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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Glucose, insulin, and incident hypertension in the multi-ethnic study of atherosclerosis.

Diabetes mellitus and hypertension commonly coexist, but the nature of this link is not well understood. The authors tested whether diabetes and higher concentrations of fasting serum glucose and insulin are associated with increased risk of developing incident hypertension in the community-based Multi-Ethnic Study of Atherosclerosis. At baseline, 3,513 participants were free of hypertension, defined as systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or use of antihypertensive medications to treat high blood pressure. Of these, 965 participants (27%) developed incident hypertension over 4.7 years' median follow-up between 2002 and 2007. Compared with participants with normal baseline fasting glucose, those with impaired fasting glucose and diabetes had adjusted relative risks of hypertension of 1.16 (95% confidence interval (CI): 0.96, 1.40) and 1.41 (95% CI: 1.17, 1.71), respectively (P = 0.0015). The adjusted relative risk of incident hypertension was 1.08 (95% CI: 1.04, 1.13) for each mmol/L higher glucose (P < 0.0001) and 1.15 (95% CI: 1.05, 1.25) for each doubling of insulin (P = 0.0016). Further adjustment for serum cystatin C, urinary albumin/creatinine ratio, and arterial elasticity measured by tonometry substantially reduced the magnitudes of these associations. In conclusion, diabetes and higher concentrations of glucose and insulin may contribute to the development of hypertension, in part through kidney disease and arterial stiffness.

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.

Allopurinol and mortality in hyperuricaemic patients.

OBJECTIVES: While studies have suggested that gout and hyperuricaemia are associated with the risk of premature death, none has investigated the role of urate-lowering therapy on this critical outcome. We examined the impact of allopurinol, the most commonly used urate-lowering drug, on the risk of mortality in hyperuricaemic patients. METHODS: From a population of hyperuricaemic veterans of [serum urate level >416 micromol/l (7.0 mg/dl)] at least 40 years of age, we compared the risk of death between incident allopurinol users (n = 2483) and non-users (n = 7441). We estimated the multivariate mortality hazard ratio (HR) of allopurinol use with Cox proportional hazards models. RESULTS: Of the 9924 veterans (males, 98% and mean age 62.7 years), 1021 died during the follow-up. Patients who began treatment with allopurinol had worse prognostic factors for mortality, including higher BMI and comorbidities. After adjusting for baseline urate levels, allopurinol treatment was associated with a lower risk of all-cause mortality (HR 0.78; 95% CI 0.67, 0.91). Further adjustment with other prognostic factors did not appreciably alter this estimate (HR 0.77; 95% CI 0.65, 0.91). The mean change from baseline in serum urate within the allopurinol group was -111 micromol/l (-1.86 mg/dl). Adjusting for baseline urate level, allopurinol users had a 40 micromol/l (0.68 mg/dl) lower follow-up serum urate value than controls (95% CI -0.55, -0.81). CONCLUSION: Our findings indicate that allopurinol treatment may provide a survival benefit among patients with hyperuricaemia.

A phase III clinical trial of exercise modalities on treatment side-effects in men receiving therapy for prostate cancer.

