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Prevention of Type 2 Diabetes <ul><li>Marshall H. Chin, MD  Carol M. Mangione, MD </li></ul><ul><li>Assoc. Prof. Of Medici...
Outline <ul><li>Background and Study Questions </li></ul><ul><li>Intervention and Measures </li></ul><ul><li>2 Study Desig...
Diabetes in the United States <ul><li>More than 16 million people in the US have diabetes </li></ul><ul><li>> 90% have Typ...
Estimated Growth in Type 2 Diabetes and US Population From 2000-2050 Bagust A, et al. Diabetes 50, Suppl 2 A205, 2001
<ul><li>Age </li></ul><ul><li>Obesity </li></ul><ul><li>Body fat distribution </li></ul><ul><li>Physical inactivity </li><...
<ul><li>Every 1 kilogram (2.2 pounds) of weight  </li></ul><ul><li>gain per 10 years is associated with a  </li></ul><ul><...
Impaired Glucose Tolerance <ul><li>Major risk factor for cardiovascular disease </li></ul><ul><li>IGT may be optimal time ...
Preclinical  state Normal IGT Clinical  disease Type 2 Diabetes Disability Death Complications Complications Primary  Seco...
<ul><li>There is a long period of glucose intolerance that precedes the  development of diabetes </li></ul><ul><li>Screeni...
Modifiable Risk Factors for  Type 2 Diabetes <ul><li>Obesity </li></ul><ul><li>Body fat distribution </li></ul><ul><li>Phy...
Study Interventions Eligible participants Randomized Standard lifestyle recommendations Intensive  Lifestyle (n = 1079) Me...
Primary Outcomes <ul><li>Annual fasting plasma glucose (FPG) and 75 gm Oral Glucose Tolerance Test   </li></ul><ul><ul><li...
Screening and eligibility Step 1  screening Step 2  OGTT Step 3  start run-in Step 4  randomization Number of participants...
Lifestyle Intervention <ul><li>An intensive program with the following specific goals: </li></ul><ul><li>>  7% loss of bod...
Lifestyle Intervention Structure <ul><li>16 session core curriculum (over 24 weeks)  </li></ul><ul><li>Long-term maintenan...
The Core Curriculum <ul><li>16 session course conducted over 24 weeks </li></ul><ul><li>Education and training in diet and...
Mean Weight Change   0  6  12  18  24  30  36  42  48 Months Lifestyle Metformin + Placebo
Lifestyle Intervention  <ul><li>74% of volunteers assigned to intensive life style achieved the minimum study goal of  >  ...
0 1 2 3 4 0 10 20 30 40 Placebo (n=1082) Metformin (n=1073, p<0.001 vs. Plac ) Lifestyle (n=1079, p<0.001 vs. Met , p<0.00...
“Pre-diabetes” <ul><li>A new post-DPP term, includes those with: </li></ul><ul><li>Impaired fasting glucose: </li></ul><ul...
Background <ul><li>Diabetes Prevention Program (DPP):  Intensive lifestyle intervention (diet and exercise) reduces relati...
Challenge of Translating DPP  to the Community <ul><li>Enrolling more generalizable population </li></ul><ul><ul><li>Funne...
General Translation Challenges in Minority Communities <ul><li>Trust </li></ul><ul><li>Enrollment </li></ul><ul><li>Value ...
Primary Study Question <ul><li>Can community interventions designed to increase physical activity and change diet prevent ...
Subquestion <ul><li>What intensity of implementation occurs when organizations are presented with a menu of choices in a p...
Common Elements of Study Design: Community-based  Participatory Research <ul><li>Community and researchers are equal partn...
Study Population <ul><li>Study setting:  Churches in African American and Latino communities of Chicago and Los Angeles; A...
Enrollment and Study Period <ul><li>Work with local PIs with longstanding community church ties </li></ul><ul><li>Pastor <...
Length of Study <ul><li>Intensive intervention:  Weekly x 16 weeks </li></ul><ul><li>Maintenance intervention:  Monthly x ...
Intervention:  Menu of Choices Physical Activity <ul><li>Goal:  Increase walking </li></ul><ul><ul><li>Guideline goal:  15...
Physical Activity Menu <ul><li>Self-monitoring, pedometer </li></ul><ul><li>Buddy system walking program </li></ul><ul><li...
