Mixed-effects Model For Repeated Measures Research Articles

Patient-reported symptoms, functioning, and quality of life (QoL) in patients treated with cemiplimab monotherapy for first-line treatment of advanced NSCLC with PD-L1 ≥ 50%: Results from EMPOWER-Lung 1 study.

9078 Background: Cemiplimab, a PD-1 inhibitor, improved survival and progression-free survival vs platinum doublet chemotherapy (chemo) in patients (pts) with advanced NSCLC and PD-ligand(L)1 expression ≥50% in the EMPOWER-Lung 1 Phase 3 study (NCT03088540). Since pts with advanced NSCLC have a high symptom burden that adversely impacts QoL and functioning, these outcomes were evaluated as secondary endpoints in the clinical trial. Methods: Pts with advanced NSCLC with PD-L1 expression ≥50% and ECOG performance status ≤1 were randomized to IV cemiplimab 350 mg Q3W (n=356) or platinum doublet chemo (n=354). At baseline (BL) and day 1 of each treatment cycle (C) to C15, pts were administered the EORTC core questionnaire (QLQ-C30) and its lung cancer specific module (QLQ-LC13) to assess symptoms, functioning, and Global Health Status (GHS)/QoL. In the intent-to-treat population, mixed-effects repeated measures models were used to estimate least squares (LS) mean change from BL on all scales. Kaplan–Meier analysis estimated time to definitive deterioration, defined as worsening ≥10 points from BL observed at all subsequent time points or patient withdrawal after worsening; hazard ratios (HR) with 95% CIs estimated the likelihood of definitive deterioration. Results: BL scores showed moderate to high levels of functioning and low symptom burden. Cemiplimab-treated pts had lower likelihood of definitive deterioration vs chemo on key symptoms of dyspnea, cough, pain in chest, pain in other body parts, fatigue, nausea/vomiting, appetite loss, constipation, and diarrhea vs chemo (all P<.05). Treatment-related symptoms of peripheral neuropathy and alopecia had a lower likelihood of definitive deterioration with cemiplimab vs chemo (both P<.05). Cemiplimab resulted in significantly greater improvements vs chemo on all functioning scales and reduced the likelihood of definitive deterioration as indicated by HR <1 (Table). GHS/QoL improvements with cemiplimab at C2 were maintained to C15; LS mean change (SE) from BL across all timepoints was 7.1 (1.0) for cemiplimab vs 1.7 (1.2) for chemo ( P<.0001). Conclusions: In pts with advanced NSCLC and PD-L1 expression ≥50%, cemiplimab significantly improved GHS/QoL, functioning, and most symptoms vs chemo. Over 1 year of treatment, cemiplimab delayed worsening of key lung cancer symptoms and functioning. Clinical trial information: NCT03088540. [Table: see text]

Venlafaxine vs. fluoxetine in postmenopausal women with major depressive disorder: an 8-week, randomized, single-blind, active-controlled study

BackgroundIn the population of postmenopausal patients with major depressive disorder (MDD), the superiority of serotonin-norepinephrine reuptake inhibitors (SNRIs) over selective serotonin reuptake inhibitors (SSRIs) has not yet been definitively proven. Consequently, a direct comparison of the efficacy of SSRIs and SNRIs in the treatment of postmenopausal depression could provide relevant data. The aim of this study was to compare the efficacy and safety of venlafaxine vs. fluoxetine in the treatment of postmenopausal MDD.MethodsThis was an 8-week, multicenter, randomized, single-blind, active-controlled trial conducted at a psychiatric hospital (Beijing Anding Hospital) and a general hospital (Beijing Chaoyang Hospital) between April 2013 and September 2017. The primary outcome measure was improving depressive symptoms (Hamilton Depression Rating Scale (HAMD-24) score). The secondary outcomes included the change of HAMD-24 anxiety/somatization factor score and Clinical Global Impressions-Improvement (CGI-I) response rate. Safety was assessed by treatment-emergent adverse events (TEAEs) and laboratory tests. Efficacy was analyzed by using the full analysis set (FAS) following the modified intention-to-treat (mITT) principle. The primary endpoint measurements were analyzed using a mixed-effect model for repeated measures (MMRM) model with patients as a random-effect factor, treatment group as the independent variable, time as a repeated measure, and baseline covariates, using a first-order ante dependence covariance matrix.ResultsA total of 184 women were randomized. The full analysis set (FAS) included 172 patients (venlafaxine, n = 82; fluoxetine, n = 90). Over the 8-week study period, the reduction in HAMD-24 scores was significant (P < 0.001) in both groups, while a significantly greater decline from baseline was observed in the venlafaxine group compared with the fluoxetine group (least-squares mean difference [95% CI]: − 2.22 [− 7.08, − 0.41]), P = 0.001). The baseline-to-week-8 least-squares mean change of the anxiety/somatization factor scores, CGI-I response rate were greater in the venlafaxine group than in the fluoxetine group (all P < 0.05). The most frequent TEAEs (≥5%) in both groups were nausea, somnolence, dizziness, headache, and dry mouth. There was no significant difference in the incidence of adverse events between the two groups.ConclusionVenlafaxine was well tolerated and compared to fluoxetine, it led to a greater improvement in the treatment of postmenopausal MDD.Trial registrationClinical Trials. gov #NCT01824433. The trial was registered on April 4, 2013.

