Better exercise adherence after treatment for cancer (BEAT Cancer) study: rationale, design, and methods

Most breast cancer survivors do not engage in regular physical activity. Our physical activity behavior change intervention for breast cancer survivors significantly improved physical activity and health outcomes post-intervention during a pilot, feasibility study. Testing in additional sites with a larger sample and longer follow-up is warranted to confirm program effectiveness short and longer term. Importantly, the pilot intervention resulted in changes in physical activity and social cognitive theory constructs, enhancing our potential for testing mechanisms mediating physical activity behavior change. Here, we report the rationale, design, and methods for a two-site, randomized controlled trial comparing the effects of the BEAT Cancer physical activity behavior change intervention to usual care on short and longer term physical activity adherence among breast cancer survivors. Secondary aims include examining social cognitive theory mechanisms of physical activity behavior change and health benefits of the intervention. Study recruitment goal is 256 breast cancer survivors with a history of ductal carcinoma in situ or Stage I, II, or IIIA disease who have completed primary cancer treatment. Outcome measures are obtained at baseline, 3 months (i.e., immediately post-intervention), 6 months, and 12 months and include physical activity, psychosocial factors, fatigue, sleep quality, lower extremity joint dysfunction, cardiorespiratory fitness, muscle strength, and waist-to-hip ratio. Confirming behavior change effectiveness, health effects, and underlying mechanisms of physical activity behavior change interventions will facilitate translation to community settings for improving the health and well-being of breast cancer survivors.     

Healthy Eating, Aerobic and Resistance Training in Youth (HEARTY): study rationale, design and methods

PurposeThe objective of the Healthy Eating Aerobic and Resistance Training in Youth (HEARTY) trial (ClinicalTrials.Gov # NCT00195858) was to examine the effects of resistance training, with and without aerobic training, on percent body fat in sedentary, post-pubertal overweight or obese adolescents aged 14–18 years. This paper describes the HEARTY study rationale, design and methods.MethodsAfter a 4-week supervised low-intensity exercise run-in period, 304 overweight or obese adolescents with a body mass index ≥ 85th percentile for age and sex were randomized to 4 groups for 22 weeks (5 months): diet + aerobic exercise, diet + resistance exercise, diet + combined aerobic and resistance exercise, or a diet only waiting-list control. All participants received dietary counseling designed to promote healthy eating with a maximum daily energy deficit of ? 250 kcal.OutcomesThe primary outcome is percent body fat measured by Magnetic Resonance Imaging. Secondary outcomes include changes in anthropometry, regional body composition, resting energy expenditure, cardiorespiratory fitness, musculoskeletal fitness, cardiometabolic risk markers, and psychological health.SummaryTo our knowledge, HEARTY is the largest clinical trial examining effects of aerobic training, resistance training, and combined aerobic and resistance training on changes in adiposity and cardiometabolic risk markers in overweight and obese adolescents. The findings will have important clinical implications regarding the role that resistance training should play in the management of adolescent obesity and its co-morbidities.     

The Initiating Dialysis Early and Late (IDEAL) study: study rationale and design.

OBJECTIVES: The primary objective of the IDEAL study is to determine whether the timing of dialysis initiation has an effect on survival in subjects with end-stage renal disease (ESRD). The secondary objectives are to determine the impact of "early start" versus "late start" dialysis on nutritional and cardiac morbidity, quality of life, and economic cost. DESIGN: Prospective multicenter randomized controlled trial. Patients are randomized to commence dialysis at a glomerular filtration rate (by Cockcroft-Gault) of either 10-14 mL/minute/1.73 m2 ("early start") or 5-7 mL/min/1.73 m2 ("late start"), with stratification for dialysis modality (hemodialysis vs peritoneal dialysis), study center, and the presence or not of diabetes mellitus. SETTING: Dialysis units throughout Australia and New Zealand. PATIENTS: Patients with ESRD commencing chronic dialysis therapy. OUTCOME MEASURES: Three years from randomization, all-cause mortality, morbidity, and economic impact; structural and functional cardiac status, nutritional state, and quality of life will be assessed. RESULTS: To date, 388 patients of a minimum 800 patients have been entered and randomized into the study. Current recruitment rates suggest sufficient patients will be enrolled by December 2004 and follow-up completed by December 2007. CONCLUSIONS: The IDEAL study will provide evidence for the optimal time to commence dialysis.     

