scholarly journals Changes in respiratory symptoms during 48-week treatment with ARD-3150 (inhaled liposomal ciprofloxacin) in bronchiectasis: results from the ORBIT-3 and -4 studies

2020 ◽  
Vol 56 (4) ◽  
pp. 2000110
Author(s):  
James D. Chalmers ◽  
David Cipolla ◽  
Bruce Thompson ◽  
Angela M. Davis ◽  
Anne O'Donnell ◽  
...  
Keyword(s):  
Repeated Measures ◽  
Respiratory Symptoms ◽  
Mixed Model ◽  
Bacterial Load ◽  
Minimum Clinically Important Difference ◽  
Symptom Improvement ◽  
Symptom Scale ◽  
Inhaled Antibiotics ◽  
Post Hoc ◽  
Relationship Of

It is not known if inhaled antibiotics improve respiratory symptoms in patients with bronchiectasis. In the recent phase-3 ORBIT trials, 48 weeks' treatment with ARD-3150 (inhaled liposomal ciprofloxacin) did not significantly improve symptoms using the prespecified method of analysis comparing baseline symptoms to those after 48 weeks, when patients had been off treatment for 28 days. This method of analysis does not take account of possible improvements in symptoms while on active treatment.A post hoc analysis of two identical randomised trials of ARD-3150 (ORBIT-3 and -4) administered 28 days on and 28 days off in patients with bronchiectasis and chronic Pseudomonas aeruginosa infection. The quality-of-life bronchiectasis respiratory symptom scale (QOL-B-RSS), which has a one-week recall period, was administered every 28 days. We examined whether respiratory symptoms improved during on-treatment periods and the relationship of changes in QOL-B-RSS to changes in bacterial load using a mixed-model repeated measures approach.ARD-3150 treatment resulted in a significant improvement in respiratory symptoms during the on-treatment periods with concordant results between ORBIT-3 (estimate 1.4 points, se 0.49; p=0.004) and ORBIT-4 (estimate 1.1 point, se 0.41; p=0.006). The proportion of patients achieving a symptom improvement above the minimum clinically important difference was higher with ARD-3150 compared with placebo during on-treatment cycles (p=0.024). Changes in respiratory symptoms were correlated with changes in bacterial load in the treatment group (r=−0.89, p<0.0001). Individual estimates for decrements in the QOL-B RSS during exacerbation were −9.4 points (se 0.91) in ORBIT-3 and −10.8 points (0.74) in ORBIT-4 (both p<0.0001).Inhaled ARD-3150 resulted in significant improvements in respiratory symptoms during the on-treatment periods which were lost during off-treatment periods. These results supports the concept that reducing bacterial load can improve respiratory symptoms in patients with bronchiectasis.

Post hoc analysis of a randomised, placebo-controlled, active-reference 6-week study of brexpiprazole in acute schizophrenia

2020 ◽  
Vol 32 (3) ◽  
pp. 153-158 ◽  
Author(s):  
Stephen R. Marder ◽  
Hans Eriksson ◽  
Yudong Zhao ◽  
Mary Hobart
Keyword(s):  
Adverse Events ◽  
Repeated Measures ◽  
Mixed Model ◽  
Least Square ◽  
Analysis Of Covariance ◽  
Sensitivity Analyses ◽  
Symptom Improvement ◽  
Syndrome Scale ◽  
Quetiapine Xr ◽  
Post Hoc

