.1 mg). Average 24-hour pain intensity decreased from 46.3 ± 16.1 to 26.8 ± 18.7 mm on a visual analog scale (absolute visual analog scale difference: -19.5 ± 17.3; P < 0.001). Among patients who completed follow-up, an improvement from baseline of at least 50% was documented for pain (46.5%), activities of daily living (39%), quality of life (31.4%), and sleep (35.3%). A total of 536 patients (46.8%) reported at least one of 1,617 drug-related adverse events, none of which were serious, and 248 patients (21.7%) stopped treatment. Over the 12-week period, 59.0% of patients reported a reduction of other pain treatments, and 7.8% reported a complete cessation of any other pharmacological pain treatments. CONCLUSION: Add-on treatment with DRO in patients with refractory CP was well tolerated and associated with a significant improvement.