Breakfast Location Effect on Breakfast Quality and Obesity Risk in Saudi Female College Students

Background: There is a lack of data regarding breakfast consumption and quality among college students in the Kingdom of Saudi Arabia. Objective: The objective of this study was to assess the prevalence of breakfast consumption and examine the effect of breakfast location on breakfast nutritional quality and obesity risk among female college students at Taibah University. Methods: A total of 658 students participated in this cross-sectional study. Based on the Child and Adult Care Food Program (CACFP) recommendations, breakfast quality scores were computed by summing the individual food components and categorizing participants according to tertiles of the breakfast score distribution. Mixed-effects repeatedmeasures models were used to examine BMI categories with increasing tertiles of breakfast quality scores, stratified by breakfast location. Results and Discussion: Approximately 68% of the participants reported having breakfast regularly. The mean breakfast quality score was determined for students who had breakfast at home (12.5 ± 0.11), at college (10.41± 0.06), and in other places (8.19± 0.48). Obesity was associated with lower average breakfast quality scores based on breakfast location [mean quintile 3 compared with 1 difference: home 13.6 (P &lt; 0.001), college 9.1 (P &lt; 0.001), other 8.6 (P &lt; 0.001)]. Conclusion: The findings presented here indicated that a high percentage of students consume breakfast regularly. Students who had breakfast at home had high scores, which indicated good breakfast quality and a decreased risk of obesity. Further research on breakfast quality is needed in this area, as it affects the nutritional status and quality of life of the younger population.

The Efficacy of Computerized Cognitive Behavioral Therapy for Depressive and Anxiety Symptoms in Patients With COVID-19: Randomized Controlled Trial.

BackgroundThe prevalence of depressive and anxiety symptoms in patients with COVID-19 is higher than usual. Previous studies have shown that there are drug-to-drug interactions between antiretroviral drugs and antidepressants. Therefore, an effective and safe treatment method was needed. Cognitive behavioral therapy (CBT) is the first-line psychological therapy in clinical treatment. Computerized CBT (cCBT) was proven to be an effective alternative to CBT and does not require face-to-face therapy between a therapist and the patient, which suited the COVID-19 pandemic response.ObjectiveThis study aims to evaluate the efficacy of the cCBT program we developed in improving depressive and anxiety symptoms among patients with COVID-19.MethodsWe customized a cCBT program focused on improving depressive and anxiety symptoms among patients with COVID-19, and then, we assessed its effectiveness. Screening was based on symptoms of depression or anxiety for patients who scored ≥7 on the Hamilton Depression Rating Scale (HAMD17) or the Hamilton Anxiety Scale (HAMA). A total of 252 patients with COVID-19 at five sites were randomized into two groups: cCBT + treatment as usual (TAU; n=126) and TAU without cCBT (n=126). The cCBT + TAU group received the cCBT intervention program for 1 week. The primary efficacy measures were the HAMD17 and HAMA scores. The secondary outcome measures were the Self-Rating Depression Scale (SDS), Self-Rating Anxiety Scale (SAS), and Athens Insomnia Scale (AIS). Assessments were carried out pre- and postintervention. The patients’ symptoms of anxiety and depression in one of the centers were assessed again within 1 month after the postintervention assessment.ResultsThe cCBT + TAU group displayed a significantly decreased score on the HAMD17, HAMA, SDS, SAS, and AIS after the intervention compared to the TAU group (all P<.001). A mixed-effects repeated measures model revealed significant improvement in symptoms of depression (HAMD17 and SDS scores, both P<.001), anxiety (HAMA and SAS scores, both P<.001), and insomnia (AIS score, P=.002) during the postintervention and follow-up periods in the cCBT + TAU group. Additionally, the improvement of insomnia among females (P=.14) and those with middle school education (P=.48) in the cCBT + TAU group showed no significant differences when compared to the TAU group.ConclusionsThe findings of this study suggest that the cCBT program we developed was an effective nonpharmacological treatment for symptoms of anxiety, depression, and insomnia among patients with COVID-19. Further research is warranted to investigate the long-term effects of cCBT for symptoms of anxiety, depression, and insomnia in patients with COVID-19.Trial RegistrationChinese Clinical Trial Registry ChiCTR2000030084; http://www.chictr.org.cn/showprojen.aspx?proj=49952

