Considerations for open-label randomized clinical trials: Design, conduct, and analysis.

Randomization and blinding are regarded as the most important tools to help reduce bias in clinical trial designs. Randomization is used to help guarantee that treatment arms differ systematically only by treatment assignment at baseline, and blinding is used to ensure that differences in endpoint evaluation and clinical decision-making during the trial arise only from the treatment received and not, for example, the expectation or desires of the people involved. However, given that there are times when it is not feasible or ethical to conduct fully blinded trials, we discuss what can be done to improve a trial, including conducting the trial as if it were a fully blinded trial and maintaining confidentiality of ongoing study results. In this article, we review how best to design, conduct, and analyze open-label trials to ensure the highest level of study integrity and the reliability of the study conclusions.

Complementary and Alternative Medicine Online Learning Intervention for Oncology Healthcare Providers: A Mixed-Methods Study.

INTRODUCTION: With the increased usage of complementary approaches in oncology comes the need for its integration into healthcare professional (HCP) education. The purpose of this single-arm, mixed-methods study was to examine the feasibility and benefits of a brief complementary and alternative medicine (CAM) learning intervention for improving HCP knowledge, attitudes, and practices regarding CAM use in cancer care, and explore the experiences of participating HCPs. METHODS: HCPs from the Tom Baker Cancer Centre in Alberta, Canada, were invited to participate in 3 online interactive learning modules that reviewed: (1) basic CAM information, (2) HCP-patient CAM communication, and (3) evidence-based CAM decision support. The study survey consisted of attitude (n = 14), knowledge (n = 31), and practice (n = 31) items, administered at baseline and two-months post-intervention. Semi-structured interviews were conducted with a subset of participants. RESULTS: Approximately 300 HCPs were invited to participate, of which 105 expressed interest in the study (35%), and 83 of them consented to participate (79%). The intervention completion rate was 73% (61/83 HCPs). There was a significant pre-post change in HCPs' attitudes and, to a lesser extent, knowledge and practices related to CAM (8/14 attitude items changed pre-post compared to 13/31 knowledge items and 5/31 practice items), in which more HCPs reported patients should be assisted in making complementary therapy (CT) decisions, exhibited greater knowledge about CAM, and more often engaged in a CAM-related clinical practice. Qualitative findings supported the beneficial effects of the modules, with HCPs describing themselves as being more likely to ask patients about their CAM use and referring them to credible CAM resources. Nonetheless, the majority did not feel adequately prepared to make recommendations about specific CTs, even after the intervention. CONCLUSION: The current study suggests that online CAM learning offers a feasible and potentially promising intervention for improving oncology HCP knowledge, attitudes, and practices regarding CAM, warranting further investigation. This study highlights a need for institutional resources to help HCPs fully integrate CT decision support into cancer patient care. A coordinated evidence-based CAM program at cancer centers may help ensure that all patients' CAM-related needs are properly attended to.

Concept End Points Informing Design Considerations for Confirmatory Clinical Trials in Osteoarthritis.

OBJECTIVE: There is an unmet need for therapies that target the underlying pathophysiology of osteoarthritis (OA). However, defining appropriate measures for clinical trials of such therapies is challenging. Our objective was to propose concept clinical end points that directly capture clinical benefit in this setting and evaluate the feasibility of their use. METHODS: This analysis used the multicenter, longitudinal, observational Osteoarthritis Initiative (OAI) database. OAI participants primarily had knee OA, with follow-up of up to 9 years and assessments of joints, surgical interventions, performance outcomes, and patient-reported outcomes. We examined this data set to identify existing outcome measures of direct clinical benefit. We evaluated the feasibility of conducting trials using these candidate end points by estimating incidence rates and resulting required sample sizes and study durations in time-to-event analyses. RESULTS: We identified candidate end points based on total knee replacement (TKR) and composite end points defined by TKR and conservative thresholds of patient-reported outcomes of pain and function. Using time to TKR as an end point, a study with an average follow-up time of 3 years requires approximately 3,000 to 18,000 subjects, depending on effect size. Alternatively, for a composite end point, such as "time to TKR or severe pain or severely impaired functioning," the required sample sizes ranged from approximately 2,000 to 11,000 for a 3-year study. CONCLUSION: The proposed concept end points can reliably and feasibly evaluate the effectiveness of therapies for this unmet need. In particular, the composite end point approach can substantially reduce sample sizes (up to approximately 40%) compared to the use of TKR alone.

