John E. Connett

The Effects of a Smoking Cessation Intervention on 14.5-Year Mortality: A Randomized Clinical Trial

Context Although there are many health benefits for smokers who stop smoking, we still lack evidence from randomized, controlled trials that smoking cessation programs reduce mortality. Contribution In this randomized, controlled trial of a 10-week-long smoking cessation intervention in 5887 smokers with asymptomatic airway obstruction, 14-year mortality rates were higher in the usual care group than in the smoking cessation group (hazard ratio, 1.18 [95% CI, 1.02 to 1.37]). The mortality benefit was greatest among the 21.7% of the intervention group who actually managed to quit smoking. Implications Smoking cessation programs substantially reduce mortality even when only a minority of patients stop smoking. The Editors Smoking cessation almost certainly has beneficial effects on subsequent mortality (1). However, the strongest support for this assertion comes from cohort studies, where smokers and quitters were self-selected. Results from randomized trials, which avoid the selection issue, have largely been disappointing because mortality benefits have not been clear or have not been clearly attributable to smoking cessation (1). The Lung Health Study (LHS) was a randomized clinical trial of smoking cessation and inhaled bronchodilator (ipratropium) therapy in smokers 35 to 60 years of age who did not consider themselves ill but had evidence of mild to moderate airway obstruction (2). Individuals with serious disease, hypertension, obesity, or excessive alcohol intake were excluded. The primary research questions were whether a smoking cessation program and use of inhaled ipratropium would decrease the rate of decline of lung function and would affect mortality and morbidity over 5 years. These results have been reported elsewhere (3, 4). The smoking cessation program was associated with cumulative reduced decline in lung function (FEV1) that was largest in participants who stopped smoking early in the study; inhaled ipratropium produced a small noncumulative increase in FEV1 that disappeared when the drug was withdrawn (3). Intention-to-treat analysis after 5 years did not reveal differences in morbidity or mortality among treatment groups (4), although subgroup analysis showed that smoking cessation was associated with significant reductions in fatal or nonfatal cardiovascular disease and coronary heart disease. This paper reports the effects of the study intervention on mortality in LHS participants 14.5 years after randomization. Methods The design of the LHS has been described in detail elsewhere (2). The participants, all volunteers, were smokers who did not consider themselves ill but had evidence of airway obstruction and little evidence of other disease. Researchers recruited participants from the community using a wide variety of techniques (5). In 10 clinical centers, 5887 participants were randomly assigned to 3 groups. Two special intervention groups received an intensive 10-week smoking cessation program. Briefly, the cessation intervention consisted of a strong physician message and 12 two-hour group sessions, using behavior modification and nicotine gum. Quitters entered a maintenance program that stressed coping skills. One special intervention group also received ipratropium, while the other received a placebo inhaler. A third group received usual care. About 75% of the original participants were followed continuously for the subsequent 10 years by biannual telephone contacts and 1 clinic visit at approximately 11 to 12 years after randomization (6). Telephone contacts served to check smoking status, morbidity, and mortality and were not part of the intervention. All study participants provided written informed consent for the original LHS before beginning the study. The consent documents stated that smoking increases the risk for chronic obstructive pulmonary disease, respiratory tract cancer, and cardiovascular disease and that smoking cessation would decrease such risks. Additional written informed consent was obtained from persons who participated in the biannual telephone calls. Institutional review boards at each of the 10 clinical centers and the coordinating center approved the study design and consent documents. When biannual phone calls revealed a participant death, staff attempted to collect death certificates, autopsy reports, relevant medical records, and interviews with attending physicians or eyewitnesses. An independent mortality and morbidity review board examined these data and classified causes of death. In addition, a National Death Index review provided date and cause of death for all U.S. study participants through the end of 2001. Vital status at 31 December 2001 or 14.5 years, whichever was earlier, was successfully determined for 98.3% of all participants; missing individuals were Canadians who had been lost to follow-up and were not accessible through the National Death Index. Mortality end points were