Tests for Patterned Alternatives Using Logarithmic Quantile Estimation

We investigate the logarithmic quantile estimation (LQE) method using fully nonparametric rank statistics to test for known trend and umbrella patterns in the main effects of three widely used designs: a fixed-effect two-factor model, a mixed-effect repeated measures model, and a mixed-effect cross-classification model. We also test for patterned alternatives in the interaction between the main effect and time in the repeated measures model. We determine the level and power of the test statistics using LQE with simulated and real data. The LQE procedure uses only the data to estimate quantiles of test statistics and does not require the estimation of the asymptotic variance nor the Satterthwaite–Smith degrees of freedom estimation. Our results show that the LQE method commonly yields conservative tests with high power when testing for patterned alternatives.

Effects of Cariprazine on Cognition in Patients With Bipolar Mania or Mixed States: Post Hoc Analysis From 3 Randomized, Controlled Phase III Studies

AbstractIntroductionCariprazine, a dopamine D3-preferring D3/D2 and serotonin 5-HT1A receptor partial agonist, is approved for the treatment of schizophrenia and for depressive, manic, or mixed episodes associated with bipolar I disorder. Previous post hoc analyses have demonstrated that cariprazine was effective versus placebo for improving cognitive symptoms in patients with schizophrenia or bipolar depression. This post hoc analysis evaluated the effects of cariprazine on cognitive symptoms in patients with acute manic or mixed bipolar episodes.MethodsData from 3 phase II/III, randomized, double-blind, placebo-controlled studies in patients with manic or mixed episodes associated with bipolar I disorder (NCT00488618, NCT01058096, NCT01058668) were pooled and analyzed. Patients were randomized to placebo or flexibly dosed cariprazine (3-12 mg/d, 3-6 mg/d, or 6-12 mg/d [1 study only]) for 3 weeks of double-blind treatment; all dose groups were combined for the pooled analysis. Cognitive symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS) Cognitive subscale (sum of PANSS items P2, N5, N7, G10, G11); a score of 15 or greater at baseline indicated the presence of cognitive symptoms. Mean changes from baseline to week 3 in PANSS cognitive subscale/item scores and Young Mania Rating Scale (YMRS) total score were evaluated in the overall intent-to-treat (ITT) population and in the subgroup of patients with baseline cognitive symptoms. A mixed-effects model for repeated measures (MMRM) was used to impute missing values.ResultsOf the 1012 patients in the ITT population, 174 (placebo=71; cariprazine=103) had a PANSS Cognitive subscale score of 15 or greater at baseline. At week 3, the cariprazine group demonstrated significantly greater mean improvement than the placebo group on PANSS cognitive subscale scores in both the ITT population (−2.2 vs −1.3; P&lt;.0001) and the subgroup with baseline cognitive symptoms (−4.0 vs −1.9; P=.0002). In patients with baseline cognitive symptoms, improvement was significantly greater for cariprazine- versus placebo-treated patients on YMRS total score (−16.7 vs −8.2; P&lt;.0001) and the individual PANSS cognitive subscale items of conceptual disorganization (−1.1 vs −0.5; P=.0004), difficulty in abstract thinking (−0.8 vs −0.3; P=.0044), stereotyped thinking (−0.3 vs −0.1; P=.0350), and poor attention (−1.1 vs −0.6; P=.0043).ConclusionIn patients with manic or mixed episodes associated with bipolar I disorder, cariprazine versus placebo was effective in improving cognitive symptoms in the overall patient population as well as in patients with baseline cognitive symptoms. In addition, cariprazine versus placebo also demonstrated efficacy in improving manic symptoms in patients with baseline cognitive symptoms. These results suggest that cariprazine may provide benefits for the treatment of cognitive symptoms in patients with bipolar I mania.FundingAbbVie Inc.

