Correction to: Fidaxomicin for the treatment of Clostridium difficile infection (CDI) in at-risk patients with inflammatory bowel disease, fulminant CDI, renal impairment or hepatic impairment: a retrospective study of routine clinical use (ANEMONE).

The article "Fidaxomicin for the treatment of Clostridium difficile infection (CDI) in at-risk patients with inflammatory bowel disease, fulminant CDI, renal impairment or hepatic impairment: a retrospective study of routine clinical use (ANEMONE)", written by M.J.G.T. Vehreschild et al., was originally published at Springerlink on 11 August 2018 without open access.

Fidaxomicin for the treatment of Clostridium difficile infection (CDI) in at-risk patients with inflammatory bowel disease, fulminant CDI, renal impairment or hepatic impairment: a retrospective study of routine clinical use (ANEMONE).

Information is limited or lacking on fidaxomicin treatment of Clostridium difficile infection (CDI) in patients with inflammatory bowel disease, fulminant or life-threatening CDI, severe renal impairment, moderate-to-severe hepatic impairment and pregnancy. The ANEMONE study investigated fidaxomicin use in a routine clinical setting, focusing on these medical conditions of specific interest (MCSIs). This retrospective, post-authorisation study reviewed hospital records from Austria, Germany, Spain and the UK (June 2012-June 2015), collecting data from hospital admission to 30 days after last fidaxomicin dose. The primary objective was to identify the proportion of fidaxomicin-treated patients with MCSIs. Secondary objectives were to describe 30-day mortality, changes in ECG and laboratory parameters, fidaxomicin exposure and CDI response (resolution of diarrhoea; 30-day recurrence). 45.3% (261/576) of patients had ≥ 1 MCSI. Thirty-day mortality (post-first dose) was 17.0% (98/576) in the total population and slightly higher (24.6-27.6%) in patients with fulminant CDI or severe renal impairment. 29.6% (24/81) deaths of known cause were attributable to CDI. Of changes in laboratory parameters or ECG findings, only a decrease in leucocyte counts appeared associated with fidaxomicin, consistent with a positive treatment response. Diarrhoea resolved in 78.0% (404/518) of treatment episodes; diarrhoea resolution was lowest in patients with fulminant CDI (investigator-defined, 67.5%, 56/88) and severe renal impairment (68.0%, 68/100). Thirty-day recurrence (18.8%, 79/420) was similar across MCSI subgroups. Although almost half of fidaxomicin-treated patients had ≥ 1 MCSI, the majority of patients in all subgroups had positive responses to treatment, and no particular safety concerns were identified.

Correlation of symptomatic improvements with functional improvements and patient-reported outcomes in adults with attention-deficit/hyperactivity disorder treated with OROS methylphenidate.

OBJECTIVES: To evaluate correlations between symptom severity and daily functioning in adults with ADHD. METHODS: In the 5-week, double-blind LAMDA study, 401 adults with ADHD were randomly assigned to Osmotic-Release Oral System (OROS) methylphenidate (MPH) 18, 36 or 72 mg/day, or placebo. The primary variable - investigator-rated Conners' Adult ADHD Rating Scale (CAARS:O-SV) - has been presented previously. Secondary endpoints included the self-reported version of CAARS (CAARS-S:S) and Clinical Global Impression - Severity (CGI-S). Daily functioning and quality of life were assessed using the Sheehan Disability Scale (SDS) and Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q). Relationships between symptom and functional outcomes were evaluated in post-hoc Pearson partial correlation, multivariate regression and mediator analyses. RESULTS: Improvements in CAARS-S:S, CGI-S and SDS scores were significantly greater in each OROS MPH arm versus placebo (P < 0.01 for all comparisons). Correlations between symptom and functioning scores were significant for all comparisons (P < 0.0001). In regression analyses, CAARS Hyperactivity/Impulsivity subscale and CGI-S were correlated with SDS (P < 0.05). CAARS Inattention was correlated with the SDS Family Life domain (P < 0.05). In a mediator analysis, the impact of treatment on SDS scores was fully mediated by improvement in CAARS:O-SV score. CONCLUSIONS: OROS MPH 18-72 mg/day was associated with significant improvements in ADHD symptoms, which correlated with improved daily functioning and health-related quality of life.

