Clinical and microbiological outcomes of ceftazidime-avibactam treatment in adults with Gram-negative bacteremia: A subset analysis from the phase 3 clinical trial program

INTRODUCTION: This exploratory analysis assessed efficacy and safety outcomes in patients with Gram-negative bacteremia treated with ceftazidime-avibactam or comparator across five phase 3, randomized, controlled, multi-center trials in adults with complicated intra-abdominal infection (cIAI), complicated urinary tract infection (cUTI)/pyelonephritis, hospital-acquired pneumonia (HAP), and ventilator-associated pneumonia (VAP). METHODS: In each trial, RECLAIM and RECLAIM 3 (cIAI; NCT01499290/NCT01726023), REPRISE (cIAI/cUTI; NCT01644643), RECAPTURE (cUTI; NCT01595438/NCT01599806), and REPROVE (HAP/VAP; NCT01808092), patients were randomized 1:1 to intravenous ceftazidime-avibactam (plus metronidazole for those with cIAI) or comparators (carbapenems in \u3e 97% patients) for 5-21 days. Efficacy assessments included clinical and microbiological responses at the test-of-cure visit in the pooled Gram-negative extended microbiologically evaluable (GNeME) population (bacteremia subset). Safety outcomes were summarized for patients with positive bacterial blood culture(s) at baseline who received ≥ 1 dose of study treatment. RESULTS: The overall safety population included 4050 patients (ceftazidime-avibactam, n = 2024; comparator, n = 2026). The GNeME population (bacteremia subset) comprised 101 patients (ceftazidime-avibactam, n = 54; comparator, n = 47). Clinical cure rates (all indications combined) were 47/54 (87.0%) for ceftazidime-avibactam and 39/47 (83.0%) for comparators; favorable microbiological response rates were 43/54 (79.6%) and 32/47 (68.1%), respectively. Clinical and microbiological responses in the bacteremia subset were generally similar to those in the overall set. The pattern of adverse events in patients with bacteremia was similar between treatment groups and was consistent with the known safety profile of ceftazidime-avibactam. CONCLUSION: This analysis provides supportive evidence of the efficacy and safety of ceftazidime-avibactam in patients with Gram-negative bacteremia associated with cIAI, cUTI/pyelonephritis, or HAP/VAP

Efficacy of venlafaxine extended release in major depressive disorder patients : effect of baseline anxiety symptom severity

Effects of baseline anxiety on the efficacy of venlafaxine extended release versus placebo were examined in a post hoc pooled subgroup analysis of 1573 patients enrolled in eight short-term studies of major depressive disorder. Anxiety subgroups were defined based on baseline 17-item Hamilton Rating Scale for Depression Item 10 score <3 (low) versus >= 3 (high). Change from baseline to final visit in Montgomery-Asberg Depression Rating Scale total score and Montgomery-Asberg Depression Rating Scale response and remission rates were analyzed. Change from baseline in Montgomery-Asberg Depression Rating Scale total score and response and remission rates was significantly greater for venlafaxine extended release versus placebo in both low and high anxiety subgroups (all P < 0.0001). A statistically significant baseline anxiety by treatment interaction was observed for Montgomery-Asberg Depression Rating Scale total score only (P = 0.0152). The adjusted mean change from baseline in Montgomery-Asberg Depression Rating Scale total score was significantly greater in the high anxiety subgroup versus low anxiety subgroup for patients treated with venlafaxine extended release (-6.27 versus -3.89; P = 0.0440) but not placebo. These results support the efficacy of venlafaxine extended release for major depressive disorder treatment in patients with anxiety symptoms. Copyright (C) 2019 The Author(s). Published by Wolters Kluwer Health, Inc

A meta-analysis of the efficacy of venlafaxine extended release 75–225 mg/day for the treatment of major depressive disorder