Noninferiority Trials to Evaluate Drug Effects in Rheumatoid Arthritis.

OBJECTIVE: The increased availability of highly effective treatments in rheumatoid arthritis (RA) necessitates a reexamination of study designs evaluating new treatments. We undertook this study to discuss possible specifications and considerations of noninferiority (NI) trials assessing drug effects in RA. METHODS: We focused on the use of approved tumor necrosis factor inhibitors (TNFi) as potential active controls and reviewed previous placebo-controlled studies. We summarized the similarities in baseline characteristics and study design of the historical placebo-controlled studies used. After performing meta-analyses to estimate the effects of TNFi on symptoms, physical function, and radiographic progression in RA, we proposed NI margins and evaluated the feasibility of NI trials in this therapeutic setting. RESULTS: We determined that an NI trial comparing an experimental treatment to a TNFi using the symptomatic end point of the American College of Rheumatology 20% improvement criteria response can feasibly provide evidence of a treatment effect, with a 12% absolute difference as one possible appropriate NI margin. For change from baseline in the Health Assessment Questionnaire disability index score, reasonable margins range from 0.10 to 0.12. In evaluating radiographic progression, an appropriate margin and the corresponding feasibility of the trial are dependent on the selected active control and the expected variability in progression. CONCLUSION: Active-controlled studies in RA with justified NI margins can provide persuasive evidence of treatment effects on symptomatic, functional, and radiographic end points. Such studies can also provide reliable, controlled safety data and relevant information for treatment decisions in clinical practice. Thus, we recommend considering NI designs in future clinical trials in RA.

"In the same boat"-a mixed-methods exploration of reasons why male gastrointestinal cancer patients joined a professionally led men-only cancer support group.

PURPOSE: Gastrointestinal (GI) cancer patients often suffer high rates of distress and social isolation, partially due to symptoms that are embarrassing or difficult to discuss with family or friends. Group support therapies mitigate illness-related stigma and standardization; however, men, in particular, are more averse to joining. Through an ongoing men-only GI cancer support group, this study sought to understand who joined the groups, what facilitated group uptake, and explore men's reasons for enrolling in the group. METHODS: A mixed-methods study design and analysis were used. A qualitative design utilizing open-ended, semi-structured interviews and thematic analysis were used; Theory of Planned Behavior (TPB) directed the inquiry towards facets of group uptake. Standardized measures were also used to assess distress, coping, and quality of life (QoL) and compared with normative values for cancer and general population. Data from qualitative and quantitative findings were triangulated. RESULTS: Participants included 35 male GI cancer patients, aged 28-72, at varying stages of illness and treatment. Themes related to group uptake and enrollment were endorsement; composition; and attitudes, and reasons for joining were learning new coping techniques and affiliations with similar others. Men's QoL and psychological distress scores were on par with cancer patient norms. The scores obtained from quantitative scales corroborated with our qualitative findings. CONCLUSIONS: Despite psychosocial, demographic, and clinical variations, participants were keen on joining a male-only Supportive-Expressive Therapy (SET) group to address their emotional, informational, and supportive care needs and express their solidarity for other patients. IMPLICATIONS FOR CANCER SURVIVORS: Findings bear clinical relevance for designing GI male-centered group formats that endorse men's needs and facilitate their accessibility to group support interventions.

Modality of exercise influences rate of decrease in depression for cancer survivors with elevated depressive symptomatology.