Predictors of treatment outcome in adults with ADHD treated with OROS® methylphenidate.

BACKGROUND: We conducted a post-hoc analysis of the Long-Acting MethylpheniDate in Adult attention-deficit hyperactivity disorder (LAMDA) study to investigate predictors of response in adults with ADHD randomly assigned to Osmotic Release Oral System (OROS)(®)-methylphenidate hydrochloride (MPH) 18, 36 or 72 mg or placebo. METHODS: LAMDA comprised a 5-week, double-blind (DB) period, followed by a 7-week, open-label (OL) period. A post-hoc analysis of covariance and a logistic regression analysis were undertaken to detect whether specific baseline parameters or overall treatment compliance during the double-blind phase contributed to response. The initial model included all covariates as independent variables; a backward stepwise selection method was used, with stay criteria of p<0.10. Six outcomes were considered: change from baseline CAARS:O-SV (physician-rated) and CAARS:S-S (self-report) scores at DB and OL end points, and response rate (≥30% decrease in CAARS:O-SV score from baseline) and normalization of CAARS:O-SV score at DB end point. RESULTS: Taking into account a significant effect of OROS(®)-MPH treatment versus placebo in the original analysis (p≤0.015), across the outcomes considered in this post-hoc analysis, higher baseline CAARS scores were most strongly predictive of superior outcomes. Male gender and lower academic achievement were also predictive for improved results with certain outcomes. CONCLUSIONS: Several baseline factors may help to predict better treatment outcomes in adults receiving OROS(®)-MPH; however, further research is required to confirm these findings and examine their neurobiological underpinnings.

Perimenstrual migraines and their response to preventive therapy with topiramate.

INTRODUCTION: Preventive treatment with topiramate is effective for overall reduction of migraine frequency, but there are few data regarding its efficacy on perimenstrual migraines. To determine whether topiramate can prevent perimenstrual migraines, we analyzed data from premenopausal women as a subgroup of the Prolonged Migraine Prevention with Topiramate (PROMPT) study. METHODS: In total, 198 women from the PROMPT study with menstrually related migraine (MRM) were evaluated. After a one-to-two-month prospective baseline period, patients received open-label topiramate (50-200 mg/day) for six months. RESULTS: During topiramate treatment, mean monthly migraine frequency was reduced from 7.03 at baseline to 4.36 (mean change: -2.66; p < .001, endpoint analysis). Mean percentage reductions were similar for migraines during and outside the perimenstrual period (-45.9% and -46.1%, respectively). In patients with aura, reductions in migraine days with (-48.3%) or without (-43.4%) aura were similar to those in patients without aura (-45.4%). Reductions were also similar whether women were taking combined oral contraceptives (-47.0%) or were not (-46.6%). CONCLUSIONS: Topiramate reduces the frequency, but not severity or duration, of perimenstrual migraines in women with MRM, including migraines with and without aura, and regardless of combined oral contraceptive use.

Factors predicting the probability of relapse after discontinuation of migraine preventive treatment with topiramate.

INTRODUCTION: Demographic and clinical variables were examined in a post hoc analysis of the PROlonged Migraine Prevention with Topiramate (PROMPT) study to determine potential contribution to relapse. METHODS: After a six-month open-label (OL) topiramate phase, patients were randomised to continue topiramate or switch to placebo in a six-month double-blind (DB) phase. 'Relapse' was investigated in terms of change in monthly migraine days after randomisation compared with the month before randomisation, and was analysed during the first ('initial relapse') and last month ('sustained relapse') of the DB phase. More than 40 potential predicting factors were entered into analyses of variance and covariance. RESULTS: For initial relapse, variable-by-treatment interactions were significant for the Headache Impact Test (HIT-6) at DB baseline, and decline in acute medication intake or reporting of 'anxiety' in the OL phase. For sustained relapse, no statistically significant interactions were observed. CONCLUSION: Relapse after topiramate discontinuation in migraine prophylaxis appears to be unaffected by patient characteristics or baseline migraine frequency.

