Mixed-effects Model Repeated Measures Analysis Research Articles

The effectiveness of mindfulness-based cognitive therapy during poststroke rehabilitation: a randomized controlled trial.

Stroke can have a range of physical, psychological, cognitive, and social impacts that are challenging for survivors. This study aimed to evaluate the efficacy of a group-based mindfulness intervention integrated into an inpatient rehabilitation program compared to standard care. A single-center, randomized, controlled trial was conducted in 93 poststroke patients. The intervention group received 6-weeks of mindfulness-based cognitive therapy (MBCT) and standard care; the control group received standard care. Primary outcomes were depression and trait anxiety; secondary outcomes were trait mindfulness and attention. Participants completed questionnaires at baseline, and postintervention (6 weeks). Mixed-effect model repeated measures analysis of variance was conducted between groups and across time. A total of 80 participants (intervention n = 43; standard care n = 37) were included in the postintervention analysis. There were no statistically significant differences in the primary outcomes between the groups over time. An improvement was found, however, on the trait mindfulness observing subscale in favor of the intervention group. Eight sessions of MBCT integrated into an inpatient stroke rehabilitation program over 6 weeks was not effective in improving depression and anxiety compared to standard care. Lack of follow-up and low to moderate pathological symptoms at baseline may have limited the effectiveness of this intervention.

Randomized Placebo-Controlled Trial of Reloxaliase in Enteric Hyperoxaluria

BackgroundEnteric hyperoxaluria is caused by increased intestinal oxalate absorption and can lead to kidney stones, chronic kidney disease, and kidney failure. Reloxaliase is an orally administered recombinant enzyme that degrades oxalate along the gastrointestinal tract, thereby preventing its absorption.MethodsWe randomly assigned participants with enteric hyperoxaluria to reloxaliase or placebo, three to five times per day with food for 4 weeks. The primary end point was percent change from baseline in 24-hour urinary oxalate (UOx) excretion during weeks 1 to 4. Secondary end points included the proportion of participants with more than a 20% reduction in 24-hour UOx and an efficacy assessment in the bariatric surgery subgroup.ResultsA total of 115 patients underwent randomization. The 24-hour UOx decreased from a baseline geometric mean of 83.2 to 67.4 mg/24 hr during weeks 1 to 4 in reloxaliase-treated participants. Corresponding data for placebo-treated participants were 84.2 to 78.1 mg/24 hr. Estimates from the mixed-effect model repeated-measures (MMRM) analysis showed a 22.6% reduction in geometric mean UOx during weeks 1 to 4 for reloxaliase and 9.7% for placebo, a difference of 14.3 percentage points (95% confidence interval [CI], 4.9 to 22.8; P=0.004). A 20% or greater reduction in 24-hour UOx was observed in 48.3% of reloxaliase-treated participants and 31.6% of placebo-treated participants (P=0.06). In the bariatric surgery subgroup, MMRM analysis showed a 21.2% reduction in geometric mean UOx for reloxaliase and a 6.0% reduction for placebo, for a difference of 16.2 percentage points (95% CI, 4.2% to 26.7%). Adverse events occurred in 69% of reloxaliase-treated participants versus 53% of individuals taking placebo and were most commonly gastrointestinal. All but one of the adverse events were grade 1 or 2 in severity; no reloxaliase-treated participants discontinued the study.ConclusionsReloxaliase treatment for 4 weeks reduced UOx excretion in patients with enteric hyperoxaluria; adverse events were relatively common, but not dose-limiting. These data establish the foundation for a clinical trial to determine the impact of reloxaliase on nephrolithiasis in patients with enteric hyperoxaluria. (Funded by Allena Pharmaceuticals; ClinicalTrials.gov number, NCT03456830.)

Effects of episodic future thinking on reinforcement pathology during smoking cessation treatment among individuals with substance use disorders

RationaleReinforcer pathology (RP) is a theoretical model based on two processes: delay discounting (DD) and drug demand. Given that RP has been shown to have a predictive value on smoking behaviors, several studies have explored which interventions can reduce RP. Consistent with the RP framework, episodic future thinking (EFT) has shown effects on treatment outcomes and RP processes. The vast majority of studies that assess the effects of EFT on RP consist of experimental studies, and no previous research has tested these effects in a clinical sample of smokers.ObjectivesThe primary aim of this study was to assess the effects of EFT on RP throughout the course of a smoking cessation intervention in smokers with substance use disorders (SUDs).MethodsParticipants were randomized to cognitive behavior therapy (CBT) + EFT (n = 39) or CBT + EFT + contingency management (n = 33). Cotinine, frequency of EFT practices, cigarette purchase task (CPT), and DD were evaluated in treatment sessions. Mixed-effects model repeated measures analysis was used to explore DD and CPT in-treatment changes as a function of EFT practices and cotinine levels.ResultsGreater practice of the EFT component significantly reduced cigarette demand (p < .020) as well as DD (p = .003). Additionally, a greater reduction in cotinine levels coupled with greater EFT practice led to a greater decrease in cigarette demand (p < .014).ConclusionsEFT reduced the two facets of RP in treatment-seeking smokers with SUDs.