AbstractObjective:We provide a closer look at the result of a randomised, placebo-controlled, active-reference (quetiapine XR), flexible-dose, 6-week study of brexpiprazole in schizophrenia, which did not meet its primary endpoint – change from baseline in Positive and Negative Syndrome Scale (PANSS) total score. We also investigate potential expectancy bias from the well-known side-effect profile of the active reference that could have affected the study outcome.Methods:Pre-specified sensitivity analyses of the primary end point were performed using analysis of covariance (ANCOVA) last observation carried forward (LOCF) and observed cases (OC). Post hoc analyses of change from baseline in PANSS total score were performed using the mixed model for repeated measures approach with treatment groups split by having typical adverse events with potential for functional unblinding, for example, somnolence, increase in weight, dizziness, dry mouth and sedation.Results:Pre-specified sensitivity analyses showed separation from placebo for brexpiprazole at week 6: LOCF, ANCOVA: −4.3 [95% CI (−8.0, −0.5), p = 0.0254]. OC, ANCOVA: −3.9 [95% CI (−7.3, −0.5), p = 0.0260]. Patients treated with brexpiprazole experiencing typical adverse events with potential for functional unblinding before or at Week 2 had a least square (LS) mean PANSS change of −29.5 (improvement), with a difference in change from baseline to Week 6 in PANSS total score between brexpiprazole and placebo of −13.5 [95% CI (−23.1, −4.0), p = 0.0057], and those who did not had an LS mean change of −18.9 and a difference between brexpiprazole and placebo of −2.9 [95% CI (−7.2, 1.4), p = 0.1809].Conclusion:Pre-specified sensitivity analyses showed separation from placebo for brexpiprazole at Week 6. A post hoc analysis suggested a potential confounding of efficacy rating towards symptom improvement in patients who experience known side effects of quetiapine XR.

scholarly journals Efficacy of galcanezumab in patients with migraine who did not benefit from commonly prescribed preventive treatments

BMC Neurology ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Dulanji K. Kuruppu ◽  
Joshua Tobin ◽  
Yan Dong ◽  
Sheena K. Aurora ◽  
Laura Yunes-Medina ◽  
...  
Keyword(s):  
Repeated Measures ◽  
Migraine Headache ◽  
Mixed Model ◽  
Preventive Treatment ◽  
Response Rates ◽  
Toxin A ◽  
Double Blind ◽  
Preventive Medication ◽  
Onabotulinum Toxin A ◽  
Post Hoc

Abstract Background Galcanezumab is a calcitonin gene-related peptide (CGRP) monoclonal antibody (mAb) indicated for the preventive treatment of migraine. While galcanezumab has demonstrated efficacy in patients who did not respond to prior preventive medications in general, its efficacy in patients who did not benefit from individual, commonly prescribed preventive treatments due to inadequate efficacy or safety/tolerability remains unknown. Methods CONQUER was a 3-month, randomized, double-blind, placebo-controlled, phase 3b study that enrolled patients with episodic or chronic migraine who had 2 to 4 migraine preventive medication category failures in the past 10 years. Patients were randomly assigned 1:1 to receive placebo (N = 230) or galcanezumab 120 mg/month (240 mg loading dose; N = 232). Post hoc analyses were conducted to determine the efficacy of galcanezumab in patients who had not benefited from six of the most commonly prescribed migraine preventive medications. The mean change from baseline in monthly migraine headache days and ≥ 50 % response rates were assessed over months 1–3. Improvement in Migraine-Specific Questionnaire Role Function-Restrictive (MSQ-RFR) scores were assessed at month 3. The endpoints were estimated via mixed model with repeated measures. Results The most common treatment failures due to inadequate efficacy or safety/tolerability, which at least 20 % of patients reported trying without benefit, included topiramate, amitriptyline, propranolol, valproate or divalproex, onabotulinum toxin A, and metoprolol. Patients who had not previously benefited from these treatments had a greater mean reduction in monthly migraine headache days across months 1–3 in the galcanezumab group compared to placebo (all p < 0.01). More patients treated with galcanezumab experienced a ≥ 50 % reduction from baseline in monthly migraine headache days across months 1–3 compared to placebo (all p < 0.05). Galcanezumab-treated patients had a greater improvement in mean MSQ-RFR scores at month 3 compared to placebo (all p < 0.01). Conclusions In this population, galcanezumab was effective in reducing monthly migraine headache days, improving response rates, and enhancing quality of life in patients who had not previously benefited from topiramate, amitriptyline, propranolol, valproate or divalproex, onabotulinum toxin A, and/or metoprolol due to inadequate efficacy or safety/tolerability. Trial registration ClinicalTrials.gov NCT03559257 (CONQUER).

scholarly journals The efficacy of cariprazine in negative symptoms of schizophrenia: Post hoc analyses of PANSS individual items and PANSS-derived factors