PURPOSE: This three-arm feasibility controlled trial examined whether different exercise modalities provide reductions in depression symptoms to cancer survivors with elevated depression. METHODS: Thirty-two participants (58.9 ± 9.4 years) were allocated to a 12-week supervised exercise group (EX; n = 10), a self-managed home-based exercise group (SMHB; n = 8), or a usual care control group (CONT; n = 14). EX performed two supervised resistance and aerobic sessions per week. SMHB were provided with printed material about benefits of exercise and encouraged to complete 150 min of exercise weekly. CONT received no exercise or printed material and were encouraged to maintain usual activity. RESULTS: A group × time interaction was found for the primary outcome of depression scores, measured using the Hospital Anxiety and Depression Scale (HADS-D; p = .008). SMHB (6.4 ± 5.3 to 2.2 ± 2.9, p = .006) and EX (6.9 ± 4.2 to 4.0 ± 2.4, p = .021) interventions both effectively reduced HADS-D scores compared to CONT (7.2 ± 2.5 to 7.7 ± 3.6). SMHB decreased depression to a greater extent, and this occurred more rapidly with greatest changes noted at 6 weeks (d = 0.50). Further favourable outcomes for exercise were also noted for several secondary outcome measures. CONCLUSION: The rate of exercise-related reduction in depression is influenced by the modality of exercise. However, increasing the duration of the programme appears to diminish the favourable short-term response to self-managed exercise with subsequent secondary outcomes of mental health favouring supervised exercise.

Exercise Improves Physical Function and Mental Health of Brain Cancer Survivors: Two Exploratory Case Studies.

Background Malignant brain tumors are unpredictable and incurable, with 5-year survival rates less than 30%. The poor prognosis combined with intensive treatment necessitates the inclusion of complementary and supportive therapies that optimize quality of life and reduce treatment-related declines in health. Exercise therapy has been shown to be beneficial in other cancer populations, but no evidence is available for brain cancer survivors. Therefore, we report results from 2 preliminary cases. Methods Two female patients diagnosed with glioblastoma multiforme and oligodendroglioma participated in a structured and supervised 12-week exercise program. The program consisted of two 1-hour resistance and aerobic exercise sessions per week and additional self-managed aerobic sessions. Outcome measures of strength, cardiovascular fitness, and several psychological indicators (depression, anxiety, and quality of life) were recorded at baseline, after 6 weeks and at the conclusion of the intervention. Results Exercise was well tolerated; both participants completed all 24 sessions and the home-based component with no adverse effects. Objective outcome measures displayed positive responses relating to reduced morbidity. Similar positive responses were found for psychological outcomes. Scores on the Hospital Anxiety and Depression Scale showed clinically meaningful improvements in depression and total distress. Conclusion These findings provide initial evidence that, despite the difficulties associated with brain cancer treatment and survivorship, exercise may be safe and beneficial and should be considered in the overall management of patients with brain cancer.

Avoiding bias and incorrect confidence interval coverage in prescription drug labeling.

BACKGROUND: The primary purpose of prescription drug labeling is to give healthcare professionals the information needed to prescribe drugs appropriately. Therefore, labeling typically reports the effects that the treatment might be expected to have on several efficacy measures, including not only the primary endpoint used to establish effectiveness but also a number of key secondary endpoints that are important to practitioners and patients. METHODS: One possible regulatory approach to drug labeling is to include results on important secondary efficacy endpoints in labeling only if there is statistical evidence of a treatment effect and a clinically meaningful estimated effect. We evaluate the statistical consequences of this approach by deriving and discussing the potential bias in point estimates and deviation from nominal coverage in confidence intervals that are reported in labeling. RESULTS: Such an approach can lead to substantial conditional bias in point estimates (toward spuriously greater effects than the truth) and undercoverage in confidence intervals. CONCLUSION: These statistical properties may have important and undesirable regulatory and public health implications. We discuss an alternative approach to include results in labeling for a selected set of reliably ascertained, clinically important endpoints whether or not there is evidence of a treatment effect.

Surveys of Cancer Patients and Cancer Health Care Providers Regarding Complementary Therapy Use, Communication, and Information Needs.