Potentially Inappropriate Medication Prescribing Detected by Computer Algorithm among Older Patients: Results from the MAPT Study.

(1) Background: Some medications may be dangerous for older patients. Potentially inappropriate medication prescribing (PIP) among older patients represents a significant cause of morbidity. The aim of this study was to create an algorithm to detect PIP in a geriatric database (Multidomain Alzheimer Preventive Trial (MAPT) study), and then to assess the algorithm construct validity by comparing the prevalence of PIP and associated factors with literature data. (2) Methods: An algorithm was constructed to detect PIP and was based on different explicit criteria among which the European list of potentially inappropriate medications (EU(7)-PIM), the STOPP and START version 2 tools. For construct validity assessment, logistic mixed-effects model repeated measures analyses were used to identify factors associated with PIP. (3) Results: Prevalence of PIP was 59.0% with the EU(7)-PIM list criteria, 43.2% with the STOPP criteria and 51.3% with the START criteria. Age, polypharmacy, and higher Charlson comorbidity index were associated with PIP. (4) Conclusions: Prevalence of PIP and associated factors are consistent with literature data, supporting the construct validity of our algorithm. This algorithm opens up interesting perspectives both in terms of analysis of very large databases and integration into e-prescribing or pharmaceutical validation software.

Perceptions of appetite do not match hormonal measures of appetite in trained competitive cyclists and triathletes following a ketogenic diet compared to a high-carbohydrate or habitual diet: A randomized crossover trial

Endurance athletes may implement rigid dietary strategies, such as the ketogenic diet (KD), to improve performance. The effect of the KD on appetite remains unclear in endurance athletes. This study analyzed the effects of a KD, a high-carbohydrate diet (HCD), and habitual diet (HD) on objective and subjective measures of appetite in trained cyclists and triathletes, and hypothesized that the KD would result in greater objective and subjective appetite suppression. Six participants consumed the KD and HCD for 2-weeks each, in a random order, following their HD. Fasting appetite measures were collected after 2-weeks on each diet. Postprandial appetite measures were collected following consumption of a ketogenic meal after the KD, high-carbohydrate meal after the HCD, and standard American/Western meal after the HD. Fasting total ghrelin (GHR) was lower and glucagon-like peptide-1 (GLP-1) and hunger were higher following the KD versus HD and HCD. Fasting insulin was not different. Mixed-effects model repeated measures analysis and effect sizes and 95% confidence intervals showed that postprandial GHR and insulin were lower and GLP-1 was higher following the ketogenic versus the standard and high-carbohydrate meals. Postprandial appetite ratings were not different across test meals. In conclusion, both fasting and postprandial concentrations of GHR were lower and GLP-1 were higher following the KD than the HC and HD, and postprandial insulin was lower on the KD. Subjective ratings of appetite did not correspond with the objective measures of appetite in trained competitive endurance athlete. More research is needed to confirm our findings.

P187 Secukinumab significantly decreased joint synovitis measured by Power Doppler ultrasonography in biologic-naive patients with active psoriatic arthritis: primary (12week) results from a randomised, placebo-controlled Phase 3 study

P187 Secukinumab significantly decreased joint synovitis measured by Power Doppler ultrasonography in biologic-naive patients with active psoriatic arthritis: primary (12week) results from a randomised, placebo-controlled Phase 3 study

The Antidiabetic Metformin as an Adjunct to Antidepressants in Patients with Major Depressive Disorder: A Proof-of-Concept, Randomized, Double-Blind, Placebo-Controlled Trial.