Patient-reported outcomes from the phase II FAST trial of zolbetuximab plus EOX compared to EOX alone as first-line treatment of patients with metastatic CLDN18.2+\u2009gastroesophageal adenocarcinoma

BackgroundZolbetuximab plus first-line EOX (epirubicin, oxaliplatin, capecitabine; ZOL/EOX) significantly prolonged progression-free survival and overall survival in the FAST trial vs EOX alone. We report the patient-reported outcomes (PROs) of FAST in patients with advanced gastroesophageal adenocarcinoma.MethodsPatients were randomized to ZOL/EOX or EOX alone. Patients could receive ≤ 8 EOX cycles and remained on zolbetuximab until disease progression. PROs were collected using the EORTC QLQ-C30 and QLQ-STO22 before drug administration at day 1/cycle 1, day 1/cycle 5, end of EOX treatment, and q12w thereafter until disease progression. Time to deterioration (TTD), defined as the first meaningful worsening from baseline, in the individual QLQ-C30/QLQ-STO22 scores was analyzed. Longitudinal changes in scores from baseline were analyzed using a mixed-effects model for repeated measures (MMRM).ResultsThe per protocol population included 143 (ZOL/EOX: 69; EOX: 74) patients. Baseline QLQ-C30 and STO22 scores were comparable between arms and denoted intermediate-to-high quality of life (QoL), intermediate-to-low global health status (GHS) and low symptom burden. Descriptive analyses showed no differences between arms until end of EOX but maintenance therapy with zolbetuximab was associated with better QoL and less symptom burden thereafter. TTD for most scores favored ZOL/EOX over EOX and reached statistical significance for GHS (p = 0.008). MMRM results support TTD findings; no statistically significant differences were observed between arms in any score except for nausea and vomiting (p = 0.0181 favoring EOX).ConclusionsZOL/EOX allowed patients to maintain good QoL and low symptom burden for longer than EOX alone.

Reduction in Bone Loss from 5 to 20 Weeks Postpartum in Adolescents Supplemented with Calcium Plus Vitamin D during Pregnancy Is Not Sustained at 1 Year Postpartum: Follow-up Study of a Randomized Controlled Trial

BackgroundCalcium plus vitamin D supplementation of pregnant Brazilian adolescents with habitually low calcium intake (∼600 mg/d) reduced bone loss during the first 20 wk postpartum. ObjectiveWe investigated maternal bone mass changes during the first year postpartum as a follow-up of the clinical trial. MethodsPregnant adolescents (14–19 y) received calcium (600 mg/d) plus cholecalciferol (200 IU/d) supplementation (n = 30) or placebo (n = 26) from 26 wk of gestation until parturition. Bone area and bone mineral content and bone mineral density (BMD) at total body, lumbar spine, and hip (total and femoral neck) were assessed by DXA at 3 time points postpartum (5 wk, 20 wk, and 56 wk). Intervention group, time postpartum, and group × time interaction effects were tested by repeated-measures mixed-effects models adjusting for calcium intake, return of menses, breastfeeding practices, and body weight. ResultsTime (P < 0.05) but not group affected several absolute bone measurements. There was a group × time interaction for femoral neck BMD (P = 0.045). Mean ± SE values (g/cm2) at 5 wk, 20 wk, and 56 wk were, respectively, 1.025 ± 0.026, 0.980 ± 0.026, and 1.022 ± 0.027 for the placebo group and 1.057 ± 0.025, 1.030 ± 0.024, and 1.055 ± 0.025 for the supplemented group. An interaction also was observed for percentage change in femoral neck BMD relative to 5 wk (P = 0.049), with a more pronounced decrease in the placebo group (−4.58 ± 0.42%) than in the supplemented group (−3.15% ± 0.42%) at 20 wk (P = 0.019), and no difference between groups at 56 wk (−0.44% ± 0.71% in the placebo and −0.76% ± 0.62% in the supplemented group; P = 0.65). ConclusionsCalcium plus vitamin D supplementation of the adolescent mothers reduces the magnitude of bone loss at the femoral neck from 5 to 20 wk postpartum without an effect on bone changes after 1 y postpartum, indicating that there is no sustained effect of the supplement tested.