BACKGROUND: Complementary therapies (CTs) are increasingly utilized by cancer patients. Nonetheless, patients report insufficient support from health care practitioners (HCPs) and there is a general lack of patient-practitioner communication about CT use. Best care practices suggest that HCPs should address the needs of patients, including CT use. This study examined current practices of patients and HCPs as well as their interactions relating to CTs. METHODS: A total of 481 cancer outpatients and 100 HCPs completed questionnaires. Patient questions addressed CT use and information needs; HCP questions addressed knowledge, opinions and beliefs about complementary and alternative medicine. Patient-practitioner communication around CT was also examined. RESULTS: 47% of patients reported using CTs since diagnosis. Many commenced CT use to improve quality of life (65%) based on recommendations from family or friends. Patients acknowledged the need for trusted sources of information and would attend a hospital-based education program (72%). HCPs reported limited training about CTs but most (90%) expressed interested in receiving more training. The majority of HCPs (>80%) reported limited knowledge about the role of CTs in cancer care or evidence to support CT use. Questions about communication and interactions revealed that 80% of patients reported not having had an HCP speak to them about CTs. However, 63% of HCPs reported addressing CT use. CONCLUSION: Results demonstrate a need for improved CT education and training for patients and HCPs. increasing HCP knowledge and clinical skills will ensure patients' information needs about CTs are acknowledged and attended to, thereby providing safer and comprehensive cancer care.

An evaluation of inferential procedures for adaptive clinical trial designs with pre-specified rules for modifying the sample size.

Many papers have introduced adaptive clinical trial methods that allow modifications to the sample size based on interim estimates of treatment effect. There has been extensive commentary on type I error control and efficiency considerations, but little research on estimation after an adaptive hypothesis test. We evaluate the reliability and precision of different inferential procedures in the presence of an adaptive design with pre-specified rules for modifying the sampling plan. We extend group sequential orderings of the outcome space based on the stage at stopping, likelihood ratio statistic, and sample mean to the adaptive setting in order to compute median-unbiased point estimates, exact confidence intervals, and P-values uniformly distributed under the null hypothesis. The likelihood ratio ordering is found to average shorter confidence intervals and produce higher probabilities of P-values below important thresholds than alternative approaches. The bias adjusted mean demonstrates the lowest mean squared error among candidate point estimates. A conditional error-based approach in the literature has the benefit of being the only method that accommodates unplanned adaptations. We compare the performance of this and other methods in order to quantify the cost of failing to plan ahead in settings where adaptations could realistically be pre-specified at the design stage. We find the cost to be meaningful for all designs and treatment effects considered, and to be substantial for designs frequently proposed in the literature.

Reliability of physiological attributes and their association with stochastic cycling performance.

PURPOSE: To assess the reliability of a 5-min-stage graded exercise test (GXT) and determine the association between physiological attributes and performance over stochastic cycling trials of varying distance. METHODS: Twenty-eight well-trained male cyclists performed 2 GXTs and either a 30-km (n = 17) or a 100-km stochastic cycling time trial (n = 9). Stochastic cycling trials included periods of high-intensity efforts for durations of 250 m, 1 km, or 4 km depending on the test being performing. RESULTS: Maximal physiological attributes were found to be extremely reliable (maximal oxygen uptake [VO2max]: coefficient of variation [CV] 3.0%, intraclass correlation coefficient [ICC] .911; peak power output [PPO]: CV 3.0%, ICC .913), but a greater variability was found in ventilatory thresholds and economy. All physiological variables measured during the GXT, except economy at 200 W, were correlated with 30-km cycling performance. Power output during the 250-m and 1-km efforts of the 30-km trial were correlated with VO2max, PPO, and the power output at the second ventilatory threshold (r = .58-.82). PPO was the only physiological attributed measured during the GXT to be correlated with performance during the 100-km cycling trial (r = .64). CONCLUSIONS: Many physiological variables from a reliable GXT were associated with performance over shorter (30-km) but not longer (100-km) stochastic cycling trials.