2019 ◽  
Vol 58 ◽  
pp. 1-9 ◽  
Author(s):  
Wolfgang Fleischhacker ◽  
Silvana Galderisi ◽  
István Laszlovszky ◽  
Balázs Szatmári ◽  
Ágota Barabássy ◽  
...  
Keyword(s):  
Negative Symptom ◽  
Repeated Measures ◽  
Negative Symptoms ◽  
Social Withdrawal ◽  
Partial Agonist ◽  
Factor Models ◽  
Symptom Improvement ◽  
Symptom Dimensions ◽  
Intent To Treat ◽  
Post Hoc

AbstractBackground:Negative symptoms in schizophrenia are heterogeneous and multidimensional; effective treatments are lacking. Cariprazine, a dopamine D3-preferring D3/D2 receptor partial agonist and serotonin 5-HT1A receptor partial agonist, was significantly more effective than risperidone in treating negative symptoms in a prospectively designed trial in patients with schizophrenia and persistent, predominant negative symptoms.Methods:Using post hoc analyses, we evaluated change from baseline at week 26 in individual items of the Positive and Negative Syndrome Scale (PANSS) and PANSS-derived factor models using a mixed-effects model for repeated measures (MMRM) in the intent-to-treat (ITT) population (cariprazine = 227; risperidone = 227).Results:Change from baseline was significantly different in favor of cariprazine versus risperidone on PANSS items N1-N5 (blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal, difficulty in abstract thinking) (P <.05), but not on N6 (lack of spontaneity/flow of conversation) or N7 (stereotyped thinking). On all PANSS-derived negative symptom factor models evaluated (PANSS-Factor Score for Negative Symptoms, Liemburg factors, Khan factors, Pentagonal Structure Model Negative Symptom factor), statistically significant improvement was demonstrated for cariprazine versus risperidone (P <.01). Small and similar changes in positive/depressive/EPS symptoms suggested that negative symptom improvement was not pseudospecific. Change from baseline was significantly different for cariprazine versus risperidone on PANSS-based factors evaluating other relevant symptom domains (disorganized thoughts, prosocial function, cognition; P <.05).Conclusions:Since items representing different negative symptom dimensions may represent different fundamental pathophysiological mechanisms, significant improvement versus risperidone on most PANSS Negative Subscale items and across all PANSS-derived factors suggests broad-spectrum efficacy for cariprazine in treating negative symptoms of schizophrenia.

Inhalative Antibiotika-Behandlung von Patienten mit chronischer Pseudomonas-aeruginosa-Infektion

2019 ◽  
Vol 7 (4) ◽  
pp. 196-197
Author(s):  
Peter Haidl
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Repeated Measures ◽  
Linear Trend ◽  
Bacterial Load ◽  
Drug Concentrations ◽  
Inhaled Antibiotics ◽  
Bronchial Infection ◽  
Inhalative Antibiotika ◽  
Respiratory Conditions ◽  
Gram Positive Cocci

Background: Inhaled antibiotics allow the delivery of higher drug concentrations at the site of infection without the systemic adverse effects observed with the use of parenteral or oral antibiotics. These antibiotics have shown to decrease the number of exacerbations, reduce bacterial load or improve pulmonary function in several chronic respiratory conditions. Objectives: The aim of this study was to describe changes in the bacteriology of sputum in patients with chronic bronchial infection with Pseudomonas aeruginosa treated with nebulized colistin. Material and Methods: All patients with chronical infection with P. aeruginosa treated with nebulised colistin attending a day care unit during a 5-year (January 2010 to December 2014) period were included. Repeated-measures t tests were used to assess whether the introduction of colistin was associated with changes in the number of exacerbations or the length of the hospitalisations. Results: Treatment with colistin was associated with a decrease in the number of ambulatory exacerbations (1.87-1.1, p = 0.007), of hospital exacerbations (1.3-0.7, p = 0.010) and of length of stay (15.7-8.6 days, p = 0.005). There was no linear trend in the proportion of isolate Enterobacteriaceae, gram-positive cocci, Haemophilus influenzae or fungi. Isolation of Enterobacteriaceae within 1 year after the beginning of the treatment with nebulized colistin was associated with an increase in the number of ambulatory exacerbations (incidence rate ratio 1.99, 95% CI 1.05-3.79). Conclusions: Nebulised colistin was effective in the treatment of chronic infection with P. aeruginosa, and no significant changes in the microbiological evolution were observed. Isolation of Enterobacteriaceae within 1 year after the beginning of the treatment with nebulised colistin was associated with an increase in the number of exacerbations.