The Childhood Asthma Management Program (CAMP): design, rationale, and methods. Childhood Asthma Management Program Research Group

The Childhood Asthma Management Program (CAMP) is a multicenter, randomized, double-masked clinical trial designed to determine the long-term effects of three inhaled treatments for mild to moderate childhood asthma: budesonide (a glucocorticoid used daily) and albuterol (a short-acting beta-agonist bronchodilator used as needed); nedocromil (a nonsteroid anti-inflammatory agent used daily) and albuterol; and placebo and albuterol. One thousand forty-one children (32% from ethnic minority groups), aged 5 to 12 years at screening, are currently participating. The primary outcome measure is lung growth as indicated by postbronchodilator forced expiratory volume in 1 second (FEV1) percent of predicted, observed over 5- to 6-year period. The trial also assesses differences between treatment groups with respect to airway responsiveness, morbidity, physical growth and development, and psychological growth and development. This report describes the design of the trial, the rationale for the design choices made, and the methods used to carry out the trial.     

Resistance Exercise in Already-Active Diabetic Individuals (READI): Study rationale,design and methods for a randomized controlled trial of resistance and aerobic exercise in type 1 diabetes

The Resistance Exercise in Already Active Diabetic Individuals (READI) trial aimed to examine whether adding a 6-month resistance training program would improve glycemic control (as reflected in reduced HbA_1c) in individuals with type 1 diabetes who were already engaged in aerobic exercise compared to aerobic training alone. After a 5-week run-in period including optimization of diabetes care and low-intensity exercise, 131 physically active adults with type 1 diabetes were randomized to two groups for 22 weeks: resistance training three times weekly, or waiting-list control. Both groups maintained the same volume, duration and intensity of aerobic exercise throughout the study as they did at baseline. HbA_1c, body composition, frequency of hypoglycemia, lipids, blood pressure, apolipoproteins B and A-1 (ApoB and ApoA1), the ApoB–ApoA1 ratio, urinary albumin excretion, serum C-reactive protein, free fatty acids, total daily insulin dose, health-related quality of life, cardiorespiratory fitness and musculoskeletal fitness were recorded at baseline, 3 (for some variables), and 6 months. To our knowledge, READI is the only trial to date assessing the incremental health-related impact of adding resistance training for individuals with type 1 diabetes who are already aerobically active. Few exercise trials have been completed in this population, and even fewer have assessed resistance exercise. With recent improvements in the quality of diabetes care, the READI study will provide conclusive evidence to support or refute a major clinically relevant effect of exercise type in the recommendations for physical activity in patients with type 1 diabetes.     

The evaluation of subcutaneous proleukin (interleukin-2) in a randomized international trial: rationale, design, and methods of ESPRIT

The Evaluation of Subcutaneous Proleukin in a Randomized International Trial (ESPRIT) is a large ongoing randomized trial of subcutaneous interleukin-2 (IL-2) plus antiretroviral therapy versus antiretroviral therapy alone in patients with HIV (human immunodeficiency virus) disease and CD4 cell counts of at least 300 cells/mm(3). The primary objective is to determine whether the addition of IL-2 to combination antiretroviral therapy improves morbidity and mortality. The aim is to recruit 4000 participants and follow them for an average of 5 years. Eligible subjects will be recruited at 275 investigational sites in 23 countries around the world. Coupled with broad eligibility criteria this will ensure widely applicable results. A range of secondary objectives will also be addressed in this setting that will include the conduct of observational studies and nested substudies with a public health focus. This article describes the rationale supporting the trial in addition to reviewing the study design, coordination, and governance.     

Physical activity across the curriculum (PAAC): rationale and design

BACKGROUND: Over the years schools have reduced physical education and recess time in favor of more academic instruction. Due to the drastic rise in obesity levels among children, some states have begun to mandate minimum amounts of physical activity (PA) that school children receive, causing schools to find alternative methods for increasing PA levels. Physical Activity Across the Curriculum (PAAC) is a 3-year randomized clinical trial incorporating moderate-intensity PA in elementary schools to reduce childhood obesity. This paper describes the rational, design, and methods of the PAAC intervention study. METHODS: Twenty-two elementary schools were randomized to either a control or intervention condition. In schools randomized to the intervention condition (PAAC), regular classroom teachers were taught how to incorporate PA into standard academic lessons. Teachers were asked to accumulate 90-100 min/week of PAAC each week through out the 3-year study period. Schools randomized to the control group did not alter their teaching methods. Direct observation of PA levels in the classroom was collected weekly. Height and weight was measured twice a year to calculate BMI. RESULTS: Two years of the intervention have been completed and only one school has left the study. The remaining 21 schools are participating in the final intervention year. CONCLUSIONS: The results from the PAAC intervention may provide schools with an alternative method to increase PA levels in children and reduce childhood obesity.     

