Predicting panel attrition in longitudinal HRQoL surveys during the COVID-19 pandemic in the US.

BACKGROUND: Online longitudinal surveys may be subject to potential biases due to sample attrition. This study was designed to identify potential predictors of attrition using a longitudinal panel survey collected during the COVID-19 pandemic. METHODS: Three waves of data were collected using Amazon Mechanical Turk (MTurk), an online crowd-sourced platform. For each wave, the study sample was collected by referencing a US national representative sample distribution of age, gender, and race, based on US census data. Variables included respondents' demographics, medical history, socioeconomic status, COVID-19 experience, changes of health behavior, productivity, and health-related quality of life (HRQoL). Results were compared to pre-pandemic US norms. Measures that predicted attrition at different times of the pandemic were identified via logistic regression with stepwise selection. RESULTS: 1467 of 2734 wave 1 respondents participated in wave 2 and, 964 of 2454 wave 2 respondents participated in wave 3. Younger age group, Hispanic origin (p ≤ 0.001) and higher self-rated survey difficulty (p ≤ 0.002) consistently predicted attrition in the following wave. COVID-19 experience, employment, productivity, and limited physical activities were commonly observed variables correlated with attrition with specific measures varying by time periods. From wave 1, mental health conditions, average daily hours worked (p = 0.004), and COVID-19 impact on work productivity (p < 0.001) were associated with a higher attrition rate at wave 2, additional to the aforementioned factors. From wave 2, support of social distancing (p = 0.032), being Republican (p < 0.001), and having just enough money to make ends meet (p = 0.003) were associated with predicted attrition at wave 3. CONCLUSIONS: Attrition in this longitudinal panel survey was not random. Besides commonly identified demographic factors that contribute to panel attrition, COVID-19 presented novel opportunities to address sample biases by correlating attrition with additional behavioral and HRQoL factors in a constantly evolving environment. While age, ethnicity, and survey difficulty consistently predicted attrition, other factors, such as COVID-19 experience, changes of employment, productivity, physical health, mental health, and financial situation impacted panel attrition during the pandemic at various degrees.

Fexapotide triflutate vs oral pharmacotherapy as initial therapy for moderate-to-severe benign prostate hyperplasia patients: a cost-effectiveness analysis.

BACKGROUND: To assess the price range in which fexapotide triflutate (FT), a novel injectable, is cost-effective relative to current oral pharmacotherapy (5 α-reductase inhibitor, α-blocker, 5 α-reductase inhibitor and α-blocker combination therapy) as initial therapy followed by surgery for moderate-to-severe benign prostate hyperplasia patients with lower urinary tract symptoms (BPH-LUTS). METHODS: We developed a microsimulation decision-analytic model to track the progression of BPH-LUTS and associated costs and quality-adjusted life years in the target population. The cost-effectiveness analysis was performed from Medicare's perspective with a time horizon of 4 years using 2019 US dollars for all costs. The microsimulation model considered treatment patterns associated with nonadherence to oral medication and progression to surgery. Model parameters were estimated from large randomized controlled trials, literature and expert opinion. For each initial treatment option, simulations were performed with 1000 iterations, with 1000 patients per iteration. RESULTS: Three upfront oral pharmacotherapy options are close in cost-effectiveness, with combination therapy being the most cost-effective option. Relative to upfront oral pharmacotherapy options, FT slightly increases quality-adjusted life years (QALY) per patient (1.870 (95% CI, 1.868 to 1.872) vs. 1.957 (95% CI, 1.955 to 1.959) QALYs). Under the willingness-to-pay (WTP) threshold of $150,000 per QALY, at price per injection of $14,000, FT is about as cost-effective as upfront oral pharmacotherapy options with net monetary benefit (NMB) $279,168.54. Under the WTP threshold of $50,000 per QALY, at price per injection of $5,000, FT is about as cost-effective as upfront oral pharmacotherapy options with NMB $92,135.18. In an alternative 10-year time horizon scenario, FT price per injection at $11,000 and $4,500 makes FT as cost-effective as oral pharmacotherapies. One-way sensitivity analysis showed this result is most sensitive to upfront therapy prices, FT efficacy and initial IPSS. At price per injections of $5,000, $10,000 and $15,000, the probability that FT is either cost-effective or dominant compared to upfront oral pharmacotherapy options using a WTP threshold of $150,000 per QALY is 100%, 93% and 40%, respectively. CONCLUSIONS: Compared to upfront oral pharmacotherapy options, FT would be cost-effective at a price per injection below $14,000, assuming a WTP threshold of $150,000 per QALY.