Nutrition / Diet Intervention <ul><li>Goal:  Decrease calories Decrease fat / sugar </li></ul><ul><li>Goals based upon wei...
Nutrition / Diet Menu <ul><li>1-on-1 individual sessions – health educator, lay coach, home visits </li></ul><ul><li>Group...
Outcome <ul><li>Primary – onset of DM (fasting plasma glucose greater than 125 mg/dl) </li></ul><ul><li>Secondary </li></u...
Process Assessment Fidelity of the Intervention <ul><li>Checklists – content and intensity of intervention </li></ul><ul><...
Randomized Controlled Trials <ul><li>Considered to be the gold standard </li></ul><ul><ul><li>randomly allocated to either...
Study Design Selection <ul><li>Challenge is translation research is that the interventions are usually complex (multifacet...
Design 1:  Randomized Encouragement Trial (RET) <ul><li>Retains experimental structure but emphasizes a pragmatic public h...
Randomized Encouragement Trial (RET) <ul><li>Facilitates participants’ autonomy with regard to treatment decisions -- may ...
Randomized Encouragement Trial (RET) <ul><li>Requires recruitment, consent, enrollment, and randomization </li></ul><ul><l...
What is Encouragement? <ul><li>Offer of resources, incentives, education, and communication (persuasive messages) designed...
Why Encouragement? <ul><li>Attempts to influence treatment adoption through participants’ autonomous choice, leaving ultim...
Randomized Encouragement Trial Analyses <ul><li>Assuming that the encouragement increases treatment adoption, it can provi...
Randomized Encouragement Trial Strengths <ul><li>Retains aspects of naturalist treatment delivery </li></ul><ul><li>May en...
Randomized Encouragement Trial Strengths <ul><li>Can provide important information about what can actually be delivered in...
Randomized Encouragement Trial Weaknesses <ul><li>Internal validity is lower than in RCTs but higher than in observational...
RET Strengths and Weaknesses > Moderate dominance, >> strong dominance Duan N., et al. Personal Communication
RET Sample Size Considerations <ul><li>DPP, assume that the treatment effect is prevention of  6.2 cases  of DM per 100 pe...
Sample size needed based on the observed effect size in the DPP
Design 2:  Quasi-Experimental with Staggered Enrollment <ul><li>Randomization of initial assignment into intervention or c...
Staggered Enrollment Analyses <ul><li>Intervention vs. control </li></ul><ul><li>Among control subjects that crossover int...
Staggered Enrollment Strengths <ul><li>Increased enrollment compared with std RCT </li></ul><ul><li>Increased subject rete...
Staggered Enrollment Weaknesses <ul><li>Secular trends </li></ul><ul><li>Possible contamination of control groups </li></u...
Back-up slides
RET Sample Size Considerations <ul><li>RET: </li></ul><ul><li>P 1  Adoption rate in the intervention group </li></ul><ul><...
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Prevention of Type 2 Diabetes

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  • DPP’s primary outcome is time to conversion to diabetes as defined by the following criteria: • From the annual visit, fasting plasma glucose value greater than or equal to 126 mg/dl or 2-hour post challenge glucose value greater than or equal to 200 mg/dl; or SLIDE • From the semi-annual visit, fasting plasma glucose value greater than or equal to 126 mg/dl. All conversions must be confirmed within 6 weeks by a repeat test with values meeting the same criteria.
  • A total of more than 158,000 individuals were screened nationwide. 30,984 had an OGTT performed, 4,706 entered the run-in, 4,081 completed the run-in, and 3,819 were randomly assigned to one of the original 4 therapies. The most common reason for exclusion in the more than 30,000 volunteers who had an OGTT was that they did not fulfill the fasting or two hour plasma glucose criteria. The 3,234 participants assigned to placebo-control, metformin therapy, or intensive life-style intervention are the focus of this presentation. 585 volunteers were assigned to the troglitazone arm, which was discontinued in June, 1998.
  • The DPP Lifestyle Intervention was an intensive program with the following goals: Participants were encouraged to lose at least 7% of their initial body weight and to maintain this weight loss throughout the trial. The primary method advocated for weight loss was to reduce fat intake to 25% of the total daily calories and To restrict daily caloric consumption Each participant was encouraged to achieve and maintain at least 150 minutes per week of physical activity, using activities similar in intensity to brisk walking.