classified in 7 categories: coronary heart disease, cardiovascular disease including coronary heart disease, lung cancer, other cancer, respiratory disease excluding lung cancer, other, and unknown. The other category included but was not limited to liver disease, kidney disease, sepsis, accidents, suicide, and AIDS. Analyses were performed on an intention-to-treat basis, comparing the special intervention group with the usual care group. The special intervention group was a combination of the groups originally assigned to receive inhaled ipratropium or placebo therapy. Both of these groups, which were very similar at baseline, received the smoking cessation program and exhibited similar rates of smoking cessation (3). Participants were also divided into 3 groups according to smoking history during the initial 5 years of the trial. Sustained quitters were participants who stopped smoking in the first year after randomization and maintained biochemically validated abstinence (3) throughout follow-up. Continuing smokers were participants who reported smoking at all follow-up visits. Intermittent quitters were participants who reported smoking at some but not all of their follow-up visits or during the time between visits. Statistical Analysis Baseline differences between the special intervention and usual care groups were tested by using t-tests for continuous variables and chi-square statistics for categorical variables. Cause-specific death rates and times to events were analyzed by using the KaplanMeier product-limit method (7). Survival was compared among groups by using the log-rank test. Hazard ratios and adjusted analyses were obtained by using the Cox proportional hazards model. Interactions were assessed by comparing hierarchically related proportional hazards models. All P values result from 2-sided tests; no adjustments were made for multiple comparisons. Role of the Funding Source This study was funded by a contract and grants from the National Heart, Lung, and Blood Institute of the National Institutes of Health. The funding source had a role in the design of the study and approved the manuscript before it was submitted for publication. Results Baseline characteristics of LHS participants are shown in Table 1. Most were middle-aged; smoked heavily; and had substantial smoking histories, airway obstruction (FEV1FVC ratio 70%), and borderline low FEV1 values. On average, participants were normotensive and had normal body mass indices. Most participants were of white ethnicity; 37% were women. The average participant had some postsecondary education and did not drink heavily. The special intervention and usual care groups did not significantly differ at baseline, except in percentage of participants who were married, which was higher in the special intervention group (P= 0.04). Smoking status after the first 5 years differed significantly between treatment groups (P 0.001). Among special intervention participants and usual care participants, respectively, 21.7% and 5.4% were sustained quitters, 29.3% and 23.3% were intermittent quitters, and 49.0% and 71.3% were continuing smokers. Table 1. Baseline Characteristics of Lung Health Study Participants There were 731 known deaths among LHS participants, as shown in Table 2. Lung cancer was the most common cause of death (n= 240 [33%]). Coronary heart disease accounted for 77 deaths (10.5%), and cardiovascular disease including coronary heart disease accounted for 163 deaths (22%). One hundred fifty-four participants (21%) died of cancer of organs other than the lung. Deaths due to respiratory disease other than cancer were relatively uncommon (n= 57 [7.8%]). The cause of death was unknown in only 17 participants (2.3%). Mortality did not significantly differ between the special intervention groups originally assigned to ipratropium or placebo (Table 2). Table 2. Causes of Death by Treatment Group Figure 1 shows all-cause survival rates in the 2 treatment groups. Death rates were significantly higher in the usual care group than in the special intervention group (10.38 per 1000 person-years vs. 8.83 per 1000 person-years; P= 0.03). The hazard ratio for mortality in the usual care group was 1.18 (95% CI, 1.02 to 1.37) compared with the special intervention group. Figure 2 shows categorical causes of death in the 2 treatment groups. In all categories except other, death rates were higher in the usual care group than in the special intervention group, but the difference was significant only for deaths from respiratory diseases not related to lung cancer (1.08 per 1000 person-years vs. 0.56 per 1000 person-years; P= 0.01). Figure 1. All-cause 14.5-year survival. P Figure 2. Mortality rates at 14.5 years by cause. When survival was analyzed according to smoking habit, it differed significantly between groups (P< 0.001), even after adjustment for baseline differences (data not shown). Mortality was 6.04 per 1000 person-years in sustained quitters, 7.77 per 1000 person-years in intermittent quitters, and 11.09 per 1000 p