<p><b>Objective:</b> To evaluate the short-term efficacy of venlafaxine extended release (ER) 75–225 mg/day compared with placebo for treating major depressive disorder (MDD) and to examine associations between baseline characteristics and efficacy outcomes in MDD patients treated with venlafaxine ER 75–225 mg/day.</p> <p><b>Research design and methods:</b> This meta-analysis included published and unpublished short-term, double-blind, placebo-controlled, Wyeth/Pfizer sponsored studies of venlafaxine ER at doses up to 225 mg/day in adults with MDD.</p> <p><b>Clinical trial registration:</b> All trials were conducted before trial registration became mandatory.</p> <p><b>Main outcome measures:</b> Change from baseline in the 17-item Hamilton Rating Scale for Depression (HAM-D₁₇) total score was analyzed over time using a mixed-effects model for repeated measures with terms for study, treatment group, visit, interaction between treatment group and visit, and baseline score as a covariate. Associations between baseline demographic and clinical characteristics and the probability of HAM-D₁₇ response and remission at week 8 were evaluated using logistic regression models, with terms for study, treatment group, and baseline characteristics in the models. Safety and tolerability was assessed based on adverse events (AEs) and discontinuations due to AEs.</p> <p><b>Results:</b> The full analysis set included 1087 patients from five studies that fulfilled selection criteria. Statistically significant separation between venlafaxine ER and placebo groups for HAM-D₁₇ total score was seen at week 2 and all subsequent assessments (<i>p</i>-values <.0001). There was no significant interaction between treatment and baseline HAM-D₁₇ total score. Probability of HAM-D₁₇ remission at week 8 decreased with increasing baseline HAM-D₁₇ total score (<i>p</i> = .0012; OR: 0.94); however, baseline HAM-D₁₇ total score did not predict response. Discontinuations due to AEs were reported for 9.4% of venlafaxine-ER-treated patients compared with 3.6% of placebo-treated patients.</p> <p><b>Key limitations:</b> Five studies met the criteria for inclusion. Several differences in design between included studies limited the analysis: one study did not include a week 3 assessment (the week 3 time point was therefore dropped from the analysis), one study had two venlafaxine ER dose arms, which were combined into one group for the meta-analysis, and mixed- and flexible-dose studies were pooled.</p> <p><b>Conclusions:</b> Venlafaxine ER 75–225 mg/day effectively reduced symptoms of depression in patients with MDD overall and in patients with either lower (≤23) or higher (>23) HAM-D₁₇ total score at baseline.</p

Desvenlafaxine Versus Placebo in a Fluoxetine-Referenced Study of Children and Adolescents with Major Depressive Disorder

Objectives: To evaluate the short-term efficacy and safety of desvenlafaxine (25-50mg/d) compared with placebo in children and adolescents with major depressive disorder (MDD). Methods: Outpatient children (7-11 years) and adolescents (12-17 years) who met DSM-IV-TR criteria for MDD and had screening and baseline Children's Depression Rating Scale-Revised (CDRS-R) total scores >40 were randomly assigned to 8-week treatment with placebo, desvenlafaxine (25, 35, or 50mg/d based on baseline weight), or fluoxetine (20mg/d). The primary efficacy endpoint was change from baseline in CDRS-R total score at week 8, analyzed using a mixed-effects model for repeated measures. Secondary efficacy endpoints included week 8 Clinical Global Impressions-Severity, Clinical Global Impressions-Improvement (CGI-I), and response (CGI-I 2). Safety assessments included adverse events, physical and vital sign measurements, laboratory evaluations, electrocardiogram, and the Columbia-Suicide Severity Rating Scale. Results: The safety population included 339 patients (children, n=130; adolescents, n=209). The primary endpoint, change from baseline in CDRS-R total score at week 8, did not statistically separate from placebo, for either desvenlafaxine (adjusted mean [standard error] change, -22.6 [1.17]) or fluoxetine (-24.8 [1.17]; placebo, -23.1 [1.18]). Week 8 CGI-I response rates were significantly greater for fluoxetine (78.2%; p=0.017) than for placebo (62.6%); desvenlafaxine (68.7%) did not differ from placebo. Other secondary outcomes were consistent with those obtained with CDRS-R. Rates of treatment-emergent adverse events were comparable among treatment groups (desvenlafaxine, 60.0%; placebo, 70.5%; and fluoxetine, 64.3%). Conclusion: Desvenlafaxine did not demonstrate efficacy for treating MDD in children and adolescents in this trial. Because neither desvenlafaxine nor the reference medication, fluoxetine, demonstrated a statistically significant difference from placebo on the primary endpoint, this was considered a failed trial and no efficacy conclusions can be drawn. Desvenlafaxine 25-50mg/d was generally safe and well tolerated in children and adolescents in this study.Pfizer Inc.12 month embargo; Published online: 30 November 2017This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Validating the SIR: a better prognostic score index for patients with brain metastases treated with stereotactic radiosurgery

