3

Examples of Large Simple Trials

KEY SPEAKER THEMES

Manson

•   The VITamin D and omegA 3 triaL (VITAL) is an example of a two-by-two factorial, placebo-controlled prevention trial being done primarily through the mail with a very large, demographically representative cohort.

•   VITAL has a cost-efficient hybrid design involving ascertainment of incident clinical events in 25,000 participants nationwide, together with in-clinic visits and in-depth phenotyping of a subset of 1,000 participants.

Choudhry

•   The Myocardial Infarction Free Rx (Prescription) Event and Economic Evaluation (MI FREEE) trial was done in partnership with a payer to test whether the elimination of out-of-pocket expenses for medications taken after a myocardial infarction would improve patient adherence to prescription medications and clinical outcomes.

•   The MI FREEE trial demonstrated that it is possible to conduct large simple trials (LSTs) with clinical and policy relevance.



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3 Examples of Large Simple Trials KEY SPEAKER THEMES Manson • The VITamin D and omegA 3 triaL (VITAL) is an example of a two-by-two factorial, placebo-controlled prevention trial being done primarily through the mail with a very large, de- mographically representative cohort. • VITAL has a cost-efficient hybrid design involving ascertain- ment of incident clinical events in 25,000 participants nation- wide, together with in-clinic visits and in-depth phenotyping of a subset of 1,000 participants. Choudhry • The Myocardial Infarction Free Rx (Prescription) Event and Economic Evaluation (MI FREEE) trial was done in part- nership with a payer to test whether the elimination of out- of-pocket expenses for medications taken after a myocardial infarction would improve patient adherence to prescription medications and clinical outcomes. • The MI FREEE trial demonstrated that it is possible to conduct large simple trials (LSTs) with clinical and policy relevance. 19

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20 LARGE SIMPLE TRIALS IN A LEARNING HEALTH SYSTEM Taveras • The High Five for Kids and Study of Technology to Accelerate Research (STAR) trials are electronic health record (EHR)- based LSTs done to test antiobesity interventions in pediatric populations. • EHR systems can be very useful for identification of potential trial participants, data collection, and provision of decision support tools for parents and clinicians. Devereaux • The Heart Outcomes Prevention Evaluation (HOPE) trial was a large, randomized trial of the angiotensin-converting-enzyme inhibitor ramipril and vitamin E in patients at high risk of cardiovascular events. • Consideration of the applicability of the results during the trial design led to a widespread impact on clinician practice. INTRODUCTION The part of the workshop described in this chapter was devoted to presentations describing four large simple trials (LSTs), some ongoing and some completed, that have different features of interest. JoAnn E. Manson, chief of the Division of Preventive Medicine at Brigham and Women’s Hos- pital and the Michael and Lee Bell Professor of Women’s Health at Harvard Medical School, presented an overview of the ongoing VITamin D and omegA 3 triaL (VITAL). Niteesh K. Choudhry, Department of Medicine, Brigham and Women’s Hospital, and associate professor, Harvard Medical School, reviewed the Post-Myocardial Infarction Free Rx (Prescription) Event and Economic Evaluation (MI FREEE) Trial. Elsie M. Taveras, asso- ciate professor of population medicine, Harvard Pilgrim Health Care Insti- tute, Harvard Medical School, reviewed two LSTs, High Five for Kids and the Study of Technology to Accelerate Research (STAR). P. J. Devereaux, Population Health Research Institute, McMaster University, discussed the Heart Outcomes Prevention Evaluation (HOPE) study. VITAMIN D AND OMEGA 3 TRIAL The VITamin D and omegA 3 triaL (VITAL; http://www.vitalstudy.org) is an example of an ongoing, placebo-controlled, primary prevention LST testing the efficacy of nutritional interventions in preventing cardiovascular