  • This slide shows the basic structure of the life style intervention. Each participant was enrolled in a was a 16 session core curriculum that was implemented over a 24 week period. All life style participants received the same core-curriculum to standardize the intervention. The core curriculum was combined with a longterm maintenance program. Both of these components were implemented and supervised by a case manager who work with subjects both individually and in groups throughout the trial. In addition, subjects had access to lifestyle support staff who could work with them to help achieve or maintain program goals. This included dietitians, behaviorists and exercise specialists
  • So, how effective was this approach? ACTIVATE DATA This slide shows weight loss at 6-month follow-up intervals for the lifestyle intervention arm in blue compared with the metformin in yellow and placebo arm in green. Since participants were recruited over several years, they have variable lengths of follow-up in the trial. The number of participants followed at each annual visit is shown at the bottom of the graph. Most participants were followed for at least 2-years, but only half were followed for 3 years, and only 10% for 4 years. Weight losses for participants who reached these follow-up windows are shown here. Participants in the lifestyle arm achieved a 6.75 kg weight loss at 6 months, maintained it through 12 months, and then experienced gradual regain. Those who reached 4 years maintained a weight loss of 3.5 kg.
  • 74% of participants in the lifestyle arm achieved the goal of adding 150 minutes per week of physical activity. Physical activity averaged 224 minutes at the end of the core curriculum and 189 minutes at the most recent lifestyle visit.
  • Transcript of "Prevention of Type 2 Diabetes"

    1. 2. Prevention of Type 2 Diabetes <ul><li>Marshall H. Chin, MD Carol M. Mangione, MD </li></ul><ul><li>Assoc. Prof. Of Medicine Prof. Of Medicine </li></ul><ul><li>University of Chicago David Geffen School of Medicine at UCLA </li></ul>
    2. 3. Outline <ul><li>Background and Study Questions </li></ul><ul><li>Intervention and Measures </li></ul><ul><li>2 Study Designs </li></ul><ul><ul><li>RCT with randomized encouragement </li></ul></ul><ul><ul><li>Quasi-experimental with staggered enrollment </li></ul></ul><ul><li>Tradeoffs </li></ul><ul><li>Discussion </li></ul>
    3. 4. Diabetes in the United States <ul><li>More than 16 million people in the US have diabetes </li></ul><ul><li>> 90% have Type 2 diabetes </li></ul><ul><ul><li>6% of the population </li></ul></ul><ul><ul><li>13% of the population older than age 40 </li></ul></ul><ul><ul><li>19% of the population older than age 65 </li></ul></ul><ul><li>35% of persons with diabetes are undiagnosed </li></ul><ul><li>798,000 new cases are diagnosed every year </li></ul>CDC National Diabetes Fact Sheet 1998
    4. 5. Estimated Growth in Type 2 Diabetes and US Population From 2000-2050 Bagust A, et al. Diabetes 50, Suppl 2 A205, 2001
    5. 6. <ul><li>Age </li></ul><ul><li>Obesity </li></ul><ul><li>Body fat distribution </li></ul><ul><li>Physical inactivity </li></ul><ul><li>Family history of diabetes </li></ul><ul><li>Race/ethnicity </li></ul><ul><li>Previous gestational diabetes (GDM) </li></ul><ul><li>Elevated fasting glucose levels </li></ul><ul><li>Impaired glucose tolerance (IGT) </li></ul>Risk Factors for Type 2 Diabetes
    6. 7. <ul><li>Every 1 kilogram (2.2 pounds) of weight </li></ul><ul><li>gain per 10 years is associated with a </li></ul><ul><li>4.5% increased risk to develop diabetes. </li></ul>Ford et al. Amer J Epidemiol 146:214,1997 Weight Gain and Sedentary Life-style Increase Risk of Developing Diabetes <ul><li>68 - 72 % of diabetes risk in the U.S. is </li></ul><ul><li>attributable to or associated with excess </li></ul><ul><li>weight. </li></ul><ul><li>Numerous studies have documented an </li></ul><ul><li>association between low levels of physical </li></ul><ul><li>activity and risk to develop diabetes </li></ul>