Final analysis results from TITAN: A phase III study of apalutamide (APA) versus placebo (PBO) in patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) receiving androgen deprivation therapy (ADT).

11 Background: TITAN evaluated APA or PBO added to ADT in pts with mCSPC. Pts with high- and low-volume disease, prior docetaxel, prior treatment for localized disease, and prior ADT (≤ 6 mos) were eligible. At the first interim analysis, with 22.7 mos median follow-up, APA significantly improved dual primary end points of overall survival (OS) (hazard ratio [HR] 0.67) and radiographic progression-free survival (rPFS) (HR 0.48) compared with PBO (Chi et al. NEJM. 2019). At that time, OS analysis was first planned interim while rPFS was final. TITAN was unblinded, allowing pts without progression who were still receiving PBO to cross over to APA. Herein, we report the final analysis of efficacy and safety results from TITAN. Methods: 1052 mCSPC pts were randomized 1:1 to receive APA (240 mg QD) or PBO plus ADT. Time-to-event end points were analyzed by Kaplan-Meier method and Cox proportional hazards model. A preplanned sensitivity analysis for OS, accounting for crossover using inverse probability censoring weighted (IPCW) log-rank test, was conducted. No formal statistical retesting was performed; nominal p values were reported without multiplicity adjustment. Change from baseline in Functional Assessment of Cancer Therapy-Prostate (FACT-P) total score was assessed using a mixed-effect repeated-measures model. Results: With 44 mos median follow-up, 405 OS events had occurred. After unblinding, 208 PBO pts (39.5%) crossed over to APA. Median treatment duration was 39.3 mos for the APA group, 20.2 mos for the entire PBO group, and 15.4 mos for the PBO→APA crossover group. OS was superior in the APA group compared with the PBO group despite crossover (Table). 48-mo survival rates were 65% (APA) vs 52% (PBO). Other end points also favored APA vs PBO (Table). Health-related quality of life (HRQoL), per total FACT-P, was maintained in the APA group through the study and was not different from the PBO group. Safety was consistent with previous reports. Conclusions: With close to 4 yrs of follow-up, the final analysis of TITAN demonstrated that in a broad population of pts with mCSPC, APA plus ADT provides an improvement in OS with a 35% reduction in risk of death, which increased to 48% reduction after adjusting for pts who crossed over from PBO to APA. In addition, there was consistent benefit with APA in other end points, including delaying castration resistance, and HRQoL continued to be maintained with an acceptable safety profile. Clinical trial information: NCT02489318. [Table: see text]

Statistical analysis plan for management of hypertension and multiple risk factors to enhance cardiovascular health in Singapore: the SingHypertension pragmatic cluster randomized controlled trial

IntroductionCardiovascular disease remains the leading cause of death in Singapore. Uncontrolled hypertension confers the highest attributable risk of CVD and remains a significant public health issue with sub-optimal blood pressure (BP) control rates. The aim of the trial is to evaluate the effectiveness and cost-effectiveness of a multicomponent intervention (MCI) versus usual care on lowering BP among adults with uncontrolled hypertension visiting primary care clinics in Singapore. This article describes the statistical analysis plan for the primary and secondary objectives related to intervention effectiveness.MethodsThe study is a cluster randomized trial enrolling 1000 participants with uncontrolled hypertension aged ≥ 40 years from eight primary care clinics in Singapore. The unit of randomization is the clinic, with eight clusters (clinics) randomized in a 1:1 ratio to either MCI or usual care. All participants will be assessed at baseline, 12 months, and 24 months with measurements of systolic and diastolic BP, antihypertensive and statin medication use, medication adherence, physical activity level, anthropometric parameters, smoking status, and dietary habits.The primary objective of this study is to assess the effectiveness of MCI versus usual care on mean SBP at the 2-year follow-up. The primary outcome is SBP at 24 months.SBP at baseline, 12, and 24 months will be modeled at the subject level using a likelihood-based, linear mixed-effects model repeated measures (MMRM) analysis with treatment group and follow-up as fixed effects, random cluster (clinic) effects, Gaussian error distribution, and adjustment to degrees of freedom using the Satterthwaite approximation. Secondary outcomes will be analyzed using a similar modeling approach incorporating generalized techniques appropriate for the type of outcome.DiscussionThe trial will allow us to determine whether the MCI has an impact on BP and cardiovascular risk factors over a 2-year follow-up period and inform recommendations for health planners in scaling up these strategies for the benefit of society at large. A pre-specified and pre-published statistical analysis plan mitigates reporting bias and data driven approaches.Trial registrationClinicalTrials.gov NCT02972619. Registered on 23 November 2016.