Long-Term Antibiotics in Bronchiectasis

2021 ◽  
Vol 42 (04) ◽  
pp. 606-615
Author(s):  
Guillermo Suarez-Cuartin ◽  
Marta Hernandez-Argudo ◽  
Lidia Perea ◽  
Oriol Sibila
Keyword(s):  
Quality Of Life ◽  
Bacterial Resistance ◽  
Bacterial Load ◽  
Significant Proportion ◽  
Exacerbation Rate ◽  
Inhaled Antibiotics ◽  
Post Hoc ◽  
The Impact

AbstractA significant proportion of bronchiectasis patients are chronically infected by potentially pathogenic microorganisms which may lead to frequent exacerbations and worse clinical outcomes. Current bronchiectasis guidelines recommend long-term inhaled antibiotics and/or oral macrolides as a part of patient management. In recent years, an increasing amount of evidence assessing the impact of these treatments on patient outcomes has been collected. Inhaled antibiotics have demonstrated significant improvements in sputum bacterial load, but their impact on patient quality of life, lung function, and exacerbation rate has not been consistent across trials. In this regard, recent post hoc analyses of inhaled antibiotics trials in bronchiectasis patients have shown that sputum bacterial load may be a key biomarker to predict treatment response in these patients. Oral macrolides, on the other hand, have proven to reduce exacerbation frequency and improve quality of life, but potential drug-related adverse effects and the increase in bacterial resistance are relevant. This review aims to summarize current important evidence for long-term antibiotic treatment in bronchiectasis patients.

scholarly journals Utility of the Actiheart Accelerometer for Estimating Exercise Energy Expenditure in Female Adolescent Runners

2010 ◽  
Vol 20 (6) ◽  
pp. 487-495 ◽  
Author(s):  
Jeanne F. Nichols ◽  
Hilary Aralis ◽  
Sonia Garcia Merino ◽  
Michelle T. Barrack ◽  
Lindsay Stalker-Fader ◽  
...  
Keyword(s):  
Heart Rate ◽  
Energy Expenditure ◽  
Repeated Measures ◽  
Mixed Model ◽  
Linear Mixed Model ◽  
Young Female ◽  
Female Adolescent ◽  
Treadmill Running ◽  
Exercise Energy Expenditure ◽  
Post Hoc

There is a growing need to accurately assess exercise energy expenditure (EEE) in athletic populations that may be at risk for health disorders because of an imbalance between energy intake and energy expenditure. The Actiheart combines heart rate and uniaxial accelerometry to estimate energy expenditure above rest. The authors’ purpose was to determine the utility of the Actiheart for predicting EEE in female adolescent runners (N = 39, age 15.7 ± 1.1 yr). EEE was measured by indirect calorimetry and predicted by the Actiheart during three 8-min stages of treadmill running at individualized velocities corresponding to each runner’s training, including recovery, tempo, and 5-km-race pace. Repeated-measures ANOVA with Bonferroni post hoc comparisons across the 3 running stages indicated that the Actiheart was sensitive to changes in intensity (p < .01), but accelerometer output tended to plateau at race pace. Pairwise comparisons of the mean difference between Actiheart- and criterion-measured EEE yielded values of 0.0436, 0.0539, and 0.0753 kcal · kg−1 · min−1 during recovery, tempo, and race pace, respectively (p < .0001). Bland–Altman plots indicated that the Actiheart consistently underestimated EEE except in 1 runner’s recovery bout. A linear mixed-model regression analysis with height as a covariate provided an improved EEE prediction model, with the overall standard error of the estimate for the 3 speeds reduced to 0.0101 kcal · kg−1 · min−1. Using the manufacturer’s equation that combines heart rate and uniaxial motion, the Actiheart may have limited use in accurately assessing EEE, and therefore energy availability, in young, female competitive runners.

scholarly journals The Linearized Disposition Index Augments Understanding of Treatment Effects in Diabetes