    7. 8. Impaired Glucose Tolerance <ul><li>Major risk factor for cardiovascular disease </li></ul><ul><li>IGT may be optimal time for intervention </li></ul><ul><ul><li>Asymptomatic </li></ul></ul><ul><ul><li>Potentially reversible </li></ul></ul><ul><ul><li>Diabetes-specific complications have not developed </li></ul></ul>
    8. 9. Preclinical state Normal IGT Clinical disease Type 2 Diabetes Disability Death Complications Complications Primary Secondary Tertiary prevention prevention prevention Stages in the History of Type 2 Diabetes 20,000,000 16,000,000
    9. 10. <ul><li>There is a long period of glucose intolerance that precedes the development of diabetes </li></ul><ul><li>Screening tests can identify persons at high risk </li></ul><ul><li>There are safe, potentially effective interventions </li></ul>Feasibility of Prevention Prevention of Type 2 diabetes should be feasible since:
    10. 11. Modifiable Risk Factors for Type 2 Diabetes <ul><li>Obesity </li></ul><ul><li>Body fat distribution </li></ul><ul><li>Physical inactivity </li></ul><ul><li>Elevated fasting and 2 hr glucose levels </li></ul>
    11. 12. Study Interventions Eligible participants Randomized Standard lifestyle recommendations Intensive Lifestyle (n = 1079) Metformin (n = 1073) Placebo (n = 1082)
    12. 13. Primary Outcomes <ul><li>Annual fasting plasma glucose (FPG) and 75 gm Oral Glucose Tolerance Test </li></ul><ul><ul><li>FPG > 126 mg/dL (7.0 mmol/L) or </li></ul></ul><ul><ul><li>2-hr > 200 mg/dL (11.0 mmol/L), </li></ul></ul><ul><ul><li>Either confirmed with repeat test </li></ul></ul><ul><li>Semi-annual FPG </li></ul><ul><ul><li>> 126 mg/dL, confirmed </li></ul></ul>
    13. 14. Screening and eligibility Step 1 screening Step 2 OGTT Step 3 start run-in Step 4 randomization Number of participants 158,177 30,985 4,719 4,080 3,819* Step 3 end run-in * 3,234 in 3 arm study (585 in troglitazone arm)
    14. 15. Lifestyle Intervention <ul><li>An intensive program with the following specific goals: </li></ul><ul><li>> 7% loss of body weight and maintenance of weight loss </li></ul><ul><ul><li>Fat gram goal -- 25% of calories from fat </li></ul></ul><ul><ul><li>Calorie intake goal -- 1200-1800 kcal/day </li></ul></ul><ul><li>> 150 minutes per week of physical activity </li></ul>
    15. 16. Lifestyle Intervention Structure <ul><li>16 session core curriculum (over 24 weeks) </li></ul><ul><li>Long-term maintenance program </li></ul><ul><li>Supervised by a case manager </li></ul><ul><li>Access to Lifestyle support staff </li></ul><ul><ul><li>Dietitian </li></ul></ul><ul><ul><li>Behaviorist </li></ul></ul><ul><ul><li>Exercise physiologist </li></ul></ul>
    16. 17. The Core Curriculum <ul><li>16 session course conducted over 24 weeks </li></ul><ul><li>Education and training in diet and exercise methods and behavior modification skills </li></ul><ul><li>Emphasis on: </li></ul><ul><ul><li>Self monitoring techniques </li></ul></ul><ul><ul><li>Problem solving </li></ul></ul><ul><ul><li>Individualizing programs </li></ul></ul><ul><ul><li>Self esteem, empowerment, and social support </li></ul></ul><ul><ul><li>Frequent contact with case manager and DPP support staff </li></ul></ul>
    17. 18. Mean Weight Change 0 6 12 18 24 30 36 42 48 Months Lifestyle Metformin + Placebo
    18. 19. Lifestyle Intervention <ul><li>74% of volunteers assigned to intensive life style achieved the minimum study goal of > 150 minutes of activity per week </li></ul><ul><li>Mean activity level: </li></ul><ul><ul><li>At end of core curriculum: 224 minutes </li></ul></ul><ul><ul><li>At most recent visit: 189 minutes </li></ul></ul>Summary
    19. 20. 0 1 2 3 4 0 10 20 30 40 Placebo (n=1082) Metformin (n=1073, p<0.001 vs. Plac ) Lifestyle (n=1079, p<0.001 vs. Met , p<0.001 vs. Plac ) Percent developing diabetes All participants Years from randomization Cumulative incidence (%)
    20. 21. “Pre-diabetes” <ul><li>A new post-DPP term, includes those with: </li></ul><ul><li>Impaired fasting glucose: </li></ul><ul><ul><li>FPG 100–125 mg/dl (5.6–6.9 mmol/l) </li></ul></ul><ul><li>Impaired glucose tolerance: </li></ul><ul><ul><li>2-h postload glucose 140–199 mg/dl (7.8–11.1 mmol/l) </li></ul></ul><ul><li>40,000,000 with pre-diabetes! </li></ul>From the 2004 American Diabetes Association Guideline