Metformin (MET) has been reported to have antidepressant effects in animal models and in diabetic patients with depression, owing to its anti-inflammatory, antioxidant, and neuroprotective activity. Accordingly, we proposed that MET would show antidepressant effects in patients with major depressive disorder (MDD) without other comorbidities. In this double-blind placebo-controlled study, 80 adult outpatients with MDD (DSM-IV criteria) and a Hamilton Depression Rating Scale (HAM-D) score >18 were randomized to receive fluoxetine 20 mg once daily plus placebo (n = 40) or fluoxetine 20 mg once daily plus MET 1000 mg once daily for 12 weeks. Patients were assessed by HAM-D score (weeks 0, 4, 8, and 12). The serum levels of TNF-α, IL-1β, IL-6, IGF-1, MDA, CRP, BDNF, and serotonin were measured before and after therapy. Mixed-effects model repeated-measures analysis of covariance was used to compare the HAM-D scores and the biological markers between the two groups. After 4, 8 and 12 weeks, patients in the MET group showed a statistically significant decline in HAM-D score relative to the placebo group (least squares mean difference [LSMD] -2.347, p = 0.000, LSMD -3.369, p = 0.000, and LSMD -3.454, p = 0.000, respectively). Response and remission rates were significantly higher in the MET group (89% and 81%, respectively) than in the placebo group (59% and 46%, respectively). Moreover, the MET group was superior in conserving the measured biological markers compared with the placebo group. Our findings suggest MET as a promising, effective, and safe short-term adjunctive approach in nondiabetic MDD patients. Trial registration ID: NCT04088448.

PD16-08 EFFECT OF CABAZITAXEL VS ABIRATERONE OR ENZALUTAMIDE ON PATIENT-REPORTED OUTCOMES IN METASTATIC CASTRATION-RESISTANT PROSTATE CANCER: A PRE-PLANNED EQ-5D-5L ANALYSIS OF THE CARD STUDY

You have accessJournal of UrologyProstate Cancer: Advanced (including Drug Therapy) II (PD16)1 Apr 2020PD16-08 EFFECT OF CABAZITAXEL VS ABIRATERONE OR ENZALUTAMIDE ON PATIENT-REPORTED OUTCOMES IN METASTATIC CASTRATION-RESISTANT PROSTATE CANCER: A PRE-PLANNED EQ-5D-5L ANALYSIS OF THE CARD STUDY Gero Kramer*, Cora N. Sternberg, Karim Fizazi, Bertrand Tombal, Jean-Christophe Eymard, Johann De Bono, Daniel Castellano, Christian Wülfing, Michail Liontos, Joan Carles, Roberto Iacovelli, Bohuslav Melichar, Ásgerður Sverrisdóttir, Christine Theodore, Susan Feyerabend, Carole Helissey, Ayse Ozatilgan, Christine Geffriaud-Ricouard, and Ronald de Wit Gero Kramer*Gero Kramer* More articles by this author , Cora N. SternbergCora N. Sternberg More articles by this author , Karim FizaziKarim Fizazi More articles by this author , Bertrand TombalBertrand Tombal More articles by this author , Jean-Christophe EymardJean-Christophe Eymard More articles by this author , Johann De BonoJohann De Bono More articles by this author , Daniel CastellanoDaniel Castellano More articles by this author , Christian WülfingChristian Wülfing More articles by this author , Michail LiontosMichail Liontos More articles by this author , Joan CarlesJoan Carles More articles by this author , Roberto IacovelliRoberto Iacovelli More articles by this author , Bohuslav MelicharBohuslav Melichar More articles by this author , Ásgerður SverrisdóttirÁsgerður Sverrisdóttir More articles by this author , Christine TheodoreChristine Theodore More articles by this author , Susan FeyerabendSusan Feyerabend More articles by this author , Carole HelisseyCarole Helissey More articles by this author , Ayse OzatilganAyse Ozatilgan More articles by this author , Christine Geffriaud-RicouardChristine Geffriaud-Ricouard More articles by this author , and Ronald de WitRonald de Wit More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000859.08AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The results of the CARD (NCT02485691) study demonstrated superiority of cabazitaxel (CBZ) vs abiraterone or enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) who had progressed on docetaxel and within 12 months on a prior alternative androgen-signaling-targeted inhibitor (ARTA). This pre-planned analysis evaluated changes in EQ-5D-5L score following treatment with CBZ or ARTA. METHODS: Patient-reported outcomes (PROs) were evaluated using the EQ-5D-5L utility index and visual analogue scale (VAS). Scores were evaluated at baseline, on Day 1 of each cycle and at the end of treatment (EOT) visit. Patients were evaluable if they had received at least one dose of CBZ or ARTA and had an EQ-5D-5L assessment at baseline and at least one subsequent assessment. A mixed-effect model repeated measures analysis of EQ-5D-5L changes from baseline was performed. RESULTS: Of the 255 patients randomized, 230 were evaluable for EQ-5D-5L, with 115 (89.1%) for CBZ and 115 (91.3%) for ARTA. At baseline, both groups had comparable mean values for utility index (0.70 for both) and VAS (65.8 vs 66.3 for CBZ vs ARTA, respectively). Changes in VAS and utility index scores from baseline during treatment and EOT favored CBZ vs ARTA. The least squares mean difference for CBZ vs ARTA ranged 1.6 to 6.4 (5.9 at EOT) for VAS and from 0.03 to 0.08 and (0.05 at EOT) for utility index. At baseline, moderate-to-severe or extreme pain/discomfort, evaluated by EQ-5D-5L, was reported by 45 (39.1%) for CBZ and 47 (40.9%) for ARTA, respectively. CBZ was associated with a greater proportion of patients reporting pain/discomfort improvement from baseline (figure). Similar trends were seen across all EQ-5D-5L subscales. CONCLUSIONS: CBZ showed a greater improvement in PROs measured by EQ-5D-5L vs abiraterone or enzalutamide in patients previously treated with docetaxel and the alternative ARTA. Source of Funding: Sanofi © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e366-e366 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Gero Kramer* More articles by this author Cora N. Sternberg More articles by this author Karim Fizazi More articles by this author Bertrand Tombal More articles by this author Jean-Christophe Eymard More articles by this author Johann De Bono More articles by this author Daniel Castellano More articles by this author Christian Wülfing More articles by this author Michail Liontos More articles by this author Joan Carles More articles by this author Roberto Iacovelli More articles by this author Bohuslav Melichar More articles by this author Ásgerður Sverrisdóttir More articles by this author Christine Theodore More articles by this author Susan Feyerabend More articles by this author Carole Helissey More articles by this author Ayse Ozatilgan More articles by this author Christine Geffriaud-Ricouard More articles by this author Ronald de Wit More articles by this author Expand All Advertisement PDF downloadLoading ...