2020 ◽  
Author(s):  
Amanda J Kile ◽  
Clarissa Hanna ◽  
Tamara S Hannon ◽  
Marian Sue Kirkman ◽  
Robert V Considine ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Repeated Measures ◽  
Treatment Effects ◽  
Mixed Model ◽  
Disposition Index ◽  
Coupling Relationship ◽  
Novel Approach ◽  
Induced Changes ◽  
Relationship Of

The Disposition Index, calculated by multiplying measures of insulin secretion and insulin sensitivity, is widely applied as a sensitivity-adjusted measure of insulin secretion. We have recently shown that linearizing the underlying relationship uniquely permits identification of terms relating to maximal insulin secretion capacity and the secretion-coupling relationship, with both terms separately contributing to differences in the secretion-sensitivity relationship across gradations of glycemia. Here we demonstrate the application of this linearized equation to the evaluation of treatment-induced changes in the insulin secretion-sensitivity relationship. We applied a combination of repeated measures multivariable linear regression (evaluating treatment-induced changes in the joint relationship of insulin sensitivity and secretion) plus mixed model repeated measures (evaluating treatment effects on maximal secretion capacity and on the secretion-sensitivity coupling slope), and compared against a usual application of the disposition index calculated from the same measurements. This novel approach allows a more informative description of treatment-induced changes compared to the usual disposition index, including isolating the source of change within the mutually adjusted relationship, and identifying treatment-induced changes in the secretion-sensitivity coupling slope and in maximal insulin secretion. Application of this linearized approach provides an expanded understanding of treatment-induced changes in the insulin sensitivity-secretion relationship.

scholarly journals Sustained, Multifaceted Improvements in Mental Well-Being Following Psychedelic Experiences in a Prospective Opportunity Sample

2021 ◽  
Vol 12 ◽  
Author(s):  
Keri Mans ◽  
Hannes Kettner ◽  
David Erritzoe ◽  
Eline C. H. M. Haijen ◽  
Mendel Kaelen ◽  
...  
Keyword(s):  
Repeated Measures ◽  
Mixed Model ◽  
Positive Impact ◽  
Well Being ◽  
Policy Implications ◽  
Attrition Rates ◽  
Before And After ◽  
Post Hoc ◽  
Prior Intention ◽  
Mental Well Being

In the last 15 years, psychedelic substances, such as LSD and psilocybin, have regained legitimacy in clinical research. In the general population as well as across various psychiatric populations, mental well-being has been found to significantly improve after a psychedelic experience. Mental well-being has large socioeconomic relevance, but it is a complex, multifaceted construct. In this naturalistic observational study, a comprehensive approach was taken to assessing well-being before and after a taking a psychedelic compound to induce a “psychedelic experience.” Fourteen measures of well-being related constructs were included in order to examine the breadth and specificity of change in well-being. This change was then analysed to examine clusters of measures changing together. Survey data was collected from volunteers that intended to take a psychedelic. Four key time points were analysed: 1 week before and 2 weeks, 4 weeks, and 2 years after the experience (N = 654, N = 315, N = 212, and N = 64, respectively). Change on the included measures was found to cluster into three factors which we labelled: 1) “Being well”, 2) “Staying well,” and 3) “Spirituality.” Repeated Measures Multivariate Analysis of Variance revealed all but the spirituality factor to be improved in the weeks following the psychedelic experience. Additional Mixed model analyses revealed selective increases in Being Well and Staying Well (but not Spirituality) that remained statistically significant up to 2 years post-experience, albeit with high attrition rates. Post-hoc examination suggested that attrition was not due to differential acute experiences or mental-health changes in those who dropped out vs. those who did not. These findings suggest that psychedelics can have a broad, robust and sustained positive impact on mental well-being in those that have a prior intention to use a psychedelic compound. Public policy implications are discussed.

