A Randomized Clinical Trial to Prevent Type 2 Diabetes

A Randomized Clinical Trial to Prevent Type 2 Diabetes in Persons at High Risk

The DPP Research Group
Institutions and Investigators
Abbas Kitabchi
U. of Tennessee

Steven Kahn
U. of Washington
Edward Horton
Joslin Diabetes Center

Richard Hamman
U. of Colorado Health Sciences Center

Steven Haffner
U. of Texas Health Science Center and many others

* 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 that can address modifiable risk

factors

Feasibility of Preventing
Type 2 Diabetes

Modifiable Risk Factors for
Type 2 Diabetes
* Obesity
* Body fat distribution
* Physical inactivity
* Elevated fasting and 2 hr glucose levels
* To prevent or delay the development of type 2 diabetes in persons with impaired

glucose tolerance (IGT)

DPP Primary Goal
DPP Secondary Goals
* Reduce cardiovascular disease (CVD) events
* Reduce CVD risk factors
* Reduce atherosclerosis

Study Design
* 3-group randomized clinical trial
* 27 clinical sites
* Standardized across clinics:
o Common protocol and procedures manual
o Staff training
o Data quality control program
Eligibility Criteria
Screening and Recruitment
Step 1 screening
Step 2 OGTT
Step 3 start run-in
Step 4 randomization
Number of participants
Step 3 end run-in

The DPP Research Group, Controlled Clin Trials (in press)
Study Interventions
Eligible participants
Randomized
Standard lifestyle recommendations
Intensive Metformin Placebo
Lifestyle
Primary Outcome: Diabetes

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

Lifestyle Intervention
An intensive program with the following specific goals:
* > 7% loss of body weight and maintenance of weight loss
o Dietary fat goal -- <25% of calories from fat
o Calorie intake goal -- 1200-1800 kcal/day
* > 150 minutes per week of physical activity

Lifestyle Intervention Structure
* 16 session core curriculum (over 24 weeks)
* Long-term maintenance program
* Supervised by a case manager
* Access to lifestyle support staff
o Dietitian
o Behavior counselor
o Exercise specialist

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

Post Core Program
* Self-monitoring and other behavioral strategies
* Monthly visits
o Must be seen in person at least every two months
* Supervised exercise sessions offered
* Periodic group classes and motivational campaigns
* Tool box strategies
o Provide exercise videotapes, pedometers
o Enroll in health club or cooking class

DPP Study Interventions:
Criteria for Drug Treatment
* Efficacy
* Safety
* Tolerability - minimal side effects
* Acceptability - dose frequency
Metformin- 850 mg per day escalating after
4 weeks to 850 mg twice per day
Placebo- Metformin placebo adjusted in
parallel with active drugs

Interventions:
Medications
DPP Population
Retention and Participation
Lifestyle Intervention: Physical Activity Results
Mean Change in Leisure Physical Activity
Placebo
Metformin
Lifestyle
Effect of Treatment on Incidence of Diabetes
Diabetes Incidence Rates by Age
Diabetes Incidence Rates by Ethnicity
Diabetes Incidence Rates by BMI
Body Mass Index (kg/m2)
Diabetes Incidence Rates by Fasting Glucose
Fasting Plasma Glucose: mg/dl (mmol/l)
Diabetes Incidence Rates by 2-hr Glucose
2-Hour Plasma Glucose (mg/dl)
Consistency of Treatment Effects
Normal Fasting Glucose
Placebo Metformin Lifestyle
Summary-1
* Both interventions were well accepted and safe
* Intensive lifestyle resulted in weight loss and increased activity level for the

duration of the study

Summary-2
* Both interventions were effective in men and women and all ethnic groups
* Intensive lifestyle intervention was effective in all age groups, including those > 60 years of age

Summary-3
* Intensive lifestyle intervention reduced the development of diabetes by 58%
* Metformin reduced the development of diabetes by 31%
* Lifestyle was more effective than metformin

Lipids by Sex and Ethnicity

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Clinical Trials and Research

Clinical Trials and Research
A Guide for Community Advisory Board Members
Participant Manual


This teaching tool was developed by the François-Xavier Bagnoud Center at the University of Medicine and Dentistry of New Jersey, with the support of the Pediatric AIDS Clinical Trials Group.

Excerpts from this publication may be freely reproduced or adapted with acknowledgement of the source, provided the material reproduced is for non-profit distribution.

PACTG Global Training Initiative


Glossary
* Clinical Trial: A way to test new medications
* Eligibility: Deciding if a person is qualified to join a clinical trial
* Phases: Stages
* Placebo: Dummy tablet
* Protocol: A written plan for the clinical trial
* Study sample: People to be studied in the clinical trial
* Volunteers: People willing to join the trial

What is a Clinical Trial?
Identify a health question.
Develop a plan.
Enroll volunteers and follow the plan.
Study the information collected.
Share the results with others.
Improve treatment.

Example of a Research Question
* Is Medicine A more effective for preventing mother-to-child transmission than
Medicine B?
Medicine “B”
Medicine “A”


Phases of Clinical Trials

Phase I:Safety(15–30 people)

Phase II:Safety and Effectiveness(Fewer than 100 people)

Phase III:
Effectiveness compared to standard of care; Safety(More than 100 to a few thousand)

Structure of a Simple Trial Comparing Two Treatments
Randomisation
Investigational Group
Control Group
Ethics Committees
* The ethics committee reviews a protocol before the study is allowed to start. Their job is to ensure that the risks of being in the study are not greater than the potential benefit.

Informed Consent
* To make informed decisions, patients need to hear and understand specific information about the research.