The Dehydroepiandrosterone And WellNess (DAWN) study: research design and methods

Levels of dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEAS), the major secretory products of the adrenal gland, decline dramatically with age, concurrent with the onset of degenerative changes and chronic diseases associated with aging. Epidemiological evidences in humans and animal studies suggest that DHEA(S) may have cardioprotective, antiobesity, antidiabetic, and immuno-enhancing properties. These observations led to the proposal that restoration of DHEA to young adult levels may have beneficial effects on age-related conditions. Most clinical trials of DHEA replacement have been limited due to small samples and short duration, restriction to one sex, failure to adjust for baseline endogenous hormone level and age, or lack of placebo comparison groups. We designed a double blind, placebo-controlled randomized trial to determine the acceptability, benefits, and adverse effects of 50 mg daily oral DHEA replacement for one year in 110 men and 115 women, aged 55 to 85, who were healthy and not currently using hormone therapy. A wide range of biological outcomes were studied including bone mineral density and metabolism, body composition and muscle strength, immune function, and cardiovascular risk factors. Steroid hormone levels, bone markers, cytokines, and the IGF-I, IGF binding protein system were measured at baseline and at 3 follow-up clinic visits. Changes in mood and well-being, cognitive function, and sexuality were assessed. Information on potentially confounding covariates such as smoking, alcohol consumption, exercise, diet and dietary supplements were obtained, and potential adverse effects of DHEA administration were monitored. This study enables an examination of the benefits of DHEA administration on the health of older men and women, and the influence of gender, age, and baseline endogenous DHEA level on each outcome variable. Potential mechanisms of DHEA action, including the biotransformation of DHEA to active steroids and steroid metabolites, enhancement of IGF-I bioavailability, and inhibition of IL-6 production can also be evaluated.     

The Arthritis,Diet and Activity Promotion Trial (ADAPT): design,rationale, and baseline results

Osteoarthritis (OA) of the knee leads to restrictions of physical activity and ability to perform activities of daily living. Obesity is a risk factor for knee OA and it appears to exacerbate knee pain and disability. The Arthritis, Diet, and Activity Promotion Trial (ADAPT) was developed to test the efficacy of lifestyle behavioral changes on physical function, pain, and disability in obese, sedentary older adults with knee OA. This controlled trial randomized 316 sedentary overweight and obese older adults in a two-by-two factorial design into one of four 18-month duration intervention groups: Healthy Lifestyle Control; Dietary Weight Loss; Structured Exercise; or Combined Exercise and Dietary Weight Loss. The weight-loss goal for the diet groups was a 5% loss at 18 months. The intervention was modeled from principles derived from the group dynamics literature and social cognitive theory. Exercise training consisted of aerobic and strength training for 60 minutes, three times per week in a group and home-based setting. The primary outcome measure was self-report of physical function using the Western Ontario and McMaster University Osteoarthritis Index. Other measurements included timed stair climb, distance walked in 6 minutes, strength, gait, knee pain, health-related quality of life, knee radiographs, body weight, dietary intake, and cost-effectiveness of the interventions. We report baseline data stratified by level of overweight and obesity focusing on self-reported physical function and physical performance tasks. The results from ADAPT will provide approaches clinicians should recommend for behavioral therapies that effectively reduce the incidence of disability associated with knee OA.     

The inhaled Steroid Treatment as Regular Therapy in early asthma (START) study: rationale and design

Although the beneficial effects of treatment with inhaled steroids in asthma are widely accepted, the role of early intervention in patients with mild asthma remains unsettled. Conventional efficacy trials are often of short duration and involve highly selected patient populations that exclude many patients typical of those encountered in routine clinical practice. Hence, a large "real-world" effectiveness study is needed to evaluate the benefits of early intervention with inhaled steroids in patients with mild, persistent asthma. In the START (inhaled Steroid Treatment As Regular Therapy in early asthma) study, patients ages 6-60 years, from 31 countries and districts worldwide with mild persistent asthma, have been randomized to once-daily treatment with budesonide, 200 microg (for patients < 11 years) or 400 microg (for patients > or = 11 years), or placebo via Turbuhaler for 3 years. The double-blind treatment period will be followed by a 2-year period of open budesonide treatment. Throughout the study, other asthma medication including glucocorticosteroids can be given as judged appropriate by the investigator. Lung function will be measured by spirometry using standardized techniques at 3-month intervals throughout the study, and bronchodilator reversibility will be measured annually. The primary outcome measures are the time to the first severe asthma-related event during the first 3 years of the study and the change in postbronchodilator forced expiratory volume in 1 second (FEV(1)) from baseline during the entire 5-year study period. These measures have been chosen to reflect the progression of mild asthma toward more severe asthma and the extent of irreversible airflow limitation, which should reflect the degree of airway remodeling.     