A randomized control study on the effects of prescriptive exercise on lean mass and fatigue in breast cancer patients undergoing treatment

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 19560-19560
Author(s):  
C. Battaglini ◽  
C. A. Dennehy
Keyword(s):  
Lean Mass ◽  
Repeated Measures ◽  
Mixed Model ◽  
Caloric Intake ◽  
Breast Cancer Patients ◽  
Significant Interaction Effect ◽  
Post Surgery ◽  
Significant Difference ◽  
Post Hoc ◽  
And Control

19560 Background: Loss of lean mass during cancer treatment has been correlated with increases in fatigue (F) levels. Exercise is related to decreases treatment related fatigue and has been shown to thwart muscle loss. Methods: Twenty female subjects, ages ranging from 35 to 70 years, were recruited for the 21 week study. A randomized two-group (exercise and control) design with multiple measurements [Pre-surgery (PS), Post-surgery (POS), 1st assessment during Chemotherapy (Chemo1), 2nd assessment (Chemo 2), 3rd assessment (Chemo 3), and at the end of the experiment (FA)] was used. Percent of lean body mass (%LBM) and F levels were measured as dependent variables. Also, creatine kinase (CK) and total caloric intake (TCI) were measured to explain changes in %LBM and F. Data were analyzed using a two-way mixed model ANOVA with repeated-measures. Results: No significant difference in %LBM from PS to FA (p = 0.82) was observed. However, a significant interaction effect between groups and %LBM from PS to FA was observed (p<0.000). Post hoc analyses revealed significant difference in %LBM between groups at the FA (p = 0.004). Significant differences in F scores were observed between PS and FA (p=0.008). Post hoc analyses revealed significant difference in F scores between groups at Chemo 1, (p=0.001), Chemo 2, (p=0.005), and FA (p=0.000). No differences in CK were noted, however significant differences were noted between groups at PS (p=0.000) and FA (p=0.000) for TCI. Conclusions: The results suggest that initiating a regular individualized prescriptive exercise immediately following surgical recovery and continuing through at least 12 weeks during chemotherapy treatment positively impacts %LBM and deceases F when compared to patients not involved in any exercise. No significant financial relationships to disclose.

scholarly journals Inhaled aztreonam improves symptoms of cough and sputum production in patients with bronchiectasis: a post hoc analysis of the AIR-BX studies

2020 ◽  
Vol 56 (1) ◽  
pp. 2000608
Author(s):  
Megan L. Crichton ◽  
Mike Lonergan ◽  
Alan F. Barker ◽  
Oriol Sibila ◽  
Pieter Goeminne ◽  
...  
Keyword(s):  
Linear Models ◽  
Response To Treatment ◽  
Symptom Scale ◽  
Trial Duration ◽  
Patient Response ◽  
Improve Symptom ◽  
Sputum Production ◽  
Inhaled Antibiotics ◽  
Post Hoc ◽  
Specific Symptoms

IntroductionInhaled antibiotics may improve symptom scores, but it is not known which specific symptoms improve with therapy. Item-level analysis of questionnaire data may allow us to identify which specific symptoms respond best to treatment.MethodsPost hoc analysis of the AIR-BX1 studies and two trials of inhaled aztreonam versus placebo in bronchiectasis. Individual items from the quality of life bronchiectasis (QOL-B) respiratory symptom scale, were extracted as representing severity of nine distinct symptoms. Generalised linear models were used to evaluate changes in symptoms with treatment versus placebo from baseline to end of first on-treatment cycle and mixed models were used to evaluate changes across the full 16-week trial.ResultsAztreonam improved cough (difference 0.22, 95% CI 0.08–0.37; p=0.002), sputum production (0.30, 95% CI 0.15–0.44; p<0.0001) and sputum colour (0.29, 95% CI 0.15–0.43; p<0.0001) versus placebo equating to a 20% improvement in cough and 25% improvement in sputum production and colour. Similar results were observed for cough, sputum production and sputum purulence across the trial duration (all p<0.05). Patients with higher sputum production and sputum colour scores had a greater response on the overall QOL-B (difference 4.82, 95% CI 1.12–8.53; p=0.011 for sputum production and 5.02, 95% CI 1.19–8.86; p=0.01 for sputum colour). In contrast, treating patients who had lower levels of bronchitic symptoms resulted in shorter time to next exacerbation (hazard ratio 1.83, 95% CI 1.02–3.28; p=0.042).ConclusionBaseline bronchitic symptoms predict response to inhaled aztreonam in bronchiectasis. More sensitive tools to measure bronchitic symptoms may be useful to better identify inhaled antibiotic responders and to evaluate patient response to treatment.

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