A psychosocial intervention for stroke survivors and carers: 12–month outcomes of a randomized controlled trial

ABSTRACT Background and Purpose: Stroke can have a devastating impact on the mental and physical health of stroke survivors and their carers. We aimed to evaluate the effectiveness of a novel psychosocial intervention designed to improve health outcomes in both groups. Methods: We conducted a randomized controlled trial of a personalized psychosocial intervention (eight 1-hour weekly sessions plus one booster) compared to usual care for adult stroke survivors and carers. Participants recruited from hospital services and community referrals completed questionnaires at baseline, 3, 6, and 12 months. Primary outcomes were quality of life and self-efficacy; secondary outcomes were depressive and anxiety symptoms, coping, illness perception, work and social adjustment, carer strain, and carer satisfaction. Mixed-effect model repeated measures analysis between groups and across time was conducted. Results: Of the 173 participants recruited (89 stroke survivors; 84 carers), a total of 137 participants – 73 stroke survivors (intervention n = 42; usual care n = 31) and 64 carers (intervention n = 35; usual care n = 29) – underwent analysis up to 12 months. No statistically significant differences were found in the primary outcomes between groups over time, though a significant improvement in carer satisfaction was found at 6 months in the intervention group compared to the usual care group. Conclusion: A personalized psychosocial intervention resulted in a significant improvement in carer satisfaction at 6 months but in no other outcomes. A lack of available services and barriers to social engagement may have impeded the effectiveness of this intervention.

Evaluation of non-linear-mixed-effect modeling to reduce the sample sizes of pediatric trials in type 2 diabetes mellitus.

Recruitment for pediatric trials in Type II Diabetes Mellitus (T2DM) is very challenging, necessitating the exploration of new approaches for reducing the sample sizes of pediatric trials. This work aimed at assessing if a longitudinal Non-Linear-Mixed-Effect (NLME) analysis of T2DM trial could be more powerful and thus require fewer patients than two standard statistical analyses commonly used as primary or sensitivity efficacy analysis: Last-Observation-Carried-Forward (LOCF) followed by (co)variance (AN(C)OVA) analysis at the evaluation time-point, and Mixed-effects Model Repeated Measures (MMRM) analysis. Standard T2DM efficacy studies were simulated, with glycated hemoglobin (HbA1c) as the main endpoint, 24weeks' study duration, 2 arms, assuming a placebo and a treatment effect, exploring three different scenarios for the evolution of HbA1c, and accounting for a dropout phenomenon. 1000 trials were simulated, then analyzed using the 3 analyses, whose powers were compared. As expected, the longitudinal modeling MMRM analysis was found to be more powerful than the LOCF + ANOVA analysis at week 24. The NLME analysis gave slightly more accurate drug-effect estimations than the two other methods, however it tended to slightly overestimate the magnitude of the drug effect, and it was more powerful than the MMRM analysis only in some scenarios of slow HbA1c decrease. The gain in power afforded by NLME was more apparent when two additional assessments enriched the design; however, the gain was not systematic for all scenarios. Finally, this work showed that NLME analyses may help to reduce significantly the required sample sizes in T2DM pediatric studies, but only for enriched designs and slow HbA1c decrease.