Geographic variation in the use of continuous outpatient inotrope infusion therapy and beta blockers.

BACKGROUND: Continuous outpatient inotrope infusion therapy (COIIT) can be used as palliative or interim treatment in patients with advanced heart failure (AHF). Despite widespread use, there is a relative lack of data informing best practices. This study aimed to examine whether patterns of COIIT use differed by region and to explore whether observed differences influenced clinical outcomes. METHODS: Retrospective study of AHF patients receiving COIIT from May 2009 through June 2016. The primary outcome was regional difference, the secondary outcome was persistence (duration) on therapy. Cox proportional hazards model was used to calculate hazard ratios for treatment regimens. RESULTS: There were 3,286 patients, mean (SD) age 61.9 (14.4) years and 74.0% (2,433) male. Inotrope selection and beta blocker use varied by region by chi square (χ2 (21) = 166.9, p < 0.001). Persistence was greater on milrinone compared to dobutamine (HR (for discontinuation) 0.54, CI 0.41-0.70, p < 0.001). Concurrent beta-blocker was associated with greater persistence for patients receiving milrinone (HR 0.13, CI 0.08-0.20, p < 0.001) and dobutamine (HR 0.36, CI 0.18-0.71, p < 0.001). CONCLUSIONS: Patterns of COIIT use varied by region, and variations in use were associated with differences in clinical outcomes.

Cost-effectiveness analysis of extended extracorporeal membrane oxygenation duration in newborns with congenital diaphragmatic hernia in the United States.

BACKGROUND: The duration of extracorporeal membrane oxygenation (ECMO) has been historically confined in many centers to two weeks. We evaluated the cost-effectiveness of additional weeks on ECMO beyond two weeks for newborns with congenital diaphragmatic hernia (CDH) who may require longer stays to maximize survival potential. METHODS: We modeled lifetime outcomes using a decision tree from the US societal perspective. Survival at discharge, probability of long-term sequelae, direct medical costs, indirect costs, and quality-adjusted life years (QALY) for long-term disability were considered. Considering the nature of severity of CDH, we used $200,000 per QALY as the willingness-to-pay threshold in the base case. RESULTS: The lifetime costs per CDH infant generated from staying on ECMO for ≤2 weeks, 2-3 weeks, and >3 weeks are $473,334, $654,771, $1,007,476, respectively (2018 USD), and the total QALYs gained from each treatment arm are 1.83, 3.6, and 5.05. In the base case, the net monetary benefits are -$108,034 for ECMO ≤2 weeks, $64,258 for 2-3 weeks, and $2955 for >3 weeks. In probabilistic simulations, a duration of ≤2 weeks is dominated by a duration of 2-3 weeks in 65.3% of cases and dominated by > 3 weeks in 60.2% of cases. A duration of 2-3 weeks is more cost-effective than >3 weeks in 68.6% of simulations. CONCLUSION: Our findings suggest that 2-3 weeks of ECMO may be the most cost-effective for CDH infants that are unable to wean off at 2 weeks from the US societal perspective. Regardless of ECMO duration, ECMO use generates positive incremental NMB at WTP of $200,000 if the survival probability is greater than 0.3. Future research must be conducted to evaluate the long-term outcomes and sequelae of CDH patients post-discharge to better inform the clinical decision-making in neonatal intensive care unit.

Where Do We Go From Here? A Framework for Using Susceptible-Infectious-Recovered Models for Policy Making in Emerging Infectious Diseases.