Objective: The aim of this paper is to validate the score index forsurvival in patients treated with stereotactic radiosurgery, using aclassification prepared to better evaluate the prognosis of patientswith brain metastasis submitted to stereotactic surgery, re-evaluatingsurvival of patients and reviewing the medical literature. Methods:Data from 100 patients with brain metastases treated with stereotacticradiosurgery at a single institution, between July 1993 and February2000, were retrospectively analyzed. The prognostic factors andscores studied were age, Karnofsky performance status, extracranialdisease status, number of brain lesions, volume of the largest lesion,primary tumor type, treated or not with whole brain radiation therapy,SIR, and RPA. Kaplan-Meier actuarial survival curves for subsets werecalculated and compared by log-rank test. Complete and backwardelimination Cox models were utilized to identify the prognostic factorsand scores independently associated with survival. Results: Karnofskyperformance status, extracranial disease status, volume of the largestbrain lesion, RPA, and SIR were significantly correlated with prognosisin Kaplan-Meier survival analysis. Applying Cox models, significancewas observed for KPS and volume of the largest lesion (p < 0.0001and p = 0.0182, respectively), as well as for SIR and RPA when testedindividually (p < 0.0001 and p = 0.0002, respectively). However, whentesting SIR and RPA together, only SIR reached independent statisticalsignificance (p < 0.0001). Conclusion: SIR classification demonstrateda better accuracy in predicting survival time than RPA. SIR was testedin other centers, showing superior accuracy and applicability than theRPA, thus validating this score

Desvenlafaxine Versus Placebo in a Fluoxetine-Referenced Study of Children and Adolescents with Major Depressive Disorder

Objectives: To evaluate the short-term efficacy and safety of desvenlafaxine (25-50mg/d) compared with placebo in children and adolescents with major depressive disorder (MDD). Methods: Outpatient children (7-11 years) and adolescents (12-17 years) who met DSM-IV-TR criteria for MDD and had screening and baseline Children's Depression Rating Scale-Revised (CDRS-R) total scores >40 were randomly assigned to 8-week treatment with placebo, desvenlafaxine (25, 35, or 50mg/d based on baseline weight), or fluoxetine (20mg/d). The primary efficacy endpoint was change from baseline in CDRS-R total score at week 8, analyzed using a mixed-effects model for repeated measures. Secondary efficacy endpoints included week 8 Clinical Global Impressions-Severity, Clinical Global Impressions-Improvement (CGI-I), and response (CGI-I 2). Safety assessments included adverse events, physical and vital sign measurements, laboratory evaluations, electrocardiogram, and the Columbia-Suicide Severity Rating Scale. Results: The safety population included 339 patients (children, n=130; adolescents, n=209). The primary endpoint, change from baseline in CDRS-R total score at week 8, did not statistically separate from placebo, for either desvenlafaxine (adjusted mean [standard error] change, -22.6 [1.17]) or fluoxetine (-24.8 [1.17]; placebo, -23.1 [1.18]). Week 8 CGI-I response rates were significantly greater for fluoxetine (78.2%; p=0.017) than for placebo (62.6%); desvenlafaxine (68.7%) did not differ from placebo. Other secondary outcomes were consistent with those obtained with CDRS-R. Rates of treatment-emergent adverse events were comparable among treatment groups (desvenlafaxine, 60.0%; placebo, 70.5%; and fluoxetine, 64.3%). Conclusion: Desvenlafaxine did not demonstrate efficacy for treating MDD in children and adolescents in this trial. Because neither desvenlafaxine nor the reference medication, fluoxetine, demonstrated a statistically significant difference from placebo on the primary endpoint, this was considered a failed trial and no efficacy conclusions can be drawn. Desvenlafaxine 25-50mg/d was generally safe and well tolerated in children and adolescents in this study.Pfizer Inc.12 month embargo; Published online: 30 November 2017This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

A plain language summary on ritlecitinib treatment for adults and adolescents with alopecia areata

What is this summary about?This is a summary of the results of the ALLEGRO phase 2b/3 clinical trial, originally published in The Lancet. ALLEGRO-2b/3 looked at how well and safely the study medicine, ritlecitinib, works in treating people with alopecia areata ('AA' for short). The immune system protects your body from outside invaders such as bacteria and viruses. AA is an autoimmune disease, meaning a disease in which one's immune system attacks healthy cells of the body by mistake. In AA, the immune system attacks hair follicles, causing hair to fall out. AA causes hair loss ranging from small bald patches to complete hair loss on the scalp, face, and/or body. Ritlecitinib is a medicine taken as a pill every day, by mouth, that is approved for the treatment of severe AA. It blocks processes that are known to play a role in causing hair loss in patients with AA.What were the results of the study?Adults and adolescents (12&nbsp;years and older) took part in the ALLEGRO-2b/3 study. They either took ritlecitinib for 48&nbsp;weeks or took a placebo (a pill with no medicine) for 24&nbsp;weeks. Participants taking placebo later switched to taking ritlecitinib for 24&nbsp;weeks. The study showed that participants taking ritlecitinib had more hair regrowth on their scalp after 24&nbsp;weeks than those taking the placebo. Hair regrowth was also seen on the eyebrows and eyelashes in participants taking ritlecitinib. Hair regrowth continued to improve to week 48 with continued ritlecitinib treatment. In addition, more participants taking ritlecitinib reported that their AA had 'moderately' or 'greatly' improved after 24&nbsp;weeks than those taking the placebo. Similar numbers of participants taking ritlecitinib or placebo had side effects after 24&nbsp;weeks. Most side effects were mild or moderate.What do the results of the study mean?Ritlecitinib was an effective and well-tolerated treatment over 48&nbsp;weeks for people with AA. Clinical Trial Registration: NCT03732807 (phase 2b/3 ALLEGRO study)