Estimating mean annual 25-hydroxyvitamin D concentrations from single measurements: the Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: The seasonal variation in circulating 25-hydroxyvitamin D [25(OH)D] concentrations is large relative to mean values. Single measurements may misclassify annual exposure, which may lead to bias in research and complicate clinical decision making. OBJECTIVE: We aimed to develop and validate a model for adjusting a single measurement of a serum 25(OH)D concentration to the time of year it was measured. DESIGN: We measured serum 25(OH)D concentrations by using mass spectrometry in 6476 participants from the Multi-Ethnic Study of Atherosclerosis at baseline and again in a subset of 368 participants at a median of 17 mo later. We estimated a cosinor model to describe the seasonal variability in 25(OH)D concentrations and evaluated this model by using follow-up 25(OH)D measurements. RESULTS: The mean age of subjects was 62.1 y, 61.2% of participants were nonwhite, and 53.3% of participants were women. The cosinor model predicted follow-up 25(OH)D concentrations better than a single measurement [difference in root mean squared error (RMSE): 1.3 ng/mL; P< 0.001]. The cosinor model also better predicted the measured annual mean 25(OH)D concentration (difference in RMSE: 1.0 ng/mL; P< 0.001). Annual mean 25(OH)D concentrations estimated from the cosinor model reclassified 7.1% of participants with regard to 25(OH)D deficiency, which was defined as <20 ng/mL. An estimated annual mean 25(OH)D concentration <20 ng/mL was significantly associated with lower bone mineral density, whereas an untransformed 25(OH)D concentration <20 ng/mL was not. CONCLUSIONS: Cross-sectional data can be used to estimate subject-specific mean annual 25(OH)D concentrations from single values by using a cosinor model. The tool we developed by using this approach may assist research and clinical care of adults in North America by reducing the misclassification of 25(OH)D deficiency.

Adaptive clinical trial designs with pre-specified rules for modifying the sample size: understanding efficient types of adaptation.

Adaptive clinical trial design has been proposed as a promising new approach that may improve the drug discovery process. Proponents of adaptive sample size re-estimation promote its ability to avoid 'up-front' commitment of resources, better address the complicated decisions faced by data monitoring committees, and minimize accrual to studies having delayed ascertainment of outcomes. We investigate aspects of adaptation rules, such as timing of the adaptation analysis and magnitude of sample size adjustment, that lead to greater or lesser statistical efficiency. Owing in part to the recent Food and Drug Administration guidance that promotes the use of pre-specified sampling plans, we evaluate alternative approaches in the context of well-defined, pre-specified adaptation. We quantify the relative costs and benefits of fixed sample, group sequential, and pre-specified adaptive designs with respect to standard operating characteristics such as type I error, maximal sample size, power, and expected sample size under a range of alternatives. Our results build on others' prior research by demonstrating in realistic settings that simple and easily implemented pre-specified adaptive designs provide only very small efficiency gains over group sequential designs with the same number of analyses. In addition, we describe optimal rules for modifying the sample size, providing efficient adaptation boundaries on a variety of scales for the interim test statistic for adaptation analyses occurring at several different stages of the trial. We thus provide insight into what are good and bad choices of adaptive sampling plans when the added flexibility of adaptive designs is desired.

Genetic variants and associations of 25-hydroxyvitamin D concentrations with major clinical outcomes.

CONTEXT: Lower serum 25-hydroxyvitamin D concentrations are associated with greater risks of many chronic diseases across large, prospective community-based studies. Substrate 25-hydroxyvitamin D must be converted to 1,25-dihydroxyvitamin D for full biological activity, and complex metabolic pathways suggest that interindividual variability in vitamin D metabolism may alter the clinical consequences of measured serum 25-hydroxyvitamin D. OBJECTIVE: To investigate whether common variation within genes encoding the vitamin D-binding protein, megalin, cubilin, CYP27B1, CYP24A1, and the vitamin D receptor (VDR) modify associations of low 25-hydroxyvitamin D with major clinical outcomes. DESIGN, SETTING, AND PARTICIPANTS: Examination of 141 single-nucleotide polymorphisms in a discovery cohort of 1514 white participants (who were recruited from 4 US regions) from the community-based Cardiovascular Health Study. Participants had serum 25-hydroxyvitamin D measurements in 1992-1993 and were followed up for a median of 11 years (through 2006). Replication meta-analyses were conducted across the independent, community-based US Health, Aging, and Body Composition (n = 922; follow-up: 1998-1999 through 2005), Italian Invecchiare in Chianti (n = 835; follow-up: 1998-2000 through 2006), and Swedish Uppsala Longitudinal Study of Adult Men (n = 970; follow-up: 1991-1995 through 2008) cohort studies. MAIN OUTCOME MEASURE: Composite outcome of incident hip facture, myocardial infarction, cancer, and mortality over long-term follow-up. RESULTS: Interactions between 5 single-nucleotide polymorphisms and low 25-hydroxyvitamin D concentration were identified in the discovery phase and 1 involving a variant in the VDR gene replicated in independent meta-analysis. Among Cardiovascular Health Study participants, low 25-hydroxyvitamin D concentration was associated with hazard ratios for risk of the composite outcome of 1.40 (95% CI, 1.12-1.74) for those who had 1 minor allele at rs7968585 and 1.82 (95% CI, 1.31-2.54) for those with 2 minor alleles at rs7968585. In contrast, there was no evidence of an association (estimated hazard ratio, 0.93 [95% CI, 0.70-1.24]) among participants who had 0 minor alleles at this single-nucleotide polymorphism. CONCLUSION: Known associations of low 25-hydroxyvitamin D with major health outcomes may vary according to common genetic differences in the vitamin D receptor.