Spinal cord collateral flow during antegrade cerebral perfusion for aortic arch surgery

ObjectiveWe aimed to monitor regional oxygen saturation levels using near-infrared spectroscopy in patients undergoing total aortic arch replacement and to determine the range of collateral flow via antegrade cerebral perfusion to the spinal cord during lower body circulatory arrest. MethodsEighteen consecutive patients undergoing total aortic arch replacement in our hospital were prospectively enrolled. Optodes of near-infrared spectroscopy were attached to the skin at the right and left forehead, and above the paravertebral muscles at the level of the third (T3) and tenth (T10) thoracic vertebra. Within- and between-group differences were compared using mixed-effect model repeated-measures analysis. ResultsRegional oxygen saturation levels, which had been rapidly declining immediately after circulatory arrest at a tympanic temperature of <25°C and a core temperature of <30°C, showed a rapid increase at the forehead with the initiation of antegrade cerebral perfusion (total flow rate 0.81 ± 0.08 L/min, perfusion pressure 37 ± 6 mm Hg, temperature 25°C). Saturation levels remained only partially elevated at the upper thoracic level (T3) and continued to decline without showing signs of recovery at the lower thoracic level (T10). ConclusionsAntegrade cerebral perfusion partially perfused the upper thoracic cord via collateral circulation from vertebral arteries through an anterior spinal artery, but it did not reach the lower thoracic cord sufficiently to change the oxygenation level. Cooling is a more important means of protection for the lower spinal cord during lower body circulatory arrest than is antegrade cerebral perfusion.

Left Atrial Electromechanical Remodeling Following 2 Years of High-Intensity Exercise Training in Sedentary Middle-Aged Adults.

Moderate intensity exercise is associated with a decreased incidence of atrial fibrillation. However, extensive training in competitive athletes is associated with an increased atrial fibrillation risk. We evaluated the effects of 24 months of high intensity exercise training on left atrial (LA) mechanical and electric remodeling in sedentary, healthy middle-aged adults. Sixty-one participants (53±5 years) were randomized to 10 months of exercise training followed by 14 months of maintenance exercise or stretching/balance control. Fourteen Masters athletes were added for comparison. Left ventricular (LV) and LA volumes underwent 3D echocardiographic assessment, and signal-averaged electrocardiographs for filtered P-wave duration and atrial late potentials were completed at 0, 10, and 24 months. Extended ambulatory monitoring was performed at 0 and 24 months. Within and between group differences from baseline were compared using mixed-effects model repeated-measures analysis. Fifty-three participants completed the study (25 control, 28 exercise) with 88±11% adherence to assigned exercise sessions. In the exercise group, both LA and LV end diastolic volumes increased proportionately (19% and 17%, respectively) after 10 months of training (peak training load). However, only LA volumes continued to increase with an additional 14 months of exercise training (LA volumes 55%; LV end diastolic volumes 15% at 24 months versus baseline; P<0.0001 for all). The LA:LV end diastolic volumes ratio did not change from baseline to 10 months, but increased 31% from baseline in the Ex group ( P<0.0001) at 24 months, without a change in controls. There were no between group differences in the LA ejection fraction, filtered P-wave duration, atrial late potentials, and premature atrial contraction burden at 24 months and no atrial fibrillation was detected. Compared with Masters athletes, the exercise group demonstrated lower absolute LA and LV volumes, but had a similar LA:LV ratio after 24 months of training. Twenty-four months of high intensity exercise training resulted in LA greater than LV mechanical remodeling with no observed electric remodeling. Together, these data suggest different thresholds for electrophysiological and mechanical changes may exist in response to exercise training, and provide evidence supporting a potential mechanism by which high intensity exercise training leads to atrial fibrillation. URL: https://www.clinicaltrials.gov . Unique identifier: NCT02039154.

