Inflammation and exercise (INFLAME): study rationale, design, and methods

PurposeThe INFLAME study is designed to determine the effect of exercise training on elevated high-sensitivity C-Reactive Protein (CRP) concentrations in initially sedentary women and men.MethodsINFLAME will recruit 170 healthy, sedentary women and men with elevated CRP (≥ 2.0 mg/L) to be randomized to either an exercise group or non-exercise control group. Exercising individuals will participate in four months of supervised aerobic exercise with a total energy expenditure of 16 kcal kg^− 1 week^− 1 (KKW). Exercise intensity will be 60–80% of maximal oxygen consumption (VO₂ max).OutcomeThe primary outcome will be changed in plasma CRP concentration. Secondary outcomes include visceral adiposity, the cytokines IL-6 and TNF-α, and heart rate variability (HRV) in order to examine potential biological mechanisms whereby exercise might affect CRP concentrations.SummaryINFLAME will help us understand the effects of moderate-to-vigorous exercise on CRP concentrations in sedentary individuals. To our knowledge this will be the largest training study specifically designed to examine the effect of exercise on CRP concentrations. This study has the potential to influence therapeutic applications since CRP measurement is becoming an important clinical measurement in Coronary Heart Disease risk assessment. This study will also contribute to the limited body of literature examining the effect of exercise on the variables of visceral adiposity, cytokines, and heart rate variability.     

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 Oslo Diet and Exercise Study (ODES): Design and objectives

The Oslo Diet and Exercise Study (ODES) is an unmasked randomized 2 × 2 factorial trial of 1-year duration for each participant. During 1990–1991 219 participants (198 males and 21 females) aged 41–50 were randomized into one of four treatment groups; no treatment (control), dietary changes alone, excercise alone, or a combination of the two treatments. At inclusion, the participants had no overt heart disease, but they had increased body weight; slightly increased blood pressure, serum triglycerides, and total cholesterol, and they had decreased HDL cholesterol. Further, they were all inactive at leisure time.The primary aim of the trial is to compare the isolated and combined effects of the four treatments on the variables fibrinogen, fibrinolytic capacity, coagulation factor VII, and platelet volume. A series of secondary hypothesis will also be tested, such as the effects on other coagulation and fibrinolytic components and activities; lipids and lipoproteins; fatty acids; glucose and insulin response to a glucose load; clinical, physiological, and anthropometric variables; and quality of life.The dietary treatments are adapted according to each participant's risk profile (level of total cholesterol, HDL cholesterol, triglycerides, blood pressure, and body weight). Fish and fish products are recommended. Special emphasis is put on caloric restriction in those who are overweight and those with elevated blood pressure.Exercise sessions take place three times a week under the guidance of highly qualified instructors. The aim is to increase peak oxygen uptake through aerobic endurance training. Adherence to the exercise program is monitored closely.     

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 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.     

Quantitation of white cell subpopulations by polymerase chain reaction using frozen whole-blood samples. Viral Activation Transfusion Study

BACKGROUND: Previous methods for processing whole blood (WB) for nucleic acid analyses of white cells (WBCs) required fresh blood samples. A simple protocol that involves the freezing of WB for quantitative polymerase chain reaction (PCR) analyses was evaluated. STUDY DESIGN AND METHODS: Controlled studies were conducted in which paired fresh and frozen WB preparations were analyzed. The integrity of WBCs in the frozen WB samples was first assessed by flow cytometry using CD45 fluorescence, and calibration beads to quantitate recovery of WBC subsets. PCR of an HLA-DQ-A sequence was used to quantitate residual WBCs in a double-filtered red cell (RBC) component spiked with serial dilutions of WBCs, as well as in 51 filtered RBCs and 19 filtered platelet concentrates. Y-chromosome-specific PCR was used to quantitate male WBCs in five female WB samples spiked with serial dilutions of male WBCs and in serially collected frozen WB samples from four females transfused with male blood components. RESULTS: By flow cytometry, all major WBC subpopulations in frozen-thawed WB were quantitatively recovered and immunologically intact, although they were nonviable. HLA-DQ-A PCR quantitation of a dilution series from 8 to 16,700 per mL of WBCs spiked into double-filtered RBCs showed linear correlation of the results with both fresh and frozen preparations of the expected WBC concentrations (r2 = 0.98, p<0.0001 for both), without significant difference between observed and expected values (p>0.05). Y- chromosome-specific PCR results in female WB samples spiked with male WBCs were not significantly different in fresh and frozen preparations over a 3 log10 range of male cells. The results of WBC survival studies on frozen WB samples were consistent with previous observations in fresh blood samples. CONCLUSION: Direct freezing of WB enables subsequent recovery of WBCs for quantitative PCR analyses, with results comparable to those of fresh preparations. This protocol should facilitate wider implementation of nucleic acid-based analyses for quality control of WBC-reduced components, as well as for prospective clinical studies of microchimerism in transfusion and transplant recipients.     