    21. 22. Background <ul><li>Diabetes Prevention Program (DPP): Intensive lifestyle intervention (diet and exercise) reduces relative risk of DM by 58% over 3 years </li></ul><ul><li>But, can it be translated to real world settings?? </li></ul>
    22. 23. Challenge of Translating DPP to the Community <ul><li>Enrolling more generalizable population </li></ul><ul><ul><li>Funnel of study enrollment for DPP </li></ul></ul><ul><li>Measurement of Impaired glucose tolerance in the community: FBS versus OGTT </li></ul><ul><li>DPP lifestyle intervention intensive – realistic? </li></ul><ul><ul><li>Training of study personnel </li></ul></ul><ul><ul><li>Intensity of intervention and F/U </li></ul></ul><ul><li>Sustainability </li></ul>
    23. 24. General Translation Challenges in Minority Communities <ul><li>Trust </li></ul><ul><li>Enrollment </li></ul><ul><li>Value of the “placebo” or “low intensity” study arm </li></ul><ul><li>Is losing weight and diabetes prevention a community priority? </li></ul>
    24. 25. Primary Study Question <ul><li>Can community interventions designed to increase physical activity and change diet prevent the onset of type 2 diabetes among overweight and obese persons with pre-diabetes? </li></ul>
    25. 26. Subquestion <ul><li>What intensity of implementation occurs when organizations are presented with a menu of choices in a program to increase physical activity and cause dietary change? </li></ul>
    26. 27. Common Elements of Study Design: Community-based Participatory Research <ul><li>Community and researchers are equal partners </li></ul><ul><li>Build on existing strengths / infrastructure in community </li></ul><ul><li>Community / patient empowerment </li></ul><ul><li>Improving community health overriding goal </li></ul><ul><li>Takes into account community and individual preferences </li></ul>
    27. 28. Study Population <ul><li>Study setting: Churches in African American and Latino communities of Chicago and Los Angeles; Aim 50 people per church </li></ul><ul><li>Pre-diabetes: Impaired fasting glucose (> 100 to 125 mg/dl), age > 50 yrs, BMI > 30 </li></ul><ul><ul><li>Fallback: Overweight or obese with DM risk factors? </li></ul></ul><ul><li>Exclusions: DM, severe disability, dementia, short life expectancy </li></ul>
    28. 29. Enrollment and Study Period <ul><li>Work with local PIs with longstanding community church ties </li></ul><ul><li>Pastor </li></ul><ul><li>Church senior ambassador / opinion leader </li></ul><ul><ul><li>Respected senior citizen with condition </li></ul></ul>
    29. 30. Length of Study <ul><li>Intensive intervention: Weekly x 16 weeks </li></ul><ul><li>Maintenance intervention: Monthly x 8 months </li></ul><ul><li>Follow-up 3 years </li></ul>
    30. 31. Intervention: Menu of Choices Physical Activity <ul><li>Goal: Increase walking </li></ul><ul><ul><li>Guideline goal: 150 minutes/week of walking </li></ul></ul><ul><ul><li>In practice, patient selects own goals </li></ul></ul>
    31. 32. Physical Activity Menu <ul><li>Self-monitoring, pedometer </li></ul><ul><li>Buddy system walking program </li></ul><ul><li>Group walking sessions </li></ul><ul><li>Collaborate with local Y or public parks </li></ul><ul><li>Exercise classes taught by high school / college congregants </li></ul><ul><li>Other suggested by community participants </li></ul><ul><li>Particpants are encouraged to select activities from the list that they feel will work best for them </li></ul>
    32. 33. Nutrition / Diet Intervention <ul><li>Goal: Decrease calories Decrease fat / sugar </li></ul><ul><li>Goals based upon weight and personal tailoring (Age, BMI, readiness to change) </li></ul><ul><li>Health educator facilitator and 4-5 volunteer lay coaches </li></ul>
    33. 34. Nutrition / Diet Menu <ul><li>1-on-1 individual sessions – health educator, lay coach, home visits </li></ul><ul><li>Group classes </li></ul><ul><li>Church social marketing campaign </li></ul><ul><li>Support groups – problem-solving & goal setting </li></ul><ul><li>Buddy system </li></ul><ul><li>Involve family </li></ul><ul><li>Other suggested by community participants </li></ul><ul><li>Participants are encouraged to select activities from the list that they feel will work best for them </li></ul>