Comparison of forward and backward postural perturbations in mild-to-moderate Parkinson's disease

BackgroundAssessing postural stability in Parkinson’s disease (PD) often relies on measuring the stepping response to an imposed postural perturbation. The standard clinical technique relies on a brisk backwards pull at the shoulders by the examiner and judgement by a trained rater. In research settings, various quantitative measures and perturbation directions have been tested, but it is unclear which metrics and perturbation direction differ most between people with PD and controls. Objectives(1) Use standardized forward vs. backward perturbations of a support surface to evaluate reactive stepping performance between PD and control participants. (2) Evaluate the utility of using principal components analysis to capture the dynamics of the reactive response and differences between groups. MethodsSixty-two individuals participated (40 mild-to-moderate PD, off medication). Standardized rapid translations of the support surface were applied, requiring at least one step, backward or forward, to restore balance. The number of steps taken and the projection of the first principal component (PC1) of the center of pressure (COP) time series were entered in linear repeated-measures mixed effect models. ResultsForward falls required significantly fewer steps to recover than backward falls. PC1 captured more than half of the variance in the COP trajectory. Analysis of the PC1 projection revealed a significant interaction effect of group (PD vs. controls) by direction, such that there was a group difference in forward stepping, but not backward. SignificanceForward reactive stepping in PD differed from controls more than backward-stepping. PC1 projections of the COP trajectory capture the dynamics of the postural response and differ between PD and controls.

Serum Vitamin D and Depressive Symptomatology among Boston-Area Puerto Ricans

Low vitamin D status, assessed using serum 25-hydroxyvitamin D [25(OH)D] concentration, has been associated with depression, but research among minority populations, such as Puerto Ricans is limited. We examined the association between serum 25(OH)D and self-reported depressive symptomatology across 3 waves of follow-up in a cohort of Puerto Rican adults residing in Massachusetts. We evaluated the cross-sectional and longitudinal associations between serum 25(OH)D and self-reported depressive symptoms in the Boston Puerto Rican Health Study (BPRHS) cohort. Participants of the BPRHS were evaluated for depressive symptoms using the Center for Epidemiologic Studies Depression Scale (CES-D). Serum 25(OH)D was measured at baseline (n=1434), year 2 (n=1218), and year 5 (n=914). We categorized serum 25(OH)D concentration as sufficient (≥20ng/mL), insufficient (12 to <20ng/mL), and deficient (<12ng/mL). Multivariable linear regression was used for cross-sectional analyses at baseline, and repeated measures mixed effects modeling was used over 3 waves of follow-up for longitudinal analyses. We conducted sensitivity analyses in vitamin D supplement nonusers and participants with complete data on baseline serum 25(OH)D and CES-D at all 3 visits. Serum 25(OH)D concentration was not associated with CES-D score in cross-sectional analysis [β = -0.85; 95% CI: -2.80, 1.10 for deficient compared with sufficient 25(OH)D; P-trend=0.59] or in longitudinal analyses over 5 y [β = -0.41; 95% CI: -1.95, 1.13 for deficient compared with sufficient 25(OH)D; P-trend=0.93]. Results were similar in sensitivity analyses restricted to vitamin D supplement nonusers (n=1371) and in analyses conducted in participants with complete measures of baseline serum 25(OH)D and CES-D score at all 3 visits (n=887) [β = -0.12; 95% CI: -1.98, 1.74 for deficient compared with sufficient 25(OH)D; P-trend=0.93]. We did not observe a significant association between serum 25(OH)D and depressive symptomatology in the BPRHS cohort.

