Initial Evaluation of Breakthrough Series 1999

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(No Transcript)
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Prevention of Type 2 Diabetes

• Marshall H. Chin, MD Carol M. Mangione, MD
• Assoc. Prof. Of Medicine Prof. Of Medicine
• University of Chicago David Geffen School of
  Medicine at UCLA

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Outline

• Background and Study Questions
• Intervention and Measures
• 2 Study Designs
• RCT with randomized encouragement
• Quasi-experimental with staggered enrollment
• Tradeoffs
• Discussion

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Diabetes in the United States

• More than 16 million people in the US have
  diabetes
• 90 have Type 2 diabetes
• 6 of the population
• 13 of the population older than age 40
• 19 of the population older than age 65
• 35 of persons with diabetes are undiagnosed
• 798,000 new cases are diagnosed every year

CDC National Diabetes Fact Sheet 1998
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Estimated Growth in Type 2 Diabetes and US
Population From 2000-2050
Bagust A, et al. Diabetes 50, Suppl 2 A205, 2001
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Risk Factors for Type 2 Diabetes

• Age
• Obesity
• Body fat distribution
• Physical inactivity
• Family history of diabetes

• Race/ethnicity
• Previous gestational diabetes (GDM)
• Elevated fasting glucose levels
• Impaired glucose tolerance (IGT)

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Weight Gain and Sedentary Life-style Increase
Risk of Developing Diabetes

• Every 1 kilogram (2.2 pounds) of weight
• gain per 10 years is associated with a
• 4.5 increased risk to develop diabetes.

• 68 - 72 of diabetes risk in the U.S. is
• attributable to or associated with excess
• weight.

• Numerous studies have documented an
• association between low levels of physical
• activity and risk to develop diabetes

Ford et al. Amer J Epidemiol 146214,1997
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Impaired Glucose Tolerance

• Major risk factor for cardiovascular disease
• IGT may be optimal time for intervention
• Asymptomatic
• Potentially reversible
• Diabetes-specific complications have not developed

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Stages in the History of Type 2 Diabetes
Type 2 Diabetes
Normal
IGT
Disability Death
Complications
Clinical disease
Preclinical state
Complications
20,000,000 16,000,000
Primary Secondary
Tertiary prevention prevention
prevention
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Feasibility of PreventionPrevention of Type 2
diabetesshould be feasible since

• There is a long period of glucose intolerance
  that precedes the development of diabetes
• Screening tests can identify persons at high risk
  
• There are safe, potentially effective
  interventions

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Modifiable Risk Factors for Type 2 Diabetes

• Obesity
• Body fat distribution
• Physical inactivity
• Elevated fasting and 2 hr glucose levels

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Study Interventions
Eligible participants Randomized Standard
lifestyle recommendations
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Primary Outcomes

• Annual fasting plasma glucose (FPG) and 75 gm
  Oral Glucose Tolerance Test
• FPG 126 mg/dL (7.0 mmol/L) or
• 2-hr 200 mg/dL (11.0 mmol/L),
• Either confirmed with repeat test
• Semi-annual FPG
• 126 mg/dL, confirmed

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Screening and eligibility
Number of participants
Step 1 screening
158,177
Step 2 OGTT
30,985
Step 3 start run-in
4,719
4,080
Step 3 end run-in
3,819
Step 4 randomization
3,234 in 3 arm study (585 in troglitazone arm)
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Lifestyle Intervention

• An intensive program with the following
  specific goals

• 7 loss of body weight and maintenance of
  weight loss
• Fat gram goal -- 25 of calories from fat
• Calorie intake goal -- 1200-1800 kcal/day
• 150 minutes per week of physical activity

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Lifestyle Intervention Structure

• 16 session core curriculum (over 24 weeks)
• Long-term maintenance program
• Supervised by a case manager
• Access to Lifestyle support staff
• Dietitian
• Behaviorist
• Exercise physiologist

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The Core Curriculum

• 16 session course conducted over 24 weeks
• Education and training in diet and exercise
  methods and behavior modification skills
• Emphasis on
• Self monitoring techniques
• Problem solving
• Individualizing programs
• Self esteem, empowerment, and social support
• Frequent contact with case manager and DPP
  support staff

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Mean Weight Change

Placebo
Metformin
Lifestyle
0 6 12 18 24 30 36 42
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Months
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Lifestyle Intervention
Summary

• 74 of volunteers assigned to intensive life
  style achieved the minimum study goal of 150
  minutes of activity per week
• Mean activity level
• At end of core curriculum 224 minutes
• At most recent visit 189 minutes

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Percent developing diabetes

All participants
Lifestyle (n1079, pPlac )
40
Metformin (n1073, p
Placebo (n1082)
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Cumulative incidence ()
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10
0
0

1

2

3

4
Years from randomization
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Pre-diabetes

• A new post-DPP term, includes those with
• Impaired fasting glucose
• FPG 100125 mg/dl (5.66.9 mmol/l)
• Impaired glucose tolerance
• 2-h postload glucose 140199 mg/dl (7.811.1
  mmol/l)
• 40,000,000 with pre-diabetes!