Safety and efficacy of galantamine (Reminyl) in severe Alzheimer's disease (the SERAD study): a randomised, placebo-controlled, double-blind trial.

BACKGROUND: The efficacy of galantamine has been shown in patients with mild, moderate, and advanced moderate Alzheimer's disease (AD). Here we report its efficacy in patients with severe AD. METHODS: Between December, 2003, and March, 2007, patients aged 84 (SD 6) years with severe AD (mini-mental state examination [MMSE] score 5-12 points), in a nursing home setting were randomly assigned to receive galantamine (n=207), titrated initially to 24 mg/day, or placebo (n=200). Co-primary efficacy measures for cognitive function and ability to undertake normal daily activities were the severe impairment battery (SIB) and the seven-item minimum data set-activities of daily living (MDS-ADL), respectively. Adverse events, vital signs, laboratory parameters, and electrocardiograms were monitored. This trial is registered with ClinicalTrials.gov, number NCT00216593. FINDINGS: 168 of 207 (81%) patients in the galantamine group and 161 of 200 (81%) in the placebo group completed the study. Mean SIB scores increased (improved) by 1.9 (95% CI -0.1 to 3.9) points with galantamine and decreased (worsened) by 3.0 (-5.6 to -0.5) points with placebo (between-group least squares mean difference 4.36, 1.3 to 7.5; p=0.006). Mean MDS-ADL self-performance score worsened by 1.2 (0.6 to 1.8) points and 1.6 (0.8 to 2.3) points, respectively (between-group least squares mean difference -0.41, -1.3 to 0.5; p=0.383). Nominally significant between-group differences in favour of galantamine occurred for the SIB domains of memory (p=0.006), praxis (p=0.010), and visuospatial ability (p=0.002), and for the MDS-ADL subitem locomotion on unit (p=0.021). 183 of 207 patients (88%) who received galantamine and 177 of 200 (89%) who received placebo had adverse events, which were mostly mild to moderate. Eight patients (4%) in the galantamine group and 21 patients (11%) in the placebo group died. ECG abnormalities were similar between the two groups. INTERPRETATION: Galantamine can be started and used safely in elderly patients with severe AD. Galantamine improved cognitive function but failed to significantly improve the co-primary parameter of overall activities of daily living.

Cessation versus continuation of 6-month migraine preventive therapy with topiramate (PROMPT): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Use of preventive therapy for migraine is often recommended for only 6-9 months, but no randomised, placebo-controlled trials have investigated migraine frequency after the end of prophylaxis. We assessed the effects of discontinuation of topiramate after a treatment period of 6 months. METHODS: 818 patients who have migraines were enrolled from 88 clinics in 21 countries. After a 4-8-week lead-in period, patients received topiramate in a 26-week open-label phase. Daily dose was increased from 25 mg to 100 mg in steps of 25 mg every week; the dose could be adjusted further in the range 50-200 mg/day, but was stable for the final 4 weeks. Patients were randomly assigned to continue this dose or switch to placebo for a 26-week double-blind phase. The primary endpoint was the difference in number of days with migraine during the last 4 weeks of the double-blind phase compared with the last 4 weeks of the open-label phase. Analysis was by intention to treat. This trial is registered with EudraCT, number 2005-000321-29. FINDINGS: 559 patients (68.3%) completed the open-label phase; 514 entered the double-blind phase and were assigned to topiramate (n=255) or placebo (n=259). The mean increase in number of migraine days was greater in the placebo group (1.19 days in 4 weeks, 95% CI 0.71 to 1.66; p<0.0001) than in the topiramate group (0.10, -0.36 to 0.56; p=0.5756; mean difference between groups -1.09, -1.75 to -0.43; p=0.0011) [corrected] Patients in the placebo group had a greater number of days on acute medication than did those in the topiramate group (mean difference between groups -0.95, -1.49 to -0.41; p=0.0007). Quality of life, as assessed by the MIDAS questionnaire, fell in the placebo group but remained stable in the topiramate group. Patients were more satisfied with the efficacy of topiramate than with that of placebo, whereas satisfaction with tolerability was similar in both treatment groups. INTERPRETATION: Sustained benefit was reported after discontinuation of topiramate, although number of migraine days did increase. These findings suggest that patients should be treated for 6 months, with the option to continue to 12 months in some patients.