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 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.     

The Improving Primary Care of African Americans with Diabetes (IPCAAD) project: rationale and design

African Americans have an increased burden of both diabetes and diabetes complications. Since many patients have high glucose levels novel interventions are needed, especially for urban patients with limited resources. In the Grady Diabetes Clinic in Atlanta, a stepped care strategy improves metabolic control. However, most diabetes patients do not receive specialized care. We will attempt to translate diabetes clinic approaches to the primary care setting by implementing a novel partnership between specialists and generalists. We hypothesize that endocrinologist-supported strategies aimed at providers will result in effective diabetes management in primary care sites, and the Improving Primary Care of African Americans with Diabetes project will test this hypothesis in a major randomized, controlled trial involving over 2000 patients. Physicians in Grady Medical Clinic units will receive (1) usual care, (2) computerized reminders that recommend individualized changes in therapy and/or (3) directed discussion by endocrinologists providing feedback on performance. We will measure outcomes related to both microvascular disease (HbA1c, which reflects average glucose levels over an approximately 2-month period) and macrovascular disease (blood pressure and lipids) and assess provider performance as well. We will compare two readily generalizable program interventions that should delineate approaches effective in a primary care setting as needed to improve care and prevent complications in urban African Americans with type 2 diabetes.     

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.     

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.     

The keys to healthy family child care homes intervention: Study design and rationale

BackgroundObesity is a major public health problem for which early preventive interventions are needed. Large numbers of young children are enrolled in some form of child care program, making these facilities influential environments in children's development. Family child care homes (FCCH) are a specific type of child care in which children are cared for within the provider's own residence. FCCHs serve approximately 1.5 million children in the U.S.; however, research to date has overlooked FCCH providers and their potential to positively influence children's health-related behaviors.MethodsKeys to Healthy Family Child Care Homes (Keys) is a cluster-randomized controlled trial testing the efficacy of an intervention designed to help providers become healthy role models, provide quality food- and physical activity-supportive FCCH environments, and implement effective business practices. The intervention is delivered through workshops, home visits, tailored coaching calls, and educational toolkits. Primary outcomes are child physical activity measured via accelerometry data and dietary intake data collected using direct observation at the FCCH. Secondary outcomes include child body mass index, provider weight-related behaviors, and observed obesogenic environmental characteristics.ConclusionKeys is an innovative approach to promoting healthy eating and physical activity in young children. The intervention operates in a novel setting, targets children during a key developmental period, and addresses both provider and child behaviors to synergistically promote health.     

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.     

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.     