Donepezil treatment of older adults with cognitive impairment and depression (DOTCODE study): Clinical rationale and design

Treatment strategies for patients with depression and cognitive impairment (DEP-CI), who are at high risk to develop a clinical diagnosis of dementia, are not established. This issue is addressed in the donepezil treatment of cognitive impairment and depression (DOTCODE) pilot clinical trial. The DOTCODE study is the first long-term treatment trial that assesses differences in conversion to dementia and cognitive change in DEP-CI patients using a study design of open antidepressant medication plus add-on randomized, double-blind, placebo-controlled treatment with the acetylcholinesterase inhibitor donepezil. In Phase 1, DEP-CI patients receive optimized antidepressant treatment for 16 weeks. In Phase 2, antidepressant treatment is continued with the addition of randomized, double-blind treatment with donepezil or placebo. The total study duration for each patient is 78 weeks (18 months). Eighty DEP-CI outpatients (age 55 to 95 years) are recruited: 40 at New York State Psychiatric Institute/Columbia University and 40 at Duke University Medical Center. The primary outcome is conversion to a clinical diagnosis of dementia. The secondary outcomes are cognitive change scores in Selective Reminding Test (SRT) total recall and the modified Alzheimer's Disease Assessment Scale (ADAS-cog). Other key assessments include the 24-item Hamilton Depression Rating Scale and antidepressant response; Clinical Global Impression (CGI) for depression, cognition, and global status; neuropsychological test battery for diagnosis; informant report of functional abilities (Pfeffer FAQ); and Treatment Emergent Symptom Scale (TESS) for somatic side effects. Apolipoprotein E ε4 status, odor identification deficits, and MRI entorhinal/hippocampal cortex atrophy at baseline are evaluated as neurobiological moderators of donepezil treatment effects.     

The Prevention of Early Asthma in Kids study: design, rationale and methods for the Childhood Asthma Research and Education network

Pediatric asthma remains an important public health concern as its prevalence and cost to the health care system is rising. In order to promote innovative research in asthma therapies, the National Heart, Lung and Blood Institute created the Childhood Asthma Research and Education Network in 1999. As its first study, the steering committee of the Childhood Asthma Research and Education Network designed a randomized clinical trial to determine if persistent asthma could be prevented in children at a high risk to develop the disease. This communication presents the design of its first clinical trial, the Prevention of Asthma in Kids (PEAK) trial and the organization of the Childhood Asthma Research and Education Network that developed and implemented this trial. Studies of the natural history of asthma have shown that, in persistent asthma, the initial asthma-like symptoms and loss of lung function occur predominately during the first years of life. Therefore, in the Prevention of Asthma in Kids study, children 2 and 3 years old with a positive asthma predictive index were randomized to twice daily treatment with fluticasone 88 microg or placebo via metered-dose inhaler and Aerochamber for 2 years. The double blind treatment period was followed by a 1-year observational period. Lung function was measured by spirometry and oscillometry technique at 4-month intervals throughout the study. Bronchodilator reversibility and exhaled nitric oxide (ENO) studies were performed at the end of the treatment and observation periods. The primary outcome measure was the number of asthma-free days. Other secondary outcomes included number of exacerbations, use of asthma medications and lung function. These measures were chosen to reflect the progression of the disease from intermittent wheezing to persistent asthma and measurement of the extent of airflow limitation and airway reactivity.     