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EXAMPLES OF LARGE SIMPLE TRIALS 21 disease (CVD) and cancer and is sponsored by the National Institutes of Health (NIH). The trial is assessing whether daily vitamin D3 or omega 3 fatty acid supplements, or both (in a two-by-two factorial design), reduces the risk of heart disease, stroke, or cancer in people with no history of those diseases. Manson began her presentation by responding to a discussion that took place after earlier presentations about the feasibility of conducting blinded placebo-controlled LSTs with large number of participants in scattered locations. She noted that large simple placebo-controlled trials had been successfully conducted by mail even before the advent of the Internet, cit- ing the Physicians’ Health Study, which delivered study pills in foil-backed calendar (blister) packs by mail. She commented that it was not clear why this approach had not been adopted more widely, especially with the avail- ability of mobile devices to stay in contact with participants. In her view, many opportunities to conduct LSTs exist. Manson discussed several completed placebo-controlled LSTs that yielded important answers about potentially effective interventions at very low cost—between $100 and $200 in direct costs per participant per year. The first Physicians’ Health Study, for example, enrolled more than 22,000 physicians and showed that aspirin substantially reduced the risk of a first heart attack. Although the Women’s Health Study found that aspirin caused a significant reduction in the incidence of stroke in women, vitamin E was found to have a null effect on the incidence of both CVD and cancer. Another study, the Women’s Antioxidant and Folic Acid Study, found no evidence of a benefit or harm of beta-carotene, vitamins C and E, folic acid, and vitamins B6, B12, C, and E on the incidence of CVD events or cancer. These trials’ findings have been concordant with the results of other trials with much higher costs per participant. Manson noted that the studies mentioned above were conducted with health professional populations to facilitate the collection of informed consent and to ensure high rates of compliance with the consumption of the medications as directed, high response rates to questionnaires, and ap- proval for medical record review. What is different about VITAL, she said, is that it is being conducted with a population that is sociodemographically representative of the U.S. population and not just health care professionals. The purpose of VITAL is to conclusively determine whether two promising interventions—vitamin D3 and omega 3 fatty acids from fish—reduce the risk of cancer or CVD, or both. VITAL has enrolled 25,000 healthy older individuals (men age 50 years and older, women age 55 years and older), which will give the trial sufficient statistical power to detect 10 to 15 percent reductions in the pri- mary outcomes. Participants are being randomly assigned to one of four treatment groups: vitamin D3 (2,000 international units a day) and placebo,

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22 LARGE SIMPLE TRIALS IN A LEARNING HEALTH SYSTEM omega 3 (1 gram per day) and placebo, both vitamin D3 and omega 3, or two placebos. VITAL is a 5-year double-blind trial in which the pills are being provided by mail in blister packs without the participants or their providers knowing if the pills contain active ingredients or placebo. The entry criteria for VITAL include few criteria for exclusion in an effort to recruit participants representative of the general population. The trial has made a special effort to recruit members of racial and ethnic mi- nority groups to ensure diversity and is on track to achieve its demographic goals. Manson detailed how 16,000 participants will provide initial blood samples and 6,000 will provide follow-up blood samples. The trial also has a hybrid design involving in-clinic visits for a subset of participants. In the Boston, Massachusetts, area, 1,000 participants are having in-depth and extensive clinical assessments (anthropometrics, blood pressure, 2-hour oral glucose tolerance tests, physical performance assessments, and imaging studies) at the baseline and after 2 years. These evaluations will enable a number of ancillary studies. POST-MYOCARDIAL INFARCTION FREE RX EVENT AND ECONOMIC EVALUATION TRIAL Within 2 years, up to half of the patients who have suffered a heart attack, or acute myocardial infarction (MI), stop taking evidence-based primary prevention therapies—such as aspirin, beta-blockers, angiotensin- converting-enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and statins—to reduce the risk of another cardiovascular event. Some observational evidence indicates that the out-of-pocket costs of medica- tions prescribed after a heart attack are a major factor in the high degree of nonadherence to doctors’ orders. To determine whether this is the case, the MI FREEE trial tested whether elimination of out-of-pocket expenses for medications prescribed after an MI would increase the percentage of patients who continue to take their medications as prescribed and therefore improve clinical outcomes and was described by Niteesh K. Chuoudhry (Choudhry, 2011). The outcomes measured were the rate of readmissions for fatal and nonfatal MI; the incidence of unstable angina, heart failure, and stroke; and the need for coronary revascularization. The trial was funded by Aetna and the Commonwealth Foundation. Chuoudhry noted that the MI FREEE trial was able to be large and simple by the use of electronic health insurance claims to collect most of the data. Six thousand participants were identified through a search of Aetna beneficiary records for those recently discharged from the hospital after an MI, and the participants were followed for 1 year. Patients who agreed to participate were randomized into two groups. The intervention, or full-coverage, group was informed that their pharmacies would not