Mild Behavioral Impairment as a Marker of Cognitive Decline in Cognitively Normal Older Adults

Mild behavioral impairment (MBI) is a neurobehavioral syndrome characterized by later life emergent neuropsychiatric symptoms (NPS) that represent an at-risk state for incident cognitive decline and dementia in people with mild cognitive impairment (MCI). We undertook a study to determine whether MBI was associated with progressive changes in neuropsychological performance in people without significant cognitive impairment. A total of 9,931 older adults enrolled in the PROTECT study who did not have MCI or dementia undertook a comprehensive neuropsychological battery measuring attention, reasoning, executive function, and working memory at baseline and 1 year. MBI was ascertained using self-administration of the Mild Behavioral Impairment Checklist at 1 year, and participants were grouped according to MBI status: No Symptoms, Intermediate NPS and MBI. All assessments were completed online, and data analyzed using mixed-effects model repeated measures analysis of covariance. A total of 949 (10%) people had MBI. These individuals had significantly worse cognitive performance at baseline and significantly greater decline over 1 year in the four composite cognitive scores measuring attentional intensity (F [2,8578] = 3.97; p = 0.019), sustained attention (F [2,8578] = 18.63; p <0.0001), attentional fluctuation (F [2,8578] = 10.13; p <0.0001) and working memory (F [2,9895] = 13.1; p <0.0001). Our novel findings show that MBI is associated with faster decline in attention and working memory in this cognitively normal sample. MBI may be an earlier marker of neurodegenerative disease than MCI, captured at the stage of subjective cognitive decline or before, raising the possibility that MBI represents a novel target for dementia clinical trials or prevention strategies.

Evaluation of health-related quality of life and symptoms in patients with advanced non-squamous non-small cell lung cancer treated with nivolumab or docetaxel in CheckMate 057

BackgroundNivolumab, a programmed death-1 inhibitor, prolonged overall survival and had a favourable safety profile versus docetaxel in previously treated patients with advanced non-squamous non-small cell lung cancer (NSCLC) in the phase III CheckMate 057 trial. AimTo evaluate health-related quality of life (HRQoL) using patient-reported outcomes. MethodsDisease-related symptoms and general health status were assessed using two validated patient-reported instruments, the Lung Cancer Symptom Scale (LCSS) and the European Quality of Life Five Dimensions (EQ-5D), respectively. The proportion of patients with disease-related symptom improvement at 12 weeks on the LCSS average symptom burden index (ASBI) was a secondary end-point. LCSS 3-item global index (3-IGI), EQ-5D utility index and EQ-5D visual analogue scale (VAS) scores were also determined. Mixed-effects model repeated measures (MMRM) and time to first deterioration analyses assessed longitudinal changes. ResultsMean baseline LCSS ASBI scores were similar in both arms. By week 12, rates of disease-related improvement (95% confidence interval) were similar between nivolumab (17.8% [13.6–22.7]) and docetaxel (19.7% [15.2–24.7]); however, numerical differences in LCSS ASBI mean change from baseline favoured nivolumab. Subsequently, LCSS ASBI scores improved with nivolumab and worsened with docetaxel, with statistically significant between-arm differences at weeks 12, 24, 30 and 42. HRQoL improvements with nivolumab versus docetaxel were also supported by the LCSS 3-IGI, EQ-5D VAS and MMRM analysis. Time to first HRQoL deterioration was longer with nivolumab than with docetaxel. ConclusionNivolumab improved disease-related symptoms and overall health status versus docetaxel for second-line treatment of advanced non-squamous NSCLC. Clinical trial registrationNCT01673867.

Missing data in clinical trials: control-based mean imputation and sensitivity analysis.

In some randomized (drug versus placebo) clinical trials, the estimand of interest is the between-treatment difference in population means of a clinical endpoint that is free from the confounding effects of "rescue" medication (e.g., HbA1c change from baseline at 24weeks that would be observed without rescue medication regardless of whether or when the assigned treatment was discontinued). In such settings, a missing data problem arises if some patients prematurely discontinue from the trial or initiate rescue medication while in the trial, the latter necessitating the discarding of post-rescue data. We caution that the commonly used mixed-effects model repeated measures analysis with the embedded missing at random assumption can deliver an exaggerated estimate of the aforementioned estimand of interest. This happens, in part, due to implicit imputation of an overly optimistic mean for "dropouts" (i.e., patients with missing endpoint data of interest) in the drug arm. We propose an alternative approach in which the missing mean for the drug arm dropouts is explicitly replaced with either the estimated mean of the entire endpoint distribution under placebo (primary analysis) or a sequence of increasingly more conservative means within a tipping point framework (sensitivity analysis); patient-level imputation is not required. A supplemental "dropout=failure" analysis is considered in which a common poor outcome is imputed for all dropouts followed by a between-treatment comparison using quantile regression. All analyses address the same estimand and can adjust for baseline covariates. Three examples and simulation results are used to support our recommendations.