* Purpose
* Medicine to be studied
* Procedures and schedule
* Risks
* Potential benefits
* Alternatives to participation
* Confidentiality
* Participation in clinical trials is always voluntary.

No, thank you, I’d rather not participate.
Yes, I would like to participate.

Research Protocol
How
Why
Where
When
What
Who

Protocol
Objectives: Clear and Specific Statements
* Which medicine is more effective in reducing mother-to-child transmission of HIV—Medicine “A” or Medicine “B”?

Medicine “B”
Medicine “A”

Eligibility
* Who may participate in this study
* Who may not (X) participate in this study

Data Safety and Monitoring Boards (DSMB)
* The job of the DSMB is to monitor the study for any problems with the safety or effectiveness of the medicines.

Safety
* A protocol must describe known risks or side effects and exactly what will be done to protect and monitor patients.

Schedule of Events
* To evaluate the effect of the medicine on their health, all patients in a trial have certain tests or procedures at regularly scheduled intervals.
Endpoints
* An endpoint is what researchers will measure to evaluate the results of a new medicine.
CAB: Part of the Research Team

* CAB members and volunteers who join clinical trials are part of the team dedicated to finding better ways to prevent and treat HIV.

How Have Clinical Trials Helped People with HIV?
* Clinical trials are critical in the effort to find better ways to treat HIV and AIDS.

How Have Clinical Trials Helped People with HIV?
* Antiretroviral medicines can greatly reduce the chance an infant will be HIV-infected during or after birth.

How Have Clinical Trials Helped People with HIV?
* They have greatly decreased sickness and death among patients who receive antiretroviral medicine.

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Clinical Trials

Clinical Trials

The Way We Make Progress Against Disease

What Are Clinical Trials?
* Research studies involving people
* Try to answer scientific questions and find better ways to prevent, diagnose, or treat disease
Why Are Clinical Trials Important?

* Clinical trials translate results of basic scientific research into better ways to prevent, diagnose, or treat disease

* The more people take part, the faster we can:
- Answer critical research questions
- Find better treatments and ways to prevent disease

Do Many People Take Part in Clinical Trials?

* Few people participate
What Are the Different Types of Clinical Trials?
* Treatment
* Prevention
* Early detection/screening
* Diagnostic
* Quality of life/supportive care

Treatment Trials
* What new treatments can help people with a particular disease?
* What is the most effective treatment for people with that disease?

Clinical Trial Phases
Phase 1 trials
* How does the agent affect the human body?
* What dosage is safe?

Phase 2 trials
* Does the agent or intervention have an effect on the disease?

Phase 3 trials
* Is the new agent or intervention (or new use of a treatment) better than the standard?
* Participants have an equal chance to be assigned to one of two or more groups

Randomized Trials
Participants have an equal chance to be assigned to one of two or more groups:
* One gets the most widely accepted treatment (standard treatment)
* The other gets the new treatment being tested, which researchers hope and have reason to believe will be better than the standard treatment

Randomization
Why is Randomization Important?
* So all groups are as alike as possible
* Provides the best way to prove the effectiveness of a new agent or intervention

Treatment Trials
* What new treatments can help people with a particular disease?
* What is the most of effective treatment for people with that disease?

Placebos are almost never used:
* Placebos are used only when no standard treatment exists
* Patients are told of this possibility before deciding to take part

Prevention Trials
* Evaluate the effectiveness of ways to reduce the risk of a particular disease
* Enroll healthy people at high risk for developing that disease

Prevention Trials
* Action studies (“doing something”)
* Agent studies (“taking something”)—also called “chemoprevention studies”

Chemoprevention Trials
* Phase 3 chemoprevention trials compare a promising new agent with either a:
--Standard agent
--Placebo

Clinical Trial Protocol
* A recipe or blueprint
* Strict scientific guidelines:

--Purpose of study
--How many people will participate
--Who is eligible to participate
--How the study will be carried out
--What information will be gathered about participants
--Endpoints

Benefits of Participation
Possible benefits:
* Patients will receive, at a minimum, the best standard treatment (if one exists)
* If the new treatment or intervention is proven to work, patients may be among the first to benefit
* Patients have a chance to help others and improve patient care

Risks of Participation
Possible risks:
* New treatments or interventions under study are not always better than, or even as good as, standard care
* Even if a new treatment has benefits, it may not work for every patient
* Health insurance and managed care providers do not always cover clinical trials

Patient Protection
* There have, unfortunately, been past abuses in patient protection
* Federal regulations ensure that people are told about the benefits, risks, and purpose of research before they agree to participate

How Are Patients’ Rights Protected?
* Informed consent
* Scientific review
* Institutional review boards (IRBs)
* Data safety and monitoring boards (DSMBs)
Informed Consent:
o Purpose
o Procedures
o Potential risks and benefits
o Individual rights
* Scientific review
* Institutional review boards (IRBs) are required by federal law for trials that are:

--Federally funded
--Subject to FDA regulation
Data and safety monitoring boards:
* Ensure that risks are minimized
* Ensure data integrity
* Stop a trial if safety concerns arise or objectives have been met


Why Do So Few People Participate in Clinical Trials?
Sometimes patients:
* Don’t know about clinical trials
* Don’t have access to clinical trials
* May be afraid or suspicious of research
* Can’t afford to participate
* May not want to go against health care provider’s wishes
Why Do So Few People Participate in Clinical Trials?
Health care providers might:
* Lack awareness of appropriate clinical trials
* Be unwilling to “lose control” of a person’s care
* Believe that standard therapy is best
* Be concerned that clinical trials add administrative burdens

Where to Find Clinical
Trial Information

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