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EXAMPLES OF LARGE SIMPLE TRIALS 23 charge them for their post-MI medications, whereas members of the con- trol group received their usual coverage for prescriptions. Patients in the trial were contacted only once, Choudhry emphasized. The information on prescriptions filled, clinical outcomes, and costs was extracted from claims and the National Death Index through the use of health services research techniques. Choudhry reported that the study did not find significant differences between the full-coverage and usual-coverage groups in the primary out- come, a major vascular event, or the need for revascularization. However, it did find significant differences in outcomes for the secondary endpoints. For example, although the adherence rates were just 41 to 55 percent in the full-coverage group, those rates were 4 to 6 percentage points higher than those for the usual-coverage group, a significant difference. The rate of major vascular events among patients in the full-coverage group was 14 percent less than that among patients in the usual-coverage group, a statistically and clinically significant difference. On average, patient spend- ing was less in the full-coverage than the usual-coverage group ($526 and $900, respectively) without increasing overall costs ($18,254 and $20,238, respectively). Choudhry mentioned some limitations of the study, such as the lag time between the initial MI and randomization (49 days, on average), the high turnover rate of the insured, and the number of patients who declined to participate; but he concluded that the MI FREEE trial demonstrated that it is possible to conduct LSTs with clinical and policy relevance. He noted that, as a result of the study, Aetna was going to begin reducing copayments for post-MI secondary prevention medications in January 2013. HIGH FIVE FOR KIDS TRIAL AND STUDY OF TECHNOLOGY TO ACCELERATE RESEARCH Elsie M. Taveras presented examples of two pediatric LSTs that used electronic health record (EHR) systems for identification of potential par- ticipants, data collection, and provision of decision support tools for par- ents and clinicians. High Five for Kids was an NIH-funded trial examining whether evi- dence-based interventions to reduce obesity in children ages 2 through 6 years are effective in a primary care setting rather than a research setting (Taveras, 2011). The High Five for Kids trial involved 500 children seen at 10 pediatric primary care offices who were randomized to usual care or the tested intervention. The intervention included four clinic visits and three motivational telephone calls made by nurse practitioners aimed at reducing television time and the intake of fast food and sugar-sweetened beverages during a 1-year intervention period. Taveras reported that the High Five