Effect of inhaled triamcinolone on the decline in pulmonary function in chronic obstructive pulmonary disease

BACKGROUND Chronic obstructive pulmonary disease (COPD) results from a progressive decline in lung function, which is thought to be the consequence of airway inflammation. We hypothesized that antiinflammatory therapy with inhaled corticosteroids would slow this decline. METHODS We enrolled 1116 persons with COPD whose forced expiratory volume in one second (FEV1) was 30 to 90 percent of the predicted value in a 10-center, placebo-controlled, randomized trial of inhaled triamcinolone acetonide administered at a dose of 600 microg twice daily. The primary outcome measure was the rate of decline in FEV1 after the administration of a bronchodilator. The secondary outcome measures included respiratory symptoms, use of health care services, and airway reactivity. In a substudy of 412 participants, we measured bone density in the lumbar spine and femur at base line and one and three years after the beginning of treatment. RESULTS The mean duration of follow-up was 40 months. The rate of decline in the FEV1 after bronchodilator use was similar in the 559 participants in the triamcinolone group and the 557 participants in the placebo group (44.2+/-2.9 vs. 47.0+/-3.0 ml per year, P= 0.50). Members of the triamcinolone group had fewer respiratory symptoms during the course of the study (21.1 per 100 person-years vs. 28.2 per 100 person-years, P=0.005) and had fewer visits to a physician because of a respiratory illness (1.2 per 100 person-years vs. 2.1 per 100 person-years, P=0.03). Those taking triamcinolone also had lower airway reactivity in response to methacholine challenge at 9 months and 33 months (P=0.02 for both comparisons). After three years, the bone density of the lumbar spine and the femur was significantly lower in the triamcinolone group (P < or = 0.007). CONCLUSIONS Inhaled triamcinolone does not slow the rate of decline in lung function in people with COPD, but it improves airway reactivity and respiratory symptoms and decreases the use of health care services for respiratory problems. These benefits should be weighed against the potential long-term adverse effects of triamcinolone on bone mineral density.

Azithromycin for prevention of exacerbations of COPD.

BACKGROUND Acute exacerbations adversely affect patients with chronic obstructive pulmonary disease (COPD). Macrolide antibiotics benefit patients with a variety of inflammatory airway diseases. METHODS We performed a randomized trial to determine whether azithromycin decreased the frequency of exacerbations in participants with COPD who had an increased risk of exacerbations but no hearing impairment, resting tachycardia, or apparent risk of prolongation of the corrected QT interval. RESULTS A total of 1577 subjects were screened; 1142 (72%) were randomly assigned to receive azithromycin, at a dose of 250 mg daily (570 participants), or placebo (572 participants) for 1 year in addition to their usual care. The rate of 1-year follow-up was 89% in the azithromycin group and 90% in the placebo group. The median time to the first exacerbation was 266 days (95% confidence interval [CI], 227 to 313) among participants receiving azithromycin, as compared with 174 days (95% CI, 143 to 215) among participants receiving placebo (P<0.001). The frequency of exacerbations was 1.48 exacerbations per patient-year in the azithromycin group, as compared with 1.83 per patient-year in the placebo group (P=0.01), and the hazard ratio for having an acute exacerbation of COPD per patient-year in the azithromycin group was 0.73 (95% CI, 0.63 to 0.84; P<0.001). The scores on the St. Georges Respiratory Questionnaire (on a scale of 0 to 100, with lower scores indicating better functioning) improved more in the azithromycin group than in the placebo group (a mean [±SD] decrease of 2.8±12.8 vs. 0.6±11.4, P=0.004); the percentage of participants with more than the minimal clinically important difference of -4 units was 43% in the azithromycin group, as compared with 36% in the placebo group (P=0.03). Hearing decrements were more common in the azithromycin group than in the placebo group (25% vs. 20%, P=0.04). CONCLUSIONS Among selected subjects with COPD, azithromycin taken daily for 1 year, when added to usual treatment, decreased the frequency of exacerbations and improved quality of life but caused hearing decrements in a small percentage of subjects. Although this intervention could change microbial resistance patterns, the effect of this change is not known. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00325897.).

Roux-en-Y gastric bypass vs intensive medical management for the control of type 2 diabetes, hypertension, and hyperlipidemia: the Diabetes Surgery Study randomized clinical trial.