Efficacy and safety of ritlecitinib in adults and adolescents with alopecia areata: a randomised, double-blind, multicentre, phase 2b–3 trial

BackgroundAlopecia areata is characterised by non-scarring loss of scalp, face, or body hair. We investigated the efficacy and safety of ritlecitinib, an oral, selective dual JAK3/TEC family kinase inhibitor, in patients with alopecia areata.MethodsIn this randomised, double-blind, multicentre, phase 2b-3 trial done at 118 sites in 18 countries, patients aged 12 years and older with alopecia areata and at least 50% scalp hair loss were randomly assigned to oral ritlecitinib or placebo once-daily for 24 weeks, with or without a 4-week loading dose (50 mg, 30 mg, 10 mg, 200 mg loading dose followed by 50 mg, or 200 mg loading dose followed by 30 mg), followed by a 24-week extension period during which ritlecitinib groups continued their assigned doses and patients initially assigned to placebo switched to ritlecitinib 50 mg or 200 mg loading dose followed by 50 mg. Randomisation was done by use of an interactive response system and was stratified by baseline disease severity and age. The sponsor, patients, and investigators were masked to treatment, and all patients received the same number of tablets to maintain masking. The primary endpoint was Severity of Alopecia Tool (SALT) score 20 or less at week 24. The primary endpoint was assessed in all assigned patients, regardless of whether they received treatment. This study was registered with ClinicalTrials.gov, NCT03732807.FindingsBetween Dec 3, 2018, and June 24, 2021, 1097 patients were screened and 718 were randomly assigned to receive ritlecitinib 200 mg + 50 mg (n=132), 200 mg + 30 mg (n=130), 50 mg (n=130), 30 mg (n=132), 10 mg (n=63), placebo to 50 mg (n=66), or placebo to 200 mg + 50 mg (n=65). 446 (62%) of 718 patients were female and 272 (38%) were male. 488 (68%) were White, 186 (26%) were Asian, and 27 (4%) were Black or African American. Of 718 patients randomly assigned, 104 patients discontinued treatment (34 withdrew, 19 adverse events [AEs], 12 physician decision, 12 lack of efficacy, 13 lost to follow up, five rolled over to long-term study transfer, four pregnancies, two protocol deviations, one declined to attend follow-up due to COVID-19, one attended last visit very late due to COVID-19, and one non-compliance). At week 24, 38 (31%) of 124 patients in the ritlecitinib 200 mg + 50 mg group, 27 (22%) of 121 patients in the 200 mg + 30 mg group, 29 (23%) of 124 patients in the 50 mg group, 17 (14%) of 119 patients in the 30 mg group, and two (2%) of 130 patients in the placebo group had a response based on SALT score 20 or less. The difference in response rate based on SALT score 20 or less between the placebo and the ritlecitinib 200 mg + 50 mg group was 29·1% (95% CI 21·2-37·9; p&lt;0·0001), 20·8% (13·7-29·2; p&lt;0·0001) for the 200 mg + 30 mg group, 21·9% (14·7-30·2; p&lt;0·0001) for the 50 mg group, and 12·8% (6·7-20·4; p=0·0002) for the 30 mg group. Up to week 48 and including the follow-up period, AEs had been reported in 108 (82%) of 131 patients in the ritlecitinib 200 mg + 50 mg group, 105 (81%) of 129 patients in the 200 mg + 30 mg group, 110 (85%) of 130 patients in the 50 mg group, 106 (80%) of 132 patients in the 30 mg group, 47 (76%) of 62 patients in the 10 mg group, 54 (83%) of 65 patients placebo to ritlecitinib 200 mg + 50 mg in the extension period, and 57 (86%) of 66 patients in the placebo to 50 mg group. The incidence of each AE was similar between groups, and there were no deaths.InterpretationRitlecitinib was effective and well tolerated in patients aged 12 years and older with alopecia areata. Ritlecitinib might be a suitable treatment option for alopecia areata in patients who are candidates for systemic therapy.FundingPfizer