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24 LARGE SIMPLE TRIALS IN A LEARNING HEALTH SYSTEM for Kids trial showed that, after 1 year, the intervention group watched less television and consumed less fast food and sugary drinks than the usual- care group but did not have a significantly lower body mass index (BMI). She noted that the trial was simplified and able to enroll a large number of children by using the health system’s EHR system to identify potential recipients meeting certain BMI criteria. Taveras said that the EHR system was also used to document the completed clinic visits and motivational calls and to assist clinicians with decision support, patient tracking, scheduling, and follow-up. Additionally, the parents in the intervention group were interviewed to obtain demographic information and information about the steps that they took to limit television, fast food, and soft drinks. The STAR trial (http://clinicaltrials.gov/show/NCT01537510), funded by the Office of Planning and Evaluation of the U.S. Department Health and Human Services, is testing whether health information technology can increase the adoption of evidence-based interventions by parents and clini- cians. Specifically, Taveras noted, STAR is seeing if point-of-care alerts and decision support tools in EHRs, with or without direct support and coach- ing of parents, can increase the adoption of evidence-based approaches to reduce obesity among 6- to 12-year-old children. The trial involves 800 patients at 14 pediatric primary care offices who will be followed for 1 year. The purpose of the trial is to see if the interventions result in increased screening and assessment of childhood obesity, increased counseling on nutrition and physical activity, a smaller increase in BMI, and improved dietary and physical activity behaviors. As in the High Five for Kids trial, the EHR system is being leveraged to simplify recruitment and to provide best practice alerts and decision sup- port tools to guide clinicians with evidence-based recommendations for pa- tient management, instructions on how to follow up with that patient, what referrals to make, and what patient instructions to print. Taveras noted that the study is also using electronic patient portals for communication between health educators and the families and patients. Finally, the EHR system is being used to obtain point-of-care outcomes, such as Healthcare Effective- ness Data and Information Set (HEDIS) codes; International Classification of Diseases, Ninth Revision, diagnosis codes; and clinical measures of BMI. HEART OUTCOMES PREVENTION EVALUATION TRIAL P. J. Devereaux described the HOPE trial, which was funded by the Canadian Institute of Health Research, the Heart and Stroke Foundation of Ontario, Canada, and several drug companies to examine the effects of ramipril versus those of placebo and the effects of vitamin E versus those of placebo on a primary composite endpoint of cardiovascular death, nonfatal

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EXAMPLES OF LARGE SIMPLE TRIALS 25 MI, and nonfatal stroke (Heart Outcomes Prevention Evaluation Study Investigators, 2000). Devereaux described that the HOPE trial was designed to detect a rela- tive risk reduction of 12 percent, which required more than 9,500 patients to be followed for between 4 and 6 years. The criteria for participation were very simple and easy to implement, which was important because the trial included 267 centers in 19 countries. Criteria for recruitment included the following: the participants had to be age 55 years or older; have coronary artery disease, peripheral vascular disease, or stroke or have diabetes and a risk factor for coronary artery disease; and not have heart failure or a low left ventricular ejection fraction and not taking an ACE inhibitor or vitamin E. The HOPE trial found a highly statistically significant reduction in the primary endpoint—the composite of cardiovascular death, non-fatal MI, and stroke—and for each of the individual components of the compos- ite endpoint with the use of ramipril compared with the reduction achieved with the use of placebo. Devereaux explained that the HOPE trial was designed as an LST be- cause the intent was to see if a treatment would have a relatively modest but highly significant effect on the incidence on a common major health condition that, if successful, would be easy for physicians to apply in clini- cal practice. This required a large sample size, broad and simple eligibility criteria, a simple intervention that would be easy to implement in real- world clinical settings (one pill a day), and easy data collection. It was also relatively inexpensive, costing $21 million to test two drugs with more than 9,500 patients over 5 years of follow-up, on average. Devereaux reported that the positive effect of ramipril was quickly evident and the trial was terminated early. The impact on clinician practice was also quick because the result—by design—was widely applicable. REFERENCES Choudhry, N., J. Avorn, R. J. Glynn, E. M. Antman, S. Schneeweiss, M. Toscano, L. Reisman, J. Fernandes, C. Spettell, J. L. Lee, R. Levin, T. Brennan, W. H. Shrank, and the Post- Myocardial Infarction Free Rx Event and Economic Evaluation (MI FREEE) Trial. 2011. Full coverage for preventative medications after myocardial infarction. New England Journal of Medicine 365:2088–2097. Heart Outcomes Prevention Evaluation Study Investigators. 2000. Effects of an angiotensin- converting-enzyme inhibitor, ramipril on cardiovascular events in high-risk patients. New England Journal of Medicine 342(3):145–153. Taveras, E. M., S. L. Gortmaker, K. H. Hohman, C. M. Horan, K. P. Kleinman, K. Mitchell, S. Price, L. A. Prosser, S. L. Rifas-Shiman, and M. W. Gillman. 2011. Randomized con- trolled trial to improve primary care to prevent and manage childhood obesity. Archives of Pediatrics & Adolescent Medicine 165(8):714–722.

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