The serum 24,25-dihydroxyvitamin D concentration, a marker of vitamin D catabolism, is reduced in chronic kidney disease.

Chronic kidney disease is characterized, in part, as a state of decreased production of 1,25-dihydroxyvitamin D (1,25(OH)(2)D); however, this paradigm overlooks the role of vitamin D catabolism. We developed a mass spectrometric assay to quantify serum concentration of 24,25-dihydroxyvitamin D (24,25(OH)(2)D), the first metabolic product of 25-hydroxyvitamin D (25(OH)D) by CYP24A1, and determined its clinical correlates and associated outcomes among 278 participants with chronic kidney disease in the Seattle Kidney Study. For eGFRs of 60 or more, 45-59, 30-44, 15-29, and under 15 ml/min per 1.73 m(2), the mean serum 24,25(OH)(2)D concentrations significantly trended lower from 3.6, 3.2, 2.6, 2.6, to 1.7 ng/ml, respectively. Non-Hispanic black race, diabetes, albuminuria, and lower serum bicarbonate were also independently and significantly associated with lower 24,25(OH)(2)D concentrations. The 24,25(OH)(2)D concentration was more strongly correlated with that of parathyroid hormone than was 25(OH)D or 1,25(OH)(2)D. A 24,25(OH)(2)D concentration below the median was associated with increased risk of mortality in unadjusted analysis, but this was attenuated with adjustment for potential confounding variables. Thus, chronic kidney disease is a state of stagnant vitamin D metabolism characterized by decreases in both 1,25(OH)(2)D production and vitamin D catabolism.

Serum 25-hydroxyvitamin D concentration and risk for major clinical disease events in a community-based population of older adults: a cohort study.

BACKGROUND: Circulating concentrations of 25-hydroxyvitamin D [25-(OH)D] are used to define vitamin D deficiency. Current clinical 25-(OH)D targets based on associations with intermediate markers of bone metabolism may not reflect optimal levels for other chronic diseases and do not account for known seasonal variation in 25-(OH)D concentration. OBJECTIVE: To evaluate the relationship of 25-(OH)D concentration with the incidence of major clinical disease events that are pathophysiologically relevant to vitamin D. DESIGN: Cohort study. SETTING: The Cardiovascular Health Study conducted in 4 U.S. communities. Data from 1992 to 2006 were included in this analysis. PARTICIPANTS: 1621 white older adults. MEASUREMENTS: Serum 25-(OH)D concentration (using a high-performance liquid chromatography-tandem mass spectrometry assay that conforms to National Institute of Standards and Technology reference standards) and associations with time to a composite outcome of incident hip fracture, myocardial infarction, cancer, or death. RESULTS: Over a median 11-year follow-up, the composite outcome occurred in 1018 participants (63%). Defining events included 137 hip fractures, 186 myocardial infarctions, 335 incidences of cancer, and 360 deaths. The association of low 25-(OH)D concentration with risk for the composite outcome varied by season (P = 0.057). A concentration lower than a season-specific Z score of -0.54 best discriminated risk for the composite outcome and was associated with a 24% higher risk in adjusted analyses (95% CI, 9% to 42%). Corresponding season-specific 25-(OH)D concentrations were 43, 50, 61, and 55 nmol/L (17, 20, 24, and 22 ng/mL) in winter, spring, summer, and autumn, respectively. LIMITATION: The observational study was restricted to white participants. CONCLUSION: Threshold concentrations of 25-(OH)D associated with increased risk for relevant clinical disease events center near 50 nmol/L (20 ng/mL). Season-specific targets for 25-(OH)D concentration may be more appropriate than static targets when evaluating health risk. PRIMARY FUNDING SOURCE: National Institutes of Health.