From the 2004 American Diabetes Association
Guideline
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Background

• Diabetes Prevention Program (DPP) Intensive
  lifestyle intervention (diet and exercise)
  reduces relative risk of DM by 58 over 3 years
• But, can it be translated to real world settings??

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Challenge of Translating DPP to the Community

• Enrolling more generalizable population
• Funnel of study enrollment for DPP
• Measurement of Impaired glucose tolerance in the
  community FBS versus OGTT
• DPP lifestyle intervention intensive realistic?
• Training of study personnel
• Intensity of intervention and F/U
• Sustainability

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General Translation Challenges in Minority
Communities

• Trust
• Enrollment
• Value of the placebo or low intensity study
  arm
• Is losing weight and diabetes prevention a
  community priority?

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Primary Study Question

• 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?

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Subquestion

• 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?

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Common Elements of Study DesignCommunity-based
Participatory Research

• Community and researchers are equal partners
• Build on existing strengths / infrastructure in
  community
• Community / patient empowerment
• Improving community health overriding goal
• Takes into account community and individual
  preferences

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Study Population

• Study setting Churches in African American and
  Latino communities of Chicago and Los Angeles
  Aim 50 people per church
• Pre-diabetes Impaired fasting glucose ( 100 to
  125 mg/dl), age 50 yrs, BMI 30
• Fallback Overweight or obese with DM risk
  factors?
• Exclusions DM, severe disability, dementia,
  short life expectancy

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Enrollment and Study Period

• Work with local PIs with longstanding community
  church ties
• Pastor
• Church senior ambassador / opinion leader
• Respected senior citizen with condition

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Length of Study

• Intensive intervention Weekly x 16 weeks
• Maintenance intervention Monthly x 8 months
• Follow-up 3 years

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Intervention Menu of ChoicesPhysical Activity

• Goal Increase walking
• Guideline goal 150 minutes/week of walking
• In practice, patient selects own goals

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Physical Activity Menu

• Self-monitoring, pedometer
• Buddy system walking program
• Group walking sessions
• Collaborate with local Y or public parks
• Exercise classes taught by high school / college
  congregants
• Other suggested by community participants
• Particpants are encouraged to select activities
  from the list that they feel will work best for
  them

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Nutrition / Diet Intervention

• Goal Decrease calories Decrease fat / sugar
• Goals based upon weight and personal tailoring
  (Age, BMI, readiness to change)
• Health educator facilitator and 4-5 volunteer lay
  coaches

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Nutrition / Diet Menu

• 1-on-1 individual sessions health educator, lay
  coach, home visits
• Group classes
• Church social marketing campaign
• Support groups problem-solving goal setting
• Buddy system
• Involve family
• Other suggested by community participants
• Participants are encouraged to select activities
  from the list that they feel will work best for
  them

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Outcome

• Primary onset of DM (fasting plasma glucose
  greater than 125 mg/dl)
• Secondary
• Physical activity - Weight, BMI
• Dietary change - Knowledge
• HgbA1c, lipids - Blood pressure
• Self-efficacy - Quality of life

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Process AssessmentFidelity of the Intervention

• Checklists content and intensity of
  intervention
• When given a choice, what do participants select
  to participate in?
• Do certain elements in the intervention have
  better uptake?
• Qualitative interviews of participants

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Randomized Controlled Trials

• Considered to be the gold standard
• randomly allocated to either intervention or
  control group
• 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
• Time consuming, expensive, complex, may require a
  large number of clusters, tight inclusion
  criteria limit generalizabilty
• Unlikely to tell you whether an intervention will
  improve routine practice

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Study Design Selection

• Challenge is translation research is that the
  interventions are usually complex (multifaceted
  with simultaneous changes in different parts of
  the community)
• Researcher has variable control over how the
  intervention is implemented
• In translation research there can be political,
  practical, and ethical barriers to randomized
  designs and other choices may be the best options