    34. 35. Outcome <ul><li>Primary – onset of DM (fasting plasma glucose greater than 125 mg/dl) </li></ul><ul><li>Secondary </li></ul><ul><ul><li>Physical activity - Weight, BMI </li></ul></ul><ul><ul><li>Dietary change - Knowledge </li></ul></ul><ul><ul><li>HgbA1c, lipids - Blood pressure </li></ul></ul><ul><ul><li>Self-efficacy - Quality of life </li></ul></ul>
    35. 36. Process Assessment Fidelity of the Intervention <ul><li>Checklists – content and intensity of intervention </li></ul><ul><ul><li>When given a choice, what do participants select to participate in? </li></ul></ul><ul><ul><li>Do certain elements in the intervention have better “uptake”? </li></ul></ul><ul><li>Qualitative interviews of participants </li></ul>
    36. 37. Randomized Controlled Trials <ul><li>Considered to be the gold standard </li></ul><ul><ul><li>randomly allocated to either intervention or control group </li></ul></ul><ul><ul><li>best way to insure that both known and unknown factors that may influence the effectiveness of the intervention are balanced in the 2 comparison groups </li></ul></ul><ul><li>Time consuming, expensive, complex, may require a large number of clusters, tight inclusion criteria limit generalizabilty </li></ul><ul><li>Unlikely to tell you whether an intervention will improve routine practice </li></ul>
    37. 38. Study Design Selection <ul><li>Challenge is translation research is that the interventions are usually complex (multifaceted with simultaneous changes in different parts of the community) </li></ul><ul><li>Researcher has variable control over how the intervention is implemented </li></ul><ul><li>In translation research there can be political, practical, and ethical barriers to randomized designs and other choices may be the best options </li></ul>Eccles M, et al. Qual Saf Health Care 2003;12;47-52
    38. 39. Design 1: Randomized Encouragement Trial (RET) <ul><li>Retains experimental structure but emphasizes a pragmatic public health perspective </li></ul><ul><li>Combines strengths of the RCT and Observational studies </li></ul><ul><li>Instead of mandating treatment assignment, randomizes participants to encouragement for the target intervention </li></ul><ul><li>Promotes a more equitable relationship between the researcher and the participant/community </li></ul>Duan N, et al. Randomized Encouragement Trial: A Pragmatic, Public Health Oriented Paradigm for Clinical Research. In preparation 2004
    39. 40. Randomized Encouragement Trial (RET) <ul><li>Facilitates participants’ autonomy with regard to treatment decisions -- may be an important feature for sustaining a life style intervention over time </li></ul><ul><li>Maintains many of the real world aspects of facilitation of behavioral change in community and medical settings. </li></ul><ul><li>Unit of randomization can be at the participant level or at a higher level </li></ul>
    40. 41. Randomized Encouragement Trial (RET) <ul><li>Requires recruitment, consent, enrollment, and randomization </li></ul><ul><li>Intervention group: </li></ul><ul><ul><li>Randomized to encouragement rather than mandatory treatment assignment </li></ul></ul><ul><li>Control group: </li></ul><ul><ul><li>no encouragement </li></ul></ul><ul><li>Maintaining personal choice, much as one would have to in practice or community settings is a critical element of this design </li></ul>
    41. 42. What is Encouragement? <ul><li>Offer of resources, incentives, education, and communication (persuasive messages) designed to increase the probability that a participant will want to adopt the treatment </li></ul><ul><li>Various encouragement strategies can be tested in a bundle, in combinations, or individually </li></ul><ul><li>Encouragement strategies can be developed collaboratively with communities and the population of interest </li></ul>