Variation in oral calcitriol response in patients with stages 3-4 CKD.

BACKGROUND: Oral calcitriol decreases parathyroid hormone (PTH) concentrations in patients who have chronic kidney disease (CKD); however, treatment response is highly variable. We evaluated whether patient characteristics affect the PTH response to oral calcitriol in nondialysis patients with CKD in a clinic-based setting. STUDY DESIGN: Cohort study. SETTING & PARTICIPANTS: This study included 379 new oral calcitriol users in the Veterans' Affairs Northwest Health Network. All had stages 3-4 CKD, hyperparathyroidism, and a serum PTH measurement before and 1-6 months after initiating oral calcitriol therapy. PREDICTORS: Patient-level characteristics hypothesized to affect calcitriol response: race, body size, concurrent medications, and kidney function. OUTCOMES: Relative decrease in serum PTH concentration after starting oral calcitriol therapy. MEASUREMENTS: Data were abstracted from the Veterans' Affairs Northwest Health Network (VISN 20) Data Warehouse, which includes electronic pharmacy and laboratory records. RESULTS: Mean estimated glomerular filtration rate was 30 mL/min/1.73 m(2) and mean initial PTH concentration was 199 pg/mL. Regular- (0.25 µg/d) and low-dose (<0.25 µg/d) oral calcitriol were associated with on average 23% and 13% relative decreases in serum PTH concentrations, respectively. After adjustment for calcitriol dosage, initial PTH concentration, and time to follow-up measurement, African American race was associated with a blunted calcitriol response (geometric mean final PTH value, 26% higher; 95% CI, 8%-47%). Serum albumin concentration <3.5 g/dL also was associated with a diminished calcitriol response (geometric mean final PTH, 19% higher; 95% CI, 6%-35%). Although numbers were small, concurrent use of benzodiazepines and nonactivated vitamin D supplements was associated with a significantly greater PTH response. LIMITATIONS: Clinic-based study is limited by the availability of PTH measurements after starting calcitriol therapy. Study of a predominantly older male population. CONCLUSIONS: In patients with stages 3-4 CKD, African American race and low serum albumin level are associated with a diminished PTH response to oral calcitriol.

Seasonal variation in 25-hydroxyvitamin D concentrations in the cardiovascular health study.

Low circulating concentrations of 25-hydroxyvitamin D (25(OH)D) are associated with adverse health outcomes in diverse populations. However, 25(OH)D concentrations vary seasonally with varying exposure to sunlight, so single measurements may poorly reflect long-term 25(OH)D exposure. The authors investigated cyclical trends in average serum 25(OH)D concentrations among 2,298 individuals enrolled in the Cardiovascular Health Study of community-based older adults (1992-1993). A sinusoidal model closely approximated observed 25(OH)D concentrations and fit the data significantly better than did a mean model (P < 0.0001). The mean annual 25(OH)D concentration was 25.1 ng/mL (95% confidence interval: 24.7, 25.5), and the mean peak-trough difference was 9.6 ng/mL (95% confidence interval: 8.5, 10.7). Male sex, higher latitude of study site, and greater physical activity levels were associated with larger peak-trough difference in 25(OH)D concentration (each P < 0.05). Serum concentrations of intact parathyroid hormone and bone-specific alkaline phosphatase also varied in a sinusoidal fashion (P < 0.0001), inversely to 25(OH)D. In conclusion, serum 25(OH)D varies in a sinusoidal manner, with large seasonal differences relative to mean concentration and laboratory evidence of biologic sequelae. Single 25(OH)D measurements might not capture overall vitamin D status, and the extent of misclassification could vary by demographic and behavioral factors. Accounting for collection time may reduce bias in research studies and improve decision-making in clinical care.