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临床试验设计的类型

Types of Trial Design
Lea Drye, PhD Johns Hopkins University
Copyright ? 2013 Johns Hopkins University and Lea Drye. All Rights Reserved.

Phases of trials
Phase I:
-First stage in testing a new intervention in humans -Usually 10-30 people -Identify tolerable dose, provide information on drug metabolism,
excretion, and toxicity
-Often not controlled
Phase II:
-Usually 30-100 people -Preliminary information on efficacy, additional information on
safety and side effects
Phase III:
-Usually 100+ people -Assess efficacy and safety -Controlled, usually randomized
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Lecture Outline
Discuss various trial design types
-Parallel -Crossover -Group allocation -Factorial -Large simple -Equivalency -Non-inferiority -Adaptive
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Section A
Comparison Structure: Parallel, Crossover, and Group Allocation Designs
The material in this video is subject to the copyright of the owners of the material and is being provided for educational purposes under rules of fair use for registered students in this course only. No additional copies of the copyrighted work may be made or

Parallel Design
Simultaneous treatment and control groups Each person is randomly assigned to one treatment group Randomization removes treatment selection bias and promotes comparability of treatment groups Statistical comparisons made between treatment groups
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Parallel Design Example: NETT

National Emphysema Treatment Trial (NETT)
- Phase III trial, unmasked

Population Sample size Allocation to treatment Treatments

People with severe emphysema
1,200
Randomized
—Lung volume reduction surgery plus medical therapy
—Medical therapy (standard therapy control)

Source: NETT Research Group (1999). Chest 1999; 116: 1750-61; NETT Research Group (1999). J Thorac Cardiovasc

Surg, 118: 518-528; Fishman, A., & Martinez, F., et al. (2003). N Engl J Med 348: 2059-73.

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Parallel Design Example: NETT

Hypothesis testing Outcomes
Follow-up Number of recruiting centers

Superiority
—Primary: mortality, exercise capacity —Secondary: quality of life, symptoms, lung function and mechanics, functional capacity Up to 7.5 years
Multi-center (17)

Source: NETT Research Group (1999). Chest 1999; 116: 1750-61; NETT Research Group (1999). J Thorac Cardiovasc

Surg, 118: 518-528; Fishman, A., & Martinez, F., et al. (2003). N Engl J Med 348: 2059-73.

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Crossover Design
Randomization of order in which treatments are received
-AB or BA -Randomization promotes balance between treatment groups in
timing of exposure
Testing of both treatments in each patient
-Each patient serves as his/her own control -Variability reduced because less variability within patient than
between patients
Fewer patients needed
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Crossover Design Graph

Group 1, Tx A

Group 2, Tx A

Group 2, Tx B

Washout

Group 1, Tx B

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Crossover Design: Disadvantages
Treatment can’t have permanent effects or cures
Potential carry-over effects of first-period treatment to second period
-Washout needs to be long enough -Unequal carry-over effects -Treatment during washout
Test for period by treatment interactions not powerful
Dropouts more significant
Analysis may be more difficult
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Crossover Design: Uses
Constant intensity of underlying disease
-Chronic diseases—asthma, hypertension, arthritis
Short-term treatment effects
-Relief of signs or symptoms of disease
Metabolic, bioavailability, or tolerability studies
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Crossover Design: Examples
Evening-dose vs. morning-dosed travoprost in open-angle glaucoma for 24-hour intraocular pressure control
Montelukast vs. salmeterol as adjuvant to inhaled fluticasone for exercise-induced asthma in children
Topical oil vs. placebo for neuropathic pain
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Group Allocation Design
Also known as “cluster randomization”
Randomization unit is a group of individuals (community, school, clinic)
Individual randomization and intervention is not feasible or is unacceptable
-Tracking -Contamination
If there is a correlation in the responses within a group, design loses some efficiency (more individuals required)
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Group Allocation Example: Sommer Vit A trial
Population
-Preschool children in northern Sumatra in 1982-83
Treatments
-Vitamin A supplementation during study -Vitamin A supplementation after study
Clusters
-Villages (450) selected using survey sampling method -Each randomly allocated to one treatment

Lancet. 1986 May 24;1(8491):1169-

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