OBJECTIVES: Throughout the coronavirus disease 2019 pandemic, susceptible-infectious-recovered (SIR) modeling has been the preeminent modeling method to inform policy making worldwide. Nevertheless, the usefulness of such models has been subject to controversy. An evolution in the epidemiological modeling field is urgently needed, beginning with an agreed-upon set of modeling standards for policy recommendations. The objective of this article is to propose a set of modeling standards to support policy decision making. METHODS: We identify and describe 5 broad standards: transparency, heterogeneity, calibration and validation, cost-benefit analysis, and model obsolescence and recalibration. We give methodological recommendations and provide examples in the literature that employ these standards well. We also develop and demonstrate a modeling practices checklist using existing coronavirus disease 2019 literature that can be employed by readers, authors, and reviewers to evaluate and compare policy modeling literature along our formulated standards. RESULTS: We graded 16 articles using our checklist. On average, the articles met 6.81 of our 19 categories (36.7%). No articles contained any cost-benefit analyses and few were adequately transparent. CONCLUSIONS: There is significant room for improvement in modeling pandemic policy. Issues often arise from a lack of transparency, poor modeling assumptions, lack of a system-wide perspective in modeling, and lack of flexibility in the academic system to rapidly iterate modeling as new information becomes available. In anticipation of future challenges, we encourage the modeling community at large to contribute toward the refinement and consensus of a shared set of standards for infectious disease policy modeling.

Diagnosing newborns with suspected mitochondrial disorders: an economic evaluation comparing early exome sequencing to current typical care.

PURPOSE: To determine the value of early exome sequencing (eES) relative to the current typical care (TC) in the diagnosis of newborns with suspected severe mitochondrial disorders (MitD). METHODS: We used a decision tree-Markov hybrid to model neonatal intensive care unit (NICU)-related outcomes and costs, lifetime costs and quality-adjusted life-years among patients with MitD. Probabilities, costs, and utilities were populated using published literature, expert opinion, and the Pediatric Health Information System database. Incremental cost-effectiveness ratios (ICER) and net monetary benefits (NMB) were calculated from lifetime costs and quality-adjusted life-years for singleton and trio eES, and TC. Robustness was assessed using univariate and probabilistic sensitivity analyses (PSA). Scenario analyses were also conducted. RESULTS: Findings indicate trio eES is a cost-minimizing and cost-effective alternative to current TC. Diagnostic probabilities and NICU length-of-stay were the most sensitive model parameters. Base case analysis demonstrates trio eES has the highest incremental NMB, and PSA demonstrates trio eES had the highest likelihood of being cost-effective at a willingness-to-pay (WTP) of $200,000 relative to TC, singleton eES, and no ES. CONCLUSION: Trio and singleton eES are cost-effective and cost-minimizing alternatives to current TC in diagnosing newborns suspected of having a severe MitD.

Cost-effectiveness of bezlotoxumab and fidaxomicin for initial Clostridioides difficile infection.

OBJECTIVES: Treatment of Clostridioides difficile infection (CDI) has undergone significant change in recent years with the introduction of fidaxomicin and bezlotoxumab. This study evaluated the cost-effectiveness of fidaxomicin and bezlotoxumab for initial CDI compared with standard therapy with oral vancomycin. METHODS: A Markov model with eight health states was built based on transition probabilities, costs and health utilities derived from literature to evaluate the cost-effectiveness of standard fidaxomicin, bezlotoxumab plus vancomycin, and extended-pulsed fidaxomicin versus standard oral vancomycin over a lifetime horizon from the US societal perspective. RESULTS: For overall CDI treatment, oral vancomycin had a cost of $39 178 and was associated with a gain of 11.64 quality-adjusted life-years (QALYs). Extended-pulsed fidaxomicin had a higher QALY gain of 11.65 at a lower cost of $37 613, and therefore was dominant over vancomycin. Standard fidaxomicin had a QALY gain of 11.94 versus vancomycin at an incremental cost of $495 per QALY. Bezlotoxumab plus vancomycin led to a QALY gain of 11.77 at an incremental cost of $17 746 per QALY. At the willingness-to-pay (WTP) threshold of $150 000 per QALY, extended-pulsed fidaxomicin, bezlotoxumab plus vancomycin and standard fidaxomicin were more cost-effective compared with vancomycin alone, yielding incremental net monetary benefits of $3248, $17 011 and $44 308, respectively. One-way sensitivity analysis suggested that the probabilities of sustained cure from the initial episode were the most sensitive inputs, and results were overall not particularly sensitive to any drug costs. CONCLUSIONS: Based on a WTP threshold of $150 000, standard fidaxomicin was estimated to be the most cost-effective treatment. Standard-of-care vancomycin was dominated by extended-pulsed fidaxomicin for treating an episode of CDI and preventing further recurrence, and the addition of bezlotoxumab to vancomycin was dominated by standard fidaxomicin.

A US Population Health Survey on the Impact of COVID-19 Using the EQ-5D-5L.