Cardiovascular and Renal Outcomes of Mineralocorticoid Receptor Antagonist Use in PARAGON-HF

ObjectivesThis study sought to evaluate the efficacy and safety of sacubitril/valsartan in patients with heart failure with preserved ejection fraction (HFpEF) according to background mineralocorticoid receptor antagonist (MRA) therapy. BackgroundCurrent guidelines recommend consideration of MRAs in selected patients with HFpEF. This study assessed cardiovascular outcomes, renal outcomes, and safety of sacubitril/valsartan compared with valsartan in patients with HFpEF according to background MRA treatment. MethodsPARAGON-HF (Prospective Comparison of ARNI [angiotensin receptor-neprilysin inhibitor] with ARB [angiotensin-receptor blockers] Global Outcomes in HF with Preserved Ejection Fraction) randomized 4,796 patients with HFpEF to sacubitril/valsartan or valsartan. In a pre-specified subgroup analysis, the effect of sacubitril/valsartan versus valsartan was evaluated according to baseline MRA use on the primary study composite of total heart failure hospitalizations and cardiovascular death using semiparametric proportional rates methods, as well as the renal composite of ≥50% decrease in estimated glomerular filtration rate, development of end-stage renal disease, or death from renal causes using Cox proportional hazards regression models. Annual decline in estimated glomerular filtration rate was analyzed with repeated-measures mixed-effect models. Key safety outcomes included incidence of hypotension, hyperkalemia, and elevations in serum creatinine above predefined thresholds. ResultsPatients treated with MRAs at baseline (n = 1,239, 26%), compared with MRA nonusers (n = 3,557, 74%), were younger (72 vs. 73 years), more often male (52% vs. 47%), had lower left ventricular ejection fraction (57% vs. 58%), and a higher proportion of prior HF hospitalization (59% vs. 44%) (all p < 0.001). Efficacy of sacubitril/valsartan compared with valsartan with regard to the primary cardiovascular (for MRA users: rate ratio: 0.73; 95% confidence interval [CI]: 0.56 to 0.95; vs. for MRA nonusers: rate ratio: 0.94; 95% CI: 0.79 to 1.11; pinteraction = 0.11) and renal endpoints (for MRA users: hazard ratio: 0.31; 95% CI: 0.13 to 0.76; vs. for MRA non-users: HR: 0.59; 95% CI: 0.36 to 0.95; pinteraction = 0.21) did not significantly vary by baseline MRA use. The incidence of key safety outcomes including hypotension and severe hyperkalemia (K > 6.0 mmol/l) did not vary by baseline MRA use. However, annual decline in estimated glomerular filtration rate was less with the combination of MRA and sacubitril/valsartan (for MRA users: absolute difference favoring sacubitril/valsartan: +1.2 ml/min/1.73 m2 per year; 95% CI: 0.6 to 1.7; vs. for MRA nonusers: +0.4; 95% CI: 0.1 to 0.7; pinteraction = 0.01). ConclusionsClinical efficacy of sacubitril/valsartan compared with valsartan with regard to predefined cardiorenal composite outcomes in PARAGON-HF was consistent in patients treated and not treated with MRA at baseline. Addition of sacubitril/valsartan rather than valsartan alone to MRA appears to be associated with a lesser decline in renal function and no increase in severe hyperkalemia. These data support possible added value of combination treatment with sacubitril/valsartan and MRA in patients with HFpEF. (Prospective Comparison of ARNI [angiotensin receptor -neprilysin inhibitor] with ARB [angiotensin-receptor blockers] Global Outcomes in HF with Preserved Ejection Fraction [PARAGON-HF]; NCT01920711)

Peripheral Neuropathy Symptoms, Pain and Functioning in Relapsed or Refractory Multiple Myeloma Patients Treated with Selinexor, Bortezomib, and Dexamethasone

Peripheral Neuropathy Symptoms, Pain and Functioning in Relapsed or Refractory Multiple Myeloma Patients Treated with Selinexor, Bortezomib, and Dexamethasone

Health-Related Quality of Life in the Cartitude-1 Study of Ciltacabtagene Autoleucel for Relapsed/Refractory Multiple Myeloma

Health-Related Quality of Life in the Cartitude-1 Study of Ciltacabtagene Autoleucel for Relapsed/Refractory Multiple Myeloma

Predictors of Health Utility in Relapsing-Remitting and Secondary-Progressive Multiple Sclerosis: Implications for Future Economic Models of Disease-Modifying Therapies.