Quality of life in patients with advanced renal cell carcinoma given nivolumab versus everolimus in CheckMate 025: a randomised, open-label, phase 3 trial

In the phase 3 CheckMate 025 study, previously treated patients with advanced renal cell carcinoma who were randomly assigned to nivolumab had an overall survival benefit compared with those assigned to everolimus. We aimed to compare health-related quality of life (HRQoL) between treatment groups in this trial. CheckMate 025 was an open-label study done at 146 oncology centres in 24 countries. Patients were randomly assigned to treatment between Oct 22, 2012, and March 11, 2014. Patients with advanced renal cell carcinoma were randomly assigned (1:1, block size of four) to receive nivolumab every 2 weeks or everolimus once per day. The study was stopped early at the planned interim analysis in July, 2015, because the study met its primary endpoint. A protocol amendment permitted patients in the everolimus group to cross over to nivolumab treatment. All patients not on active study therapy are being followed up for survival. At the interim analysis, HRQoL was assessed with the Functional Assessment of Cancer Therapy-Kidney Symptom Index-Disease Related Symptoms (FKSI-DRS) and European Quality of Life (EuroQol)-5 Dimensions (EQ-5D) questionnaires. Prespecified endpoints were to assess, in each treatment group, disease-related symptom progression rate based on the FKSI-DRS and changes in reported global health outcomes based on the EQ-5D. Other endpoints were post hoc. We calculated the proportion of FKSI-DRS questionnaires completed using the number of patients with non-missing data at baseline and at least one post-baseline visit. We defined FKSI-DRS completion as completion of five or more of the nine items in the questionnaire; otherwise data were treated as missing. FKSI-DRS symptom index score was prorated for missing items. We made no adjustments for missing EQ-5D data. We used descriptive statistics and multivariate analyses, including mixed-effects model repeated-measures, for between group comparisons. Analyses were powered according to the original study protocol, and we analysed FKSI-DRS and EQ-5D data for all patients who underwent randomisation and had a baseline assessment and at least one post-baseline assessment. CheckMate 025 is registered with ClinicalTrials.gov, number NCT01668784. HRQoL data were collected at baseline for 362 (88%) of 410 patients in the nivolumab group and 344 (84%) of 411 patients in the everolimus group. The mean difference in FKSI-DRS scores between the nivolumab and everolimus groups was 1·6 (95% CI 1·4-1·9; p<0·0001) with descriptive statistics and 1·7 (1·2-2·1; p<0·0001) with mixed-effects model repeated-measures analysis. In terms of FKSI-DRS score, more patients had a clinically meaningful (ie, an increase of at least 2 points from baseline) HRQoL improvement with nivolumab (200 [55%] of 361 patients) versus everolimus (126 [37%] of 343 patients; p<0·0001). Median time to HRQoL improvement was shorter in patients given nivolumab (4·7 months, 95% CI 3·7-7·5) than in patients given everolimus (median not reached, NE-NE). Nivolumab was associated with HRQoL improvement compared with everolimus in previously treated patients with advanced renal cell carcinoma. Bristol-Myers Squibb.

Trial for the Prevention of Depression (TriPoD) in final-year secondary students: study protocol for a cluster randomised controlled trial.

BackgroundEvidence suggests that current treatments cannot fully alleviate the burden of disease associated with depression but that prevention approaches offer a promising opportunity to further reduce this burden. Adolescence is a critical period in the development of mental illness, and final school examinations are a significant and nearly universal stressor that may act as a trigger for mental health difficulties such as depression. The aim of the present trial is to investigate the impact of SPARX-R, an online, gamified intervention based on cognitive behavioural principles, on the prevention of depression in secondary school students before their final examinations.Methods/DesignGovernment, independent and Catholic secondary schools in New South Wales, Australia, will be recruited to participate in the trial. All students enrolled in their final year of high school (year 12) in participating schools will be invited to participate. To account for possible attrition, the target sample size was set at 1600 participants across 30 schools. Participating schools will be cluster randomised at the school level to receive either SPARX-R or lifeSTYLE, an attention-controlled placebo comparator. The control intervention is an online program aimed at maintaining a healthy lifestyle. The primary outcome will be symptoms of depression, and secondary outcomes will include symptoms of anxiety, suicidal ideation and behaviours, stigma and academic performance. Additional measures of cost-effectiveness, as well as process variables (e.g., adherence, acceptability) and potential predictors of response to treatment, will be collected. Consenting parents will be invited to complete measures regarding their own mental health and expectations for their child. Assessments will be conducted pre- and post-intervention and at 6- and 18-month follow-up. Primary analyses will compare changes in levels of depressive symptomatology for the intervention group relative to the attention control condition using mixed-effects model repeated-measures analyses to account for clustering within schools.DiscussionThis is the first trial of a universal depression prevention intervention delivered to school students in advance of a specific, significant stressor. If found to be effective, this program may offer schools a new approach to preparing students for their final year of schooling.Trial registrationAustralian New Zealand Clinical Trials Registry identifier: ACTRN12614000316606. Registered 25 March 2014.Electronic supplementary materialThe online version of this article (doi:10.1186/s13063-015-0929-1) contains supplementary material, which is available to authorized users.