IMPORTANCE Controlling glycemia, blood pressure, and cholesterol is important for patients with diabetes. How best to achieve this goal is unknown. OBJECTIVE To compare Roux-en-Y gastric bypass with lifestyle and intensive medical management to achieve control of comorbid risk factors. DESIGN, SETTING, AND PARTICIPANTS A 12-month, 2-group unblinded randomized trial at 4 teaching hospitals in the United States and Taiwan involving 120 participants who had a hemoglobin A1c (HbA1c) level of 8.0% or higher, body mass index (BMI) between 30.0 and 39.9, C peptide level of more than 1.0 ng/mL, and type 2 diabetes for at least 6 months. The study began in April 2008. INTERVENTIONS Lifestyle-intensive medical management intervention and Roux-en-Y gastric bypass surgery. Medications for hyperglycemia, hypertension, and dyslipidemia were prescribed according to protocol and surgical techniques that were standardized. MAIN OUTCOMES AND MEASURES Composite goal of HbA1c less than 7.0%, low-density lipoprotein cholesterol less than 100 mg/dL, and systolic blood pressure less than 130 mm Hg. RESULTS All 120 patients received the intensive lifestyle-medical management protocol and 60 were randomly assigned to undergo Roux-en-Y gastric bypass. After 12-months, 28 participants (49%; 95% CI, 36%-63%) in the gastric bypass group and 11 (19%; 95% CI, 10%-32%) in the lifestyle-medical management group achieved the primary end points (odds ratio [OR], 4.8; 95% CI, 1.9-11.7). Participants in the gastric bypass group required 3.0 fewer medications (mean, 1.7 vs 4.8; 95% CI for the difference, 2.3-3.6) and lost 26.1% vs 7.9% of their initial body weigh compared with the lifestyle-medical management group (difference, 17.5%; 95% CI, 14.2%-20.7%). Regression analyses indicated that achieving the composite end point was primarily attributable to weight loss. There were 22 serious adverse events in the gastric bypass group, including 1 cardiovascular event, and 15 in the lifestyle-medical management group. There were 4 perioperative complications and 6 late postoperative complications. The gastric bypass group experienced more nutritional deficiency than the lifestyle-medical management group. CONCLUSIONS AND RELEVANCE In mild to moderately obese patients with type 2 diabetes, adding gastric bypass surgery to lifestyle and medical management was associated with a greater likelihood of achieving the composite goal. Potential benefits of adding gastric bypass surgery to the best lifestyle and medical management strategies of diabetes must be weighed against the risk of serious adverse events. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00641251.

C-reactive protein and mortality in mild to moderate chronic obstructive pulmonary disease

Background: Although C-reactive protein (CRP) levels are increased in chronic obstructive pulmonary disease (COPD), it is not certain whether they are associated with adverse clinical outcomes. Methods: Serum CRP levels were measured in 4803 participants in the Lung Health Study with mild to moderate COPD. The risk of all-cause and disease specific causes of mortality was determined as well as cardiovascular event rates, adjusting for important covariates such as age, sex, cigarette smoking, and lung function. Cardiovascular events were defined as death from coronary heart disease or stroke, or non-fatal myocardial infarction or stroke requiring admission to hospital. Results: CRP levels were associated with all-cause, cardiovascular, and cancer specific causes of mortality. Individuals in the highest quintile of CRP had a relative risk (RR) for all-cause mortality of 1.79 (95% confidence interval (CI) 1.25 to 2.56) compared with those in the lowest quintile of CRP. For cardiovascular events and cancer deaths the corresponding RRs were 1.51 (95% CI 1.20 to 1.90) and 1.85 (95% CI 1.10 to 3.13), respectively. CRP levels were also associated with an accelerated decline in forced expiratory volume in 1 second (p<0.001). The discriminative property of CRP was greatest during the first year of measurement and decayed over time. Comparing the highest and lowest CRP quintiles, the RR was 4.03 (95% CI 1.23 to 13.21) for 1 year mortality, 3.30 (95% CI 1.38 to 7.86) for 2 year mortality, and 1.82 (95% CI 1.22 to 2.68) for ⩾5 year mortality. Conclusions: CRP measurements provide incremental prognostic information beyond that achieved by traditional markers of prognosis in patients with mild to moderate COPD, and may enable more accurate detection of patients at a high risk of mortality.