BACKGROUND: Androgen deprivation therapy (ADT) is accompanied by a number of adverse side effects including reduced bone mass and increased risk for fracture, reduced lean mass and muscle strength, mood disturbance and increased fat mass compromising physical functioning, independence, and quality of life. The purpose of this investigation is to examine the effects of long term exercise on reversing musculoskeletal-related side effects, and cardiovascular and diabetes risk factors in men receiving androgen deprivation for their prostate cancer. Specifically, we aim to investigate the effects of a 12-month exercise program designed to load the musculoskeletal system and reduce cardiovascular and diabetes disease progression on the following primary endpoints: 1) bone mineral density; 2) cardiorespiratory function and maximal oxygen capacity; 3) body composition (lean mass and fat mass); 4) blood pressure and cardiovascular function; 5) lipids and glycemic control; and 6) quality of life and psychological distress. METHODS/DESIGN: Multi-site randomized controlled trial of 195 men (65 subjects per arm) undergoing treatment for prostate cancer involving ADT in the cities of Perth and Brisbane in Australia. Participants will be randomized to (1) resistance/impact loading exercise, (2) resistance/cardiovascular exercise groups and (3) usual care/delayed exercise. Participants will then undergo progressive training for 12 months. Measurements for primary and secondary endpoints will take place at baseline, 6 and 12 months (end of the intervention). DISCUSSION: The principal outcome of this project will be the determination of the strength of effect of exercise on the well established musculoskeletal, cardiovascular and insulin metabolism side effects of androgen deprivation in prostate cancer patients. As this project is much longer term than previous investigations in the area of exercise and cancer, we will gain knowledge as to the continuing effects of exercise in this patient population specifically targeting bone density, cardiovascular function, lean and fat mass, physical function and falls risk as primary study endpoints. In terms of advancement of prostate cancer care, we expect dissemination of the knowledge gained from this project to reduce fracture risk, improve physical and functional ability, quality of life and ultimately survival rate in this population. CLINICAL TRIAL REGISTRY: A Phase III clinical trial of exercise modalities on treatment side-effects in men receiving therapy for prostate cancer; ACTRN12609000200280.

Effect of concurrent resistance and endurance training on physiologic and performance parameters of well-trained endurance cyclists.

The purpose of this study was to investigate the effect of concurrent resistance and endurance cycle training on physiologic and performance parameters of cyclists. Before and after a 6-week training intervention period, 14 well-trained male cyclists completed a maximal graded exercise test, a 30-km dynamic cycling test with 3 intermittent 250-m and 1-km sprints, and a 1 repetition maximum (1RM) squat test for the assessment of lower-limb strength. Subjects were allocated into 2 groups: a resistance training group (RT; n = 7) that completed a 6-week undulating, periodized resistance training program (3/wk) in conjunction with their regular cycle training and a control group (CON; n = 7) that maintained their usual cycle training. Upon completion of the training intervention, there was no change in graded exercise test parameters in either group, but the RT group showed a significantly greater increase in 1RM squat strength compared with CON (p < 0.05). Moreover, the change in 30-km time trial and sprinting performance did not differ between RT and CON, except for the final 1-km sprint where the percent change in 1-km final sprint performance was greater in CON (+11%) compared with RT (-5%). In conclusion, although concurrent resistance and endurance training in well-trained cyclists enhanced 1RM strength, it did not improve overall cycle time trial performance and in fact was shown to reduce 1-km final cycle sprint performance compared with a CON group performing their normal cycle training.

Stepping backward can improve sprint performance over short distances.

The use of a backward (false) step to initiate forward movement has been regarded as an inferior starting technique and detrimental to sprinting performance over short distances as it requires additional time to be completed, but little evidence exists to support or refute this claim. Therefore, we recruited 27 men to examine the temporal differences among three standing starts that employed either a step forward (F) or a step backward (B) to initiate movement. An audio cue was used to mark the commencement of each start and to activate the subsequent timing gates. Three trials of each starting style were performed, and movement (0 m), 2.5 m, and 5 m times were recorded. Despite similar performances to the first timing gate (0.80 and 0.81 s for F and B, respectively), utilizing a step forward to initiate movement resulted in significantly slower sprint times to both 2.5 and 5 m (6.4% and 5.3%, respectively). Furthermore, when the movement times were removed and performances were compared between gates 1 and 2, and 2 and 3, all significant differences were seen before reaching a distance of only 2.5 m. The results from this investigation question the advocacy of removing the false step to improve an athlete's sprint performance over short distances. In fact, if the distance to be traveled is as little as 0.5 m in the forward direction, adopting a starting technique in which a step backward is employed may result in superior performance.