Tadalafil 5 mg once daily for the treatment of Asian men with lower urinary tract symptoms secondary to benign prostatic hyperplasia: analyses of data pooled from three randomized, double-blind, placebo-controlled studies.

Assess the efficacy and safety of tadalafil 5 mg once-daily in Asian men with lower urinary tract symptoms by pooling data from three clinical studies. Data on 1199 Japanese, Korean, and Taiwanese men given tadalafil 5 mg (n = 601) or placebo (n = 598) were pooled from three double-blind, placebo-controlled, 12-week studies. Efficacy measures included International Prostate Symptom Score, and Patient and Clinician Global Impressions of Improvement. These measures were also assessed for patient subgroups (age categories, baseline disease severity and/or prostate volume, prior alpha-blocker treatment). Safety measures included adverse events, including those in selected body systems. Efficacy measure changes throughout treatment were assessed by mixed-effect model repeated-measures analysis; baseline to end-point changes for the total population and subgroups were evaluated by analysis of covariance. Tadalafil 5 mg led to significant improvement (vs placebo) in all International Prostate Symptom Scores at all time-points (week 4 P ≤ 0.013 for all measures; week 8 P ≤ 0.005, week 12 P < 0.001). End-point results for both global impressions scales also favored tadalafil (both P < 0.001 vs placebo). Tadalafil efficacy was similar between patient subgroups of varied disease severity (interaction P = 0.097), prior alpha-blocker use (P = 0.580), and prostate volume (P = 0.921). The drug was slightly less effective in older men (interaction P = 0.042). No unexpected adverse events were reported, and no meaningful adverse effects were observed in visual, auditory, or cardiovascular systems. Tadalafil 5 mg once-daily for 12 weeks is efficacious and safe in Asian men with lower urinary tract symptoms. Tadalafil is also effective in men of different ages, disease severity, prior alpha-blocker exposure, and prostate volumes.

Weight changes over time in adults treated with the oral or depot formulations of olanzapine: a pooled analysis of 86 clinical trials

Several analytical approaches were used to characterize time progression of weight changes observed in adults treated with olanzapine from a 12,425-patient database of 86 studies of oral and depot formulations of olanzapine (mean modal dose 13.3 mg/day). Descriptive mean profile plots for completer and modified completer groups showed weight increasing throughout each observed period, with apparent slowing in rate of change after 3 or 4 months. Mixed-effects model repeated measures analyses also showed that weight increased most rapidly early in treatment and slowed within 2 to 4 months. The slowing in rate of change was greatest for patients obese at baseline and least for patients underweight at baseline. This pattern was also observed in a nonparametric regression-based profile. Based on visual inspection of profile plots, 2, 3, 4, and 5 months were postulated as potential 'change points' beyond which rate of increase might slow, and the proportions of patients whose slope after each change point was ≤ 90% of the slope before change point were calculated. Over 85% of patients who gained weight showed slowing rate of weight change after each postulated change point. Potential consequences of weight gain should be considered prior to starting olanzapine. Olanzapine-treated patients should receive regular weight monitoring.

Failure to Replicate Genetic Associations with Antidepressant Treatment Response in Duloxetine-Treated Patients

Recent studies have identified associations of polymorphisms in several target genes with antidepressant treatment response of serotonin reuptake inhibitors and a tricyclic antidepressant. We sought to replicate these associations in a study of a serotonin-norepinephrine reuptake inhibitor. In 250 outpatients with nonpsychotic major depressive disorder, response to treatment with once-daily duloxetine (60 mg/day) over 6 weeks was examined for associations with polymorphisms in eight candidate genes previously associated with antidepressant response using mixed-effect model repeated-measures analysis. Treatment response was quantified on the basis of changes from baseline using 17-item Hamilton Depression Rating Scale total scores. Polymorphisms in PDE1A, PDE1C, PDE6A, PDE11A, ABCB1, GRIK4, SLC6A4, and OPRM1 genes showed no statistically significant associations (uncorrected, two-tailed p > .05) with duloxetine treatment response. Previously, described associations between polymorphisms in candidate genes and antidepressant treatment response were not replicated in this study. This result may suggest that previous associations are specific to serotonin reuptake inhibitors.