BackgroundDecision-analytic models used in economic evaluations of disease-modifying therapies for relapsing–remitting multiple sclerosis (RRMS) have characterized disease progression and accrue quality-adjusted life-years from utility values based on the Expanded Disability Status Scale (EDSS), the occurrence of relapses, and progression to secondary-progressive multiple sclerosis (SPMS). The EDSS, used to characterize disability progression, has several limitations. If the EDSS is the only disability measure used in economic evaluations, the long-term clinical and economic implications of disease-modifying therapies may not be properly assessed.ObjectiveThe objective of this study was to explore if supplementary disability measures including the Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9HPT), and Paced Auditory Serial Addition Test (PASAT) significantly contribute additional information on health utility in RRMS and SPMS otherwise not captured by the EDSS and relapses and, therefore, should be considered in future economic evaluations of disease-modifying therapies.MethodsShort-Form Six-Dimension utility scores were derived from the RAND 36-Item Health Survey 1.0 individual-level data available in the Multiple Sclerosis Outcome Assessment Consortium (MSOAC) Placebo Database. Repeated-measures mixed-effects models were conducted to estimate the effects of EDSS, T25FW, 9HPT (dominant and non-dominant hand), PASAT, and relapses on changes in utility over time, controlling for demographics.ResultsA higher level of EDSS, longer time to complete the T25FW test, and a recent relapse were significant predictors of lower utility in people with RRMS and SPMS. 9HPT and PASAT were not significant predictors.ConclusionsThis study suggests that in addition to EDSS and recent relapses, T25FW significantly predicts utility in RRMS and SPMS. These findings support the use of T25FW to supplement the EDSS and the occurrence of relapses to characterize the course of disease progression and to more accurately accrue quality-adjusted life-years in future economic evaluations of disease-modifying therapies for the treatment of RRMS.Electronic supplementary materialThe online version of this article (10.1007/s40273-020-00964-w) contains supplementary material, which is available to authorized users.

Effects of Ferulic Acid and Angelica archangelica Extract (Feru-guard®) on Mild Cognitive Impairment: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Prospective Trial.

We conducted a multicenter, randomized, double-blind, placebo-controlled prospective trial examining a supplement containing ferulic acid and Angelica archangelica extract (Feru-guard ®) for mild cognitive impairment (MCI). In the intention-to-treat population, Mini-Mental State Examination (MMSE) scores were significantly better at 24 weeks (p = 0.041) in the active group. In the per protocol population, MMSE was significantly better in the active group at 24 weeks (p = 0.008), and mixed effect models for repeated measures (MMRM) showed significant difference (p = 0.016). ADAS-Jcog was significantly better at 24 (p = 0.035) and 48 weeks (p = 0.015) in the active group, and MMRM was significant (p = 0.031). Thus, Feru-guard ® may be useful for MCI.

PERsistent Sitagliptin treatment & Outcomes (PERS&O 2.0) study, long-term results: a real-world observation on DPP4-inhibitor effectiveness

IntroductionSitagliptin is a dipeptidyl peptidase 4 inhibitor for the treatment of type 2 diabetes (T2D). Limited real-world data on its effectiveness and safety are available from an Italian population.Research design...

An application of the mixed-effects model and pattern mixture model to treatment groups with differential missingness suspected not-missing-at-random.

Likelihood-based, mixed-effects models for repeated measures (MMRMs) are occasionally used in primary analyses for group comparisons of incomplete continuous longitudinal data. Although MMRM analysis is generally valid under missing-at-random assumptions, it is invalid under not-missing-at-random (NMAR) assumptions. We consider the possibility of bias of estimated treatment effect using standard MMRM analysis in a motivational case, and propose simple and easily implementable pattern mixture models within the framework of mixed-effects modeling, to handle the NMAR data with differential missingness between treatment groups. The proposed models are a new form of pattern mixture model that employ a categorical time variable when modeling the outcome and a continuous time variable when modeling the missingness-data patterns. The models can directly provide an overall estimate of the treatment effect of interest using the average of the distribution of the missingness indicator and a categorical time variable in the same manner as MMRM analysis. Our simulation results indicate that the bias of the treatment effect for MMRM analysis was considerably larger than that for the pattern mixture model analysis under NMAR assumptions. In the case study, it would be dangerous to interpret only the results of the MMRM analysis, and the proposed pattern mixture model would be useful as a sensitivity analysis for treatment effect evaluation.

Study protocol for a mixed methods prospective cohort study to explore experiences of care following a suicidal crisis in the Australian healthcare system

IntroductionFor individuals presenting to the emergency department (ED) for a suicide attempt, the period after discharge from hospital is marked by heightened vulnerability for further suicide attempts. Effective care following...