Eccles M, et al. Qual Saf Health Care
20031247-52
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Design 1 Randomized Encouragement Trial (RET)

• Retains experimental structure but emphasizes a
  pragmatic public health perspective
• Combines strengths of the RCT and Observational
  studies
• Instead of mandating treatment assignment,
  randomizes participants to encouragement for the
  target intervention
• Promotes a more equitable relationship between
  the researcher and the participant/community

Duan N, et al. Randomized Encouragement Trial A
Pragmatic, Public Health Oriented Paradigm for
Clinical Research. In preparation 2004
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Randomized Encouragement Trial (RET)

• Facilitates participants autonomy with regard to
  treatment decisions -- may be an important
  feature for sustaining a life style intervention
  over time
• Maintains many of the real world aspects of
  facilitation of behavioral change in community
  and medical settings.
• Unit of randomization can be at the participant
  level or at a higher level

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Randomized Encouragement Trial (RET)

• Requires recruitment, consent, enrollment, and
  randomization
• Intervention group
• Randomized to encouragement rather than mandatory
  treatment assignment
• Control group
• no encouragement
• Maintaining personal choice, much as one would
  have to in practice or community settings is a
  critical element of this design

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What is Encouragement?

• Offer of resources, incentives, education, and
  communication (persuasive messages) designed to
  increase the probability that a participant will
  want to adopt the treatment
• Various encouragement strategies can be tested in
  a bundle, in combinations, or individually
• Encouragement strategies can be developed
  collaboratively with communities and the
  population of interest

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Why Encouragement?

• Attempts to influence treatment adoption through
  participants autonomous choice, leaving ultimate
  decisions to the participants
• Choices are voluntary
• Some participants might reject all menu choices
  in the intervention, some might select some
• Some controls may figure out how to get access to
  the intervention through other means

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Randomized Encouragement Trial Analyses

• Assuming that the encouragement increases
  treatment adoption, it can provide an evaluation
  of treatment effectiveness using an
  intent-to-treat analysis
• Provides important qualitative and quantitative
  findings with regard to adoption and what is
  desirable and feasible in the community context
• Pragmatic by nature
• stronger external validity than the RCT
• stronger internal validity than observational
  studies

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Randomized Encouragement Trial Strengths

• Retains aspects of naturalist treatment delivery
• May enhance the appeal of participation in
  effectiveness and translational research by
  maintaining autonomous choice which will enhance
  recruitment of more representative samples
• 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

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Randomized Encouragement Trial Strengths

• Can provide important information about what can
  actually be delivered in real world settings

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Randomized Encouragement Trial Weaknesses

• Internal validity is lower than in RCTs but
  higher than in observational designs
• By its less controlled nature RETs tend to have
  smaller effect sizes and greater within group
  variance therefore require bigger sample sizes.

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RET Strengths and Weaknesses
Moderate dominance, strong dominance
Duan N., et al. Personal Communication
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RET Sample Size Considerations

• DPP, assume that the treatment effect is
  prevention of 6.2 cases of DM per 100
  person-years
• Then in the RET, if adoption Pd0.5, then RET
  treatment effect is 3.1 cases of DM per 100
  person years
• Then inflation factor is (1/0.5)2 4 times more
  sample needed for the same power!

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Sample size needed based on the observed effect
size in the DPP
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Design 2 Quasi-Experimental with Staggered
Enrollment

• Randomization of initial assignment into
  intervention or control arm
• After 1 year, control participants transfer into
  intervention arm

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Staggered Enrollment Analyses

• Intervention vs. control
• Among control subjects that crossover into
  intervention, each subject can serve as own
  control

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Staggered Enrollment Strengths

• Increased enrollment compared with std RCT
• Increased subject retention compared with std RCT
• Intervention and control subjects drawn from same
  population
• Subjects initially randomized to control group
  can serve as own controls

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Staggered Enrollment Weaknesses

• Secular trends
• Possible contamination of control groups
• Learning effects control group has 1 more year
  in study
• Shorter F/U time in initial control group

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Back-up slides
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RET Sample Size Considerations

• RET
• P1 Adoption rate in the intervention group
• P0 Adoption rate in the control group
• RET the incremental adoption rate is Pd
  P1-P0
• RCT
• Q1 Adoption rate in the intervention group
• Q0 Adoption rate in the control group
• RCT with perfect adherence adoption rate is
  Qd Q1
• Assume treatment effect is constant M, then RET
  intervention effects are PdX M and RCT effects
  are QdX M and the inflation factor is (Qd/ Pd )2