BACKGROUND: The COVID-19 pandemic has resulted in negative impacts on the economy, population health, and health-related quality-of-life (HRQoL). OBJECTIVE: To assess the impact of COVID-19 on US population HRQoL using the EQ-5D-5L. DESIGN: We surveyed respondents on physical and mental health, demographics, socioeconomics, brief medical history, current COVID-19 status, sleep, dietary, financial, and spending changes. Results were compared to online and face-to-face US population norms. Predictors of EQ-5D-5L utility were analyzed using both standard and post-lasso OLS regressions. Robustness of regression coefficients against unmeasured confounding was analyzed using the E-Value sensitivity analysis. SUBJECTS: Amazon MTurk workers (n=2776) in the USA. MAIN MEASURES: EQ-5D-5L utility and VAS scores by age group. KEY RESULTS: We received n=2746 responses. Subjects 18-24 years reported lower mean (SD) health utility (0.752 (0.281)) compared with both online (0.844 (0.184), p=0.001) and face-to-face norms (0.919 (0.127), p<0.001). Among ages 25-34, utility was worse compared to face-to-face norms only (0.825 (0.235) vs. 0.911 (0.111), p<0.001). For ages 35-64, utility was better during pandemic compared to online norms (0.845 (0.195) vs. 0.794 (0.247), p<0.001). At age 65+, utility values (0.827 (0.213)) were similar across all samples. VAS scores were worse for all age groups (p<0.005) except ages 45-54. Increasing age and income were correlated with increased utility, while being Asian, American Indian or Alaska Native, Hispanic, married, living alone, having history of chronic illness or self-reported depression, experiencing COVID-19-like symptoms, having a family member diagnosed with COVID-19, fear of COVID-19, being underweight, and living in California were associated with worse utility scores. Results were robust to unmeasured confounding. CONCLUSIONS: HRQoL decreased during the pandemic compared to US population norms, especially for ages 18-24. The mental health impact of COVID-19 is significant and falls primarily on younger adults whose health outcomes may have been overlooked based on policy initiatives to date.

Reconstruction After Salvage Total Laryngectomy: A Cost-effectiveness Analysis.

OBJECTIVE: To determine the most cost-effective reconstruction method after salvage total laryngectomy. STUDY DESIGN: Cost-effectiveness analysis. SETTING: Tertiary care hospitals with head and neck oncologic and reconstructive surgeons. SUBJECTS AND METHODS: We constructed a Markov-based decision model to compare reconstruction by primary closure to pectoralis flap and free flap after salvage total laryngectomy. The model simulated disease with transition probabilities and health utilities found in primary literature and estimated the average overall cost of each reconstructive method using Medicare billing codes. Effectiveness was compared using quality-adjusted life years (QALYs). One-way and probabilistic sensitivity analyses were performed to scrutinize the conclusions of our model. Reconstruction methods were compared using incremental cost-effectiveness ratios (ICERs). In the United States, less than $150,000 per QALY gained is considered cost-effective (2019 US dollars). RESULTS: Our base case analysis revealed that primary closure was less expensive ($44,370) and yielded more QALYs (0.91) than both pectoralis ($45,163, 0.81 QALYs) and free flap ($46,244, 0.85 QALYs), making it the most cost-effective option. Between flaps, free flap was cost-effective over pectoralis flap (ICER = $27,025/QALY gained). Sensitivity analyses showed primary closure as cost-effective 69% of the time over either flap. These conclusions were sensitive to the health utilities (quality of life) of each method of reconstruction. CONCLUSION: Tissue flaps to augment closure after salvage total laryngectomy are not always the most cost-effective reconstructive option. The long-term morbidity of flap surgery oftentimes outweighs the benefit of lowering fistula rates after surgery. Careful consideration must be taken when advising patients of their reconstructive options.

Characterizing the Validity and Real-World Utility of Health Technology Assessments in Healthcare: Future Directions Comment on "Problems and Promises of Health Technologies: The Role of Early Health Economic Modelling".