Topiramate monotherapy as broad-spectrum antiepileptic drug in a naturalistic clinical setting.

Topiramate was assessed in an open-label trial as broad-spectrum antiepileptic monotherapy, independently from the epilepsy type or syndrome. Adults and children aged 2 years and older, who were diagnosed with epilepsy within the last 5 years, treatment-naive or failing prior treatment with one antiepileptic drug (AED), received individually adjusted doses of topiramate, after escalation to 100mg/day over 4 weeks (maximum 400mg/day) or 3mg/kg/day over 6 weeks (maximum 9 mg/kg/day), respectively. Patients were followed for >or=7 months and optionally up to a maximum of 13 months. Data were analysed for all patients (n=692), as well as for focal (n=421) and generalized epilepsies (n=148). The median topiramate dose used was 125 mg/day in adults and 3.3mg/kg/day in children (or=50% reduction in mean monthly seizure frequency. Patients with focal and generalized epilepsies alike responded to treatment (73.9 and 83.8% with at least 50% seizure reduction): 39.4% of patients with focal epilepsy and 61.5% of those with generalized epilepsy were seizure-free. The mean monthly seizure frequency was significantly reduced versus baseline at all visits (p<0.001). Similar response rates were obtained from the 237 patients completing the 1-year observation period. During the mandatory 7-month period of study, 8.8% of patients reported insufficient tolerability as a reason for dropout. The most frequent adverse event was paraesthesia. Our results support findings that emerge from controlled studies that topiramate is effective and well tolerated when used as initial or second monotherapy. They also suggest that in a naturalistic setting, overall good retention on treatment and seizure freedom are observed at low doses in a broad spectrum of epilepsies.

Time course of adverse events in patients with localization-related epilepsy receiving topiramate added to carbamazepine.

PURPOSE: To explore the time course of treatment-emergent adverse events (AEs) during topiramate (TPM) adjunctive therapy. METHODS: Post hoc analyses were performed by using data from a large (264 subjects) multicenter, double-blind, placebo-controlled trial in which 200 mg/day TPM was added to carbamazepine (CBZ) with or without another antiepileptic drug (AED) in adults with treatment-resistant partial-onset seizures. The daily incidence and mean duration of the most common (> or =5% incidence) AEs were calculated for patients completing the 12-week study. RESULTS: The daily incidence of somnolence, headache, loss of appetite, nervousness, fatigue, dizziness, upper respiratory tract infection, and vertigo peaked during titration and declined to rates similar to that of placebo after the target TPM dose had been reached. In contrast, the daily incidence of paresthesia increased during titration and was maintained for the study duration. Relatively few patients had cognitive symptoms (9% with TPM, 5% with placebo), but these were the most common AEs associated with treatment discontinuation. Patient/investigator reports of weight loss increased gradually over the course of the trial, corresponding with the pattern of change in weight measured at study visits. CONCLUSIONS: This study demonstrates that most of the more common AEs with TPM adjunctive therapy are transient. Patients can be counseled that most AEs emerging when TPM is initially added to CBZ can be expected to diminish with continued therapy.