Sequenced treatment alternatives to relieve depression (STAR*D): rationale and design

STAR*D is a multisite, prospective, randomized, multistep clinical trial of outpatients with nonpsychotic major depressive disorder. The study compares various treatment options for those who do not attain a satisfactory response with citalopram, a selective serotonin reuptake inhibitor antidepressant. The study enrolls 4000 adults (ages 18-75) from both primary and specialty care practices who have not had either a prior inadequate response or clear-cut intolerance to a robust trial of protocol treatments during the current major depressive episode. After receiving citalopram (level 1), participants without sufficient symptomatic benefit are eligible for randomization to level 2 treatments, which entail four switch options (sertraline, bupropion, venlafaxine, cognitive therapy) and three citalopram augment options (bupropion, buspirone, cognitive therapy). Those who receive cognitive therapy (switch or augment options) at level 2 without sufficient improvement are eligible for randomization to one of two level 2A switch options (venlafaxine or bupropion). Level 2 and 2A participants are eligible for random assignment to two switch options (mirtazapine or nortriptyline) and to two augment options (lithium or thyroid hormone) added to the primary antidepressant (citalopram, bupropion, sertraline, or venlafaxine) (level 3). Those without sufficient improvement at level 3 are eligible for level 4 random assignment to one of two switch options (tranylcypromine or the combination of mirtazapine and venlafaxine). The primary outcome is the clinician-rated, 17-item Hamilton Rating Scale for Depression, administered at entry and exit from each treatment level through telephone interviews by assessors masked to treatment assignments. Secondary outcomes include self-reported depressive symptoms, physical and mental function, side-effect burden, client satisfaction, and health care utilization and cost. Participants with an adequate symptomatic response may enter the 12-month naturalistic follow-up phase with brief monthly and more complete quarterly assessments.     

Biofeedback therapy in cardiovascular disease: rationale and research overview

Biofeedback has much therapeutic potential in cardiovascular diseases, since many of these diseases involve dysregulation of the autonomic nervous system. Studies have clearly demonstrated that patients can use biofeedback techniques to regulate the input of the autonomic nervous system to the heart, but the clinical utility of these techniques has not been well explored in systematic trials. Much biofeedback research to date has focused on patients with hypertension, but outcomes have been inconclusive. Preliminary studies suggest that heart rate variability biofeedback may be useful in improving symptoms and quality of life in patients with cardiac disease, and early studies suggest a possible effect of biofeedback on remodeling of the failing heart. Both of these areas require further research, however. Biofeedback is increasingly used as an adjunct to stress management in cardiac rehabilitation programs, providing the impetus for a large-scale, systematic study of self-regulation in cardiac disease.     

NIDA Clinical Trials Network CTN-0051, Extended-Release Naltrexone vs. Buprenorphine for Opioid Treatment (X:BOT): Study design and rationale

IntroductionFor opioid-dependent patients in the US and elsewhere, detoxification and counseling-only aftercare are treatment mainstays. Long-term abstinence is rarely achieved; many patients relapse and overdose after detoxification. Methadone, buprenorphine-naloxone (BUP-NX) and extended-release naltrexone (XR-NTX) can prevent opioid relapse but are underutilized. This study is intended to develop an evidence-base to help patients and providers make informed choices and to foster wider adoption of relapse-prevention pharmacotherapies.MethodsThe National Institute on Drug Abuse's Clinical Trials Network (CTN) study CTN-0051, X:BOT, is a comparative effectiveness study of treatment for 24 weeks with XR-NTX, an opioid antagonist, versus BUP-NX, a high affinity partial opioid agonist, for opioid dependent patients initiating treatment at 8 short-term residential (detoxification) units and continuing care as outpatients. Up to 600 participants are randomized (1:1) to XR-NTX or BUP-NX.ResultsThe primary outcome is time to opioid relapse (i.e., loss of persistent abstinence) across the 24-week treatment phase. Differences between arms in the distribution of time-to-relapse will be compared (construction of the asymptotic 95% CI for the hazard ratio of the difference between arms). Secondary outcomes include proportions retained in treatment, rates of opioid abstinence, adverse events, cigarette, alcohol, and other drug use, and HIV risk behaviors; opioid cravings, quality of life, cognitive function, genetic moderators, and cost effectiveness.ConclusionsXR-NTX and BUP-NX differ considerably in their characteristics and clinical management; no studies to date have compared XR-NTX with buprenorphine maintenance. Study design choices and compromises inherent to a comparative effectiveness trial of distinct treatment regimens are reviewed.Clinical Trial Registration: NCT02032433.