Inhaled corticosteroids and mortality in chronic obstructive pulmonary disease

Background: Clinical studies suggest that inhaled corticosteroids reduce exacerbations and improve health status in chronic obstructive pulmonary disease (COPD). However, their effect on mortality is unknown. Methods: A pooled analysis, based on intention to treat, of individual patient data from seven randomised trials (involving 5085 patients) was performed in which the effects of inhaled corticosteroids and placebo were compared over at least 12 months in patients with stable COPD. The end point was all-cause mortality. Results: Overall, 4% of the participants died during a mean follow up period of 26 months. Inhaled corticosteroids reduced all-cause mortality by about 25% relative to placebo. Stratification by individual trials and adjustments for age, sex, baseline post-bronchodilator percentage predicted forced expiratory volume in 1 second, smoking status, and body mass index did not materially change the results (adjusted hazard ratio (HR) 0.73; 95% confidence interval (CI) 0.55 to 0.96). Although there was considerable overlap between subgroups in terms of effect sizes, the beneficial effect was especially noticeable in women (adjusted HR 0.46; 95% CI 0.24 to 0.91) and former smokers (adjusted HR 0.60; 95% CI 0.39 to 0.93). Conclusions: Inhaled corticosteroids reduce all-cause mortality in COPD. Further studies are required to determine whether the survival benefits persist beyond 2–3 years.

A Candidate Gene Approach Identifies the CHRNA5-A3-B4 Region as a Risk Factor for Age-Dependent Nicotine Addiction

People who begin daily smoking at an early age are at greater risk of long-term nicotine addiction. We tested the hypothesis that associations between nicotinic acetylcholine receptor (nAChR) genetic variants and nicotine dependence assessed in adulthood will be stronger among smokers who began daily nicotine exposure during adolescence. We compared nicotine addiction—measured by the Fagerstrom Test of Nicotine Dependence—in three cohorts of long-term smokers recruited in Utah, Wisconsin, and by the NHLBI Lung Health Study, using a candidate-gene approach with the neuronal nAChR subunit genes. This SNP panel included common coding variants and haplotypes detected in eight α and three β nAChR subunit genes found in European American populations. In the 2,827 long-term smokers examined, common susceptibility and protective haplotypes at the CHRNA5-A3-B4 locus were associated with nicotine dependence severity (p = 2.0×10−5; odds ratio = 1.82; 95% confidence interval 1.39–2.39) in subjects who began daily smoking at or before the age of 16, an exposure period that results in a more severe form of adult nicotine dependence. A substantial shift in susceptibility versus protective diplotype frequency (AA versus BC = 17%, AA versus CC = 27%) was observed in the group that began smoking by age 16. This genetic effect was not observed in subjects who began daily nicotine use after the age of 16. These results establish a strong mechanistic link among early nicotine exposure, common CHRNA5-A3-B4 haplotypes, and adult nicotine addiction in three independent populations of European origins. The identification of an age-dependent susceptibility haplotype reinforces the importance of preventing early exposure to tobacco through public health policies.

Effects of randomized assignment to a smoking cessation intervention and changes in smoking habits on respiratory symptoms in smokers with early chronic obstructive pulmonary disease : The Lung Health Study

PURPOSE To evaluate the effects of randomly assigning smokers who have early chronic obstructive pulmonary disease (COPD) to a smoking-cessation intervention on the symptoms of chronic cough, chronic phlegm production, wheezing and shortness of breath, and to determine the effects of quitting smoking on these symptoms. SUBJECTS AND METHODS A total of 5,887 male and female smokers 35 to 60 years of age with early COPD [defined as a forced expiratory volume in the first second (FEV1) of 55% to 90% of predicted and FEV1/forced vital capacity (FVC) <0.70] were enrolled in a 5-year clinical trial. Two-thirds of participants were randomly assigned to smoking-intervention groups and one-third to a usual-care group. The intervention groups attended 12 intensive smoking-cessation sessions that included behavior modification techniques and the use of nicotine chewing gum. One intervention group was treated with ipratropium bromide by inhaler; the other intervention group received placebo inhalers. The usual-care group was advised to stop smoking. All participants were followed annually. Smoking status was biochemically validated by salivary cotinine measurements or exhaled carbon monoxide values. RESULTS Validated 5-year sustained smoking cessation occurred in 22% of participants in the intervention compared with only 5% of participants in the usual-care group. At the end of the study, the prevalence of each of the four symptoms in the two intervention groups was significantly less than in the usual-care group (P <0.0001). For example, among participants who did not report cough at baseline, 15% of those in the intervention groups had cough at least 3 months during the year, compared with 23% of those in usual care. Sustained quitters had the lowest prevalence of all four symptoms, whereas continuous smokers had the greatest prevalence of these symptoms. Changes in symptoms occurred primarily in the first year after smoking cessation. Respiratory symptoms were associated with greater declines in FEV1 during the study (P <0.001). Ipratropium bromide had no long-term effects on respiratory symptoms. CONCLUSIONS In this prospective randomized trial using an intention-to-treat analysis, smokers with early COPD who were assigned to a smoking-cessation intervention had fewer respiratory symptoms after 5 years of follow-up.