With their article, Grutters et al raise an important question: What do successful health technology assessments (HTAs) look like, and what is their real-world utility in decision-making? While many HTAs are published in peer-reviewed journals, many are considered proprietary and their attributes remain confidential, limiting researchers' ability to answer these questions. Models for economic evaluations like cost-effectiveness analyses (CEAs) synthesize a wide range of evidence, are often statistically and mathematically sophisticated, and require untestable assumptions. As such, there is nearly universal agreement among researchers that enhancing transparency is an important issue in health economic modeling. However, the definition of transparency and guidelines for its implementation vary. Model registration combined with a linked database of model-based economic evaluations has been proposed as a solution, whereby registered models and their accompanying technical and nontechnical documentation are sourced into a single publicly-available repository, ideally in a standardized format to ensure consistent and complete representation of features, code, data sources, results, validation exercises, and policy recommendations. When such a repository is ultimately created, modelers will not have to reinvent the wheel for every new drug launched or new treatment pathway. These more open and transparent approaches will have substantial implications for model accuracy, reliability, and validity, improving trust and acceptance by healthcare decision-makers.

Outcomes and Utilization of Adjuvant Chemotherapy for Stage II Colon Cancer in the Oxaliplatin Period: A SEER-Medicare Analysis.

PURPOSE: Previous SEER (Surveillance, Epidemiology, and End Results)-Medicare analyses have shown no definitive survival benefit for adjuvant chemotherapy (AC) with fluoropyrimidines. Impact of oxaliplatin-containing regimens for elderly stage II patients in real-world setting is unknown. We explored the utilization and outcome of AC after the Food and Drug Administration (FDA) approval of oxaliplatin. PATIENTS AND METHODS: Patients with stage II colon cancer (2004-2011) who underwent resection were selected for this analysis. Medicare claims data were used to ascertain the administration of AC within 120 days after surgery. The primary endpoint of the analysis was overall survival. We used the Cox proportional hazards model to estimate the effect of AC while adjusting for clinical and sociodemographic variables available in SEER. To adjust for referral pattern, a source of selection bias, we conducted an instrumental variable analysis using the surgeon of record and health service area. RESULTS: A total of 16,468 patients were identified and 12.1% received AC. AC recipients were significantly younger, more likely to be male, nonwhite, married, and had lower comorbidity index. Their tumors had a more advanced stage, more likely to be left sided, and were less differentiated. The hazard ratio (HR) from the Cox model showed a statistically significant survival advantage for AC (HR=0.847, 95% confidence interval: 0.782-0.916). However, results from the instrumental variable analysis indicated that there was no definitive benefit of survival in AC recipients (HR=1.779, 95% confidence interval: 0.927-3.415). AC use decreased over time. CONCLUSIONS: After controlling for referral patterns, administration of AC provided no definitive survival benefit. Future studies may elucidate the elderly population who may benefit from AC.

Cost-Effectiveness Analysis of Four Common Diagnostic Methods for Clostridioides difficile Infection.

BACKGROUND: No studies have evaluated the cost-effectiveness of single and two-step different diagnostic test strategies for Clostridioides difficile infection (CDI), including direct and indirect costs. OBJECTIVE: To evaluate the cost-effectiveness of commonly available diagnostic tests for CDI including nucleic acid amplification testing (NAAT) alone, glutamate dehydrogenase followed by enzyme immunoassay for toxin (GDH/EIA), GDH then NAAT (GDH/NAAT), and NAAT then EIA (NAAT/EIA). DESIGN: Decision tree model from the US societal perspective with inputs derived from the literature. Willingness-to-pay threshold was set at $150,000 per quality-adjusted life year (QALY) gained. To assess the impact of uncertainty in model inputs on the findings, we performed one-way and probabilistic sensitivity analyses. PARTICIPANTS: We conducted the analysis to represent a population aged 65 years old with diarrhea who received a CDI diagnostic test. MAIN MEASURES: Incremental cost-effectiveness ratios (ICER) and incremental net monetary benefits (INMB). KEY RESULTS: NAAT alone was the most cost-effective approach overall; GDH/NAAT was the most cost-effective two-step option. NAAT alone led to the highest QALYs gained, at an incremental cost of $54,547 (vs. GDH/NAAT), $55,410 (vs. GDH/EIA), and $50,231 (vs. NAAT/EIA) per QALY gained. NAAT/EIA was not cost-effective compared to any other strategy. GDH/NAAT resulted in a higher QALY compared to GDH/EIA, at an incremental cost of $96,841 per QALY gained. Variability in the likelihood of comorbidities, CDI probability, and age at disease onset did not substantially change the results. One-way sensitivity analyses showed that results were most sensitive to likelihood of recurrence, followed by CDI mortality rate and probability of severe CDI. Probabilistic sensitivity analyses explored known uncertainties in the base case and confirmed the robustness of the results. CONCLUSIONS: NAAT alone and GDH/NAAT (among the two-step options) were the most cost-effective diagnostic test approaches for CDI.