Asthma randomized trial of indoor wood smoke (ARTIS): rationale and methods

BackgroundParticulate matter (PM) exposures have been linked with poor respiratory health outcomes, especially among susceptible populations such as asthmatic children. Smoke from biomass combustion for residential home heating is an important source of PM in many rural or peri-urban areas in the United States.AimTo assess the efficacy of residential interventions that reduce indoor PM exposure from wood stoves and to quantify the corresponding improvements in quality of life and health outcomes for asthmatic children.DesignThe asthma randomized trial of indoor wood smoke (ARTIS) study is an in-home intervention study of susceptible children exposed to biomass combustion smoke. Children, ages 7 to 17, with persistent asthma and living in homes that heat with wood stoves were recruited for this three arm randomized placebo-controlled trial. Two household-level intervention strategies, wood stove replacement and air filters, were compared to a sham air filter placebo. Improvement in quality of life of asthmatic children was the primary outcome. Secondary asthma-related health outcomes included peak expiratory flow (PEF) and forced expiratory volume in first second (FEV₁), biomarkers in exhaled breath condensate, and frequency of asthma symptoms, medication usage, and healthcare utilization. Exposure outcomes included indoor and outdoor PM_2.5 mass, particle counts of several size fractions, and carbon monoxide.DiscussionTo our knowledge, this was the first randomized trial in the US to utilize interventions targeting residential wood stoves to assess the impact on indoor PM and health outcomes in a susceptible population.     

The effects of urate lowering therapy on inflammation,endothelial function,and blood pressure (SURPHER) study design and rationale

BackgroundThe association between hyperuricemia and hypertension is controversial. Animal models, epidemiological data, and small clinical trials have favored a causative role for hyperuricemia in hypertension but more studies are necessary to elucidate putative mechanisms, population susceptibility, and potential for urate-lowering therapies (ULT) to decrease blood pressure (BP).PurposeTo describe the background and design of the Serum Urate Reduction to Prevent Hypertension (SURPHER) study.MethodsSURPHER is a single center, double-blinded, crossover trial in which participants are randomly assigned to allopurinol (300 mg) or placebo. Enrollment focused on adults 18–40 years old with baseline systolic blood pressure ≥ 120 and < 160 mm Hg or diastolic blood pressure ≥ 80 and < 100 mm Hg, and serum urate ≥ 5.0 mg/dL or ≥ 4.0 mg/dL for men or women, respectively. SURPHER recruitment targets participants without chronic kidney disease (estimated glomerular filtration rate > 60 mL/min/1.73 m2), and without prior diagnosis of gout or use of ULT to treat gout. The primary outcome is change from baseline in blood pressure assessed by 24 hour ambulatory blood pressure monitoring and mechanistic outcomes include changes in endothelial function as measured by flow-mediated dilation, as well as C-reactive protein levels.ResultsSince June 16, 2014 until present, SURPHER is recruiting participants in the city of Birmingham, Alabama.LimitationsThe study aims to enroll otherwise healthy young adults for a pharmacological intervention study with multiple study-related procedures. Challenges related to recruitment are anticipated and multiple strategies for increasing recruitment and retention are planned if necessary.     

A randomized trial of Evidence-based OutReach (EBOR): rationale and design.

There is increasing interest in evaluating the methods used to implement the findings from medical research. This paper describes the Evidence-based OutReach (EBOR) trial, which is the first large randomized study in the United Kingdom that will evaluate the effectiveness and efficiency of educational outreach visits by trained pharmacists who are delivering messages derived from four evidence-based clinical practice guidelines. General practices form the unit of allocation and analysis. The study design addresses important factors that may influence the effectiveness of the intervention, such as the pharmacist who delivers the messages, the health authority in which practices are located, and the size of a practice.     

Program to improve mobility in aging (PRIMA) study: Methods and rationale of a task-oriented motor learning exercise program

Walking difficulty is a common and costly problem in older adults. A potentially important yet unaddressed strategy to enhance walking ability through exercise intervention is to add a timing and coordination component in gait training (i.e. task specific timing and coordination exercise intervention) to the usual strength, endurance, and flexibility training. We describe the methods and rationale of a randomized single-blind, physical therapist supervised, exercise intervention trial to compare the effects of a standard strength, endurance, and flexibility program to a standard plus timing and coordination program in community-dwelling older adults walking slower than the desired gait speed of 1.2 m/s. Exercise sessions are twice weekly for 12 weeks. Participants are assessed at baseline, 12 weeks (post intervention), 24 weeks and 36 weeks. The primary outcome is gait speed, secondary outcomes represent components of the interventions (strength, endurance, flexibility, timing and coordination), and tertiary outcomes are measure of activity and participation (Late Life Function and Disability Instrument and physical activity). The findings of this trial will (1) establish if a standard-plus task specific timing and coordination program is superior to a standard strength and endurance program in improving mobility, activity and participation and (2) determine if the improvements are sustained over time. The information derived from this project will provide valuable insight into the prevention and management of walking difficulty, which is so common in older Americans.