Fibrotic extracellular matrix activates a profibrotic positive feedback loop

Pathological remodeling of the extracellular matrix (ECM) by fibroblasts leads to organ failure. Development of idiopathic pulmonary fibrosis (IPF) is characterized by a progressive fibrotic scarring in the lung that ultimately leads to asphyxiation; however, the cascade of events that promote IPF are not well defined. Here, we examined how the interplay between the ECM and fibroblasts affects both the transcriptome and translatome by culturing primary fibroblasts generated from IPF patient lung tissue or nonfibrotic lung tissue on decellularized lung ECM from either IPF or control patients. Surprisingly, the origin of the ECM had a greater impact on gene expression than did cell origin, and differences in translational control were more prominent than alterations in transcriptional regulation. Strikingly, genes that were translationally activated by IPF-derived ECM were enriched for those encoding ECM proteins detected in IPF tissue. We determined that genes encoding IPF-associated ECM proteins are targets for miR-29, which was downregulated in fibroblasts grown on IPF-derived ECM, and baseline expression of ECM targets could be restored by overexpression of miR-29. Our data support a model in which fibroblasts are activated to pathologically remodel the ECM in IPF via a positive feedback loop between fibroblasts and aberrant ECM. Interrupting this loop may be a strategy for IPF treatment.

Simvastatin for the Prevention of Exacerbations in Moderate-to-Severe COPD

BACKGROUND Retrospective studies have shown that statins decrease the rate and severity of exacerbations, the rate of hospitalization, and mortality in chronic obstructive pulmonary disease (COPD). We prospectively studied the efficacy of simvastatin in preventing exacerbations in a large, multicenter, randomized trial. METHODS We designed the Prospective Randomized Placebo-Controlled Trial of Simvastatin in the Prevention of COPD Exacerbations (STATCOPE) as a randomized, controlled trial of simvastatin (at a daily dose of 40 mg) versus placebo, with annual exacerbation rates as the primary outcome. Patients were eligible if they were 40 to 80 years of age, had COPD (defined by a forced expiratory volume in 1 second [FEV1] of less than 80% and a ratio of FEV1 to forced vital capacity of less than 70%), and had a smoking history of 10 or more pack-years, were receiving supplemental oxygen or treatment with glucocorticoids or antibiotic agents, or had had an emergency department visit or hospitalization for COPD within the past year. Patients with diabetes or cardiovascular disease and those who were taking statins or who required statins on the basis of Adult Treatment Panel III criteria were excluded. Participants were treated from 12 to 36 months at 45 centers. RESULTS A total of 885 participants with COPD were enrolled for approximately 641 days; 44% of the patients were women. The patients had a mean (±SD) age of 62.2±8.4 years, an FEV1 that was 41.6±17.7% of the predicted value, and a smoking history of 50.6±27.4 pack-years. At the time of study closeout, the low-density lipoprotein cholesterol levels were lower in the simvastatin-treated patients than in those who received placebo. The mean number of exacerbations per person-year was similar in the simvastatin and placebo groups: 1.36±1.61 exacerbations and 1.39±1.73 exacerbations, respectively (P=0.54). The median number of days to the first exacerbation was also similar: 223 days (95% confidence interval [CI], 195 to 275) and 231 days (95% CI, 193 to 303), respectively (P=0.34). The number of nonfatal serious adverse events per person-year was similar, as well: 0.63 events with simvastatin and 0.62 events with placebo. There were 30 deaths in the placebo group and 28 in the simvastatin group (P=0.89). CONCLUSIONS Simvastatin at a daily dose of 40 mg did not affect exacerbation rates or the time to a first exacerbation in patients with COPD who were at high risk for exacerbations. (Funded by the National Heart, Lung, and Blood Institute and the Canadian Institutes of Health Research; STATCOPE ClinicalTrials.gov number, NCT01061671.).