Now Is the Time for Transparency in Value-Based Healthcare Decision Modeling.

In contrast to many other countries, during the 20 years since the founding of Value in Health, the United States has moved further away from using value-based healthcare decision modeling (VHDM) for drugs and other medical care choices. US public and private health plans can be typically characterized as using "budget impact" decision making rather than VHDM, with drugs having low per-member per-month spending likely to be covered and reimbursed regardless of value. Orphan drugs and specialty drugs with relatively few patients (eg, end-stage cancer drugs) are often covered, whether cost-effective or not, because health plans want to avoid negative publicity. Although there are many explanations for the poor US uptake of VHDM, a key reason is that VHDM models and data often lack transparency and are not generally made available to researchers for independent verification and reproducibility. This violates the scientific method, and is counter to the stated position of the National Academy of Sciences and the top journals in the sciences and social sciences. Value in Health and related peer-reviewed journals could make a key contribution to improving scientific rigor and real-world healthcare decision-maker acceptability by requiring that VHDM models, source code, and data used in published articles be made freely available to interested readers.

Early onset sepsis calculator-based management of newborns exposed to maternal intrapartum fever: a cost benefit analysis.

OBJECTIVE: To determine potential net monetary benefit of an early onset sepsis calculator-based approach for management of neonates exposed to maternal intrapartum fever, compared to existing guidelines. STUDY DESIGN: We performed a cost-benefit analysis comparing two management approaches for newborns >34 weeks gestational age exposed to maternal intrapartum fever. Probabilities of sepsis and meningitis, consequences of infection and antibiotic use, direct medical costs, and indirect costs for long-term disability and mortality were considered. RESULTS: A calculator-based approach resulted in a net monetary benefit of $3998 per infant with a 60% likelihood of net benefit in probabilistic sensitivity analysis. Our model predicted a 67% decrease in antibiotic use in the calculator arm. The absolute difference for all adverse clinical outcomes between approaches was ≤0.6%. CONCLUSIONS: Compared to existing guidelines, a calculator-based approach for newborns exposed to maternal intrapartum fever yields a robust net monetary benefit, largely by preventing unnecessary antibiotic treatment.

Lifestyle intervention for adults with spinal cord injury: Results of the USC-RLANRC Pressure Ulcer Prevention Study.

CONTEXT/OBJECTIVE: Medically serious pressure injuries (MSPrIs), a common complication of spinal cord injury (SCI), have devastating consequences on health and well-being and are extremely expensive to treat. We aimed to test the efficacy of a lifestyle-based intervention designed to reduce incidence of MSPrIs in adults with SCI. DESIGN: A randomized controlled trial (RCT), and a separate study wing involving a nonrandomized standard care control group. SETTING: Rancho Los Amigos National Rehabilitation Center, a large facility serving ethnically diverse, low income residents of Los Angeles County. PARTICIPANTS: Adults with SCI, with history of one or more MSPrIs over the past 5 years: N=166 for RCT component, N=66 in nonrandomized control group. INTERVENTIONS: The Pressure Ulcer Prevention Program, a 12-month lifestyle-based treatment administered by healthcare professionals, largely via in-home visits and phone contacts. OUTCOME MEASURES: Blinded assessments of annualized MSPrI incidence rates at 12 and 24 months, based on: skin checks, quarterly phone interviews with participants, and review of medical charts and billing records. Secondary outcomes included number of surgeries and various quality-of-life measures. RESULTS: Annualized MSPrI rates did not differ significantly between study groups. At 12 months, rates were .56 for intervention recipients, .48 for randomized controls, and .65 for nonrandomized controls. At follow-up, rates were .44 and .39 respectively for randomized intervention and control participants. CONCLUSIONS: Evidence for intervention efficacy was inconclusive. The intractable nature of MSPrI threat in high-risk SCI populations, and lack of statistical power, may have contributed to this inability to detect an effect. TRIAL REGISTRATION: ClinicalTrials.gov NCT01999816.