    42. 43. Why Encouragement? <ul><li>Attempts to influence treatment adoption through participants’ autonomous choice, leaving ultimate decisions to the participants </li></ul><ul><li>Choices are voluntary </li></ul><ul><li>Some participants might reject all menu choices in the intervention, some might select some </li></ul><ul><li>Some controls may figure out how to get access to the intervention through other means </li></ul>
    43. 44. Randomized Encouragement Trial Analyses <ul><li>Assuming that the encouragement increases treatment adoption, it can provide an evaluation of treatment effectiveness using an intent-to-treat analysis </li></ul><ul><li>Provides important qualitative and quantitative findings with regard to adoption and what is desirable and feasible in the community context </li></ul><ul><li>Pragmatic by nature </li></ul><ul><ul><li>stronger external validity than the RCT </li></ul></ul><ul><ul><li>stronger internal validity than observational studies </li></ul></ul>
    44. 45. Randomized Encouragement Trial Strengths <ul><li>Retains aspects of naturalist treatment delivery </li></ul><ul><li>May enhance the appeal of participation in effectiveness and translational research by maintaining autonomous choice which will enhance recruitment of more representative samples </li></ul><ul><li>Rather than viewing treatment choice as a threat to internal validity, it is part of the primary data collection that informs the researcher about participant decision processes </li></ul>
    45. 46. Randomized Encouragement Trial Strengths <ul><li>Can provide important information about what can actually be delivered in real world settings </li></ul>
    46. 47. Randomized Encouragement Trial Weaknesses <ul><li>Internal validity is lower than in RCTs but higher than in observational designs </li></ul><ul><li>By its less controlled nature RETs tend to have smaller effect sizes and greater within group variance therefore require bigger sample sizes. </li></ul>
    47. 48. RET Strengths and Weaknesses > Moderate dominance, >> strong dominance Duan N., et al. Personal Communication
    48. 49. RET Sample Size Considerations <ul><li>DPP, assume that the treatment effect is prevention of 6.2 cases of DM per 100 person-years </li></ul><ul><li>Then in the RET, if adoption P d =0.5, then RET treatment effect is 3.1 cases of DM per 100 person years </li></ul><ul><li>Then inflation factor is (1/0.5) 2 = 4 times more sample needed for the same power! </li></ul>
    49. 50. Sample size needed based on the observed effect size in the DPP
    50. 51. Design 2: Quasi-Experimental with Staggered Enrollment <ul><li>Randomization of initial assignment into intervention or control arm </li></ul><ul><li>After 1 year, control participants transfer into intervention arm </li></ul>
    51. 52. Staggered Enrollment Analyses <ul><li>Intervention vs. control </li></ul><ul><li>Among control subjects that crossover into intervention, each subject can serve as own control </li></ul>
    52. 53. Staggered Enrollment Strengths <ul><li>Increased enrollment compared with std RCT </li></ul><ul><li>Increased subject retention compared with std RCT </li></ul><ul><li>Intervention and control subjects drawn from same population </li></ul><ul><li>Subjects initially randomized to control group can serve as own controls </li></ul>
    53. 54. Staggered Enrollment Weaknesses <ul><li>Secular trends </li></ul><ul><li>Possible contamination of control groups </li></ul><ul><li>Learning effects – control group has 1 more year in study </li></ul><ul><li>Shorter F/U time in initial control group </li></ul>
    54. 55. Back-up slides
    55. 56. RET Sample Size Considerations <ul><li>RET: </li></ul><ul><li>P 1 Adoption rate in the intervention group </li></ul><ul><li>P 0 Adoption rate in the control group </li></ul><ul><li>RET the incremental adoption rate is: P d = P 1 -P 0 </li></ul><ul><li>RCT </li></ul><ul><li>Q 1 Adoption rate in the intervention group </li></ul><ul><li>Q 0 Adoption rate in the control group </li></ul><ul><li>RCT with perfect adherence adoption rate is: Q d = Q 1 </li></ul><ul><li>Assume treatment effect is constant M, then RET intervention effects are P d X M and RCT effects are Q d X M and the inflation factor is: (Q d / P d ) 2 </li></ul>
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