临床试验设计的类型(1)

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


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Assess efficacy and safety Controlled, usually randomized
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Lecture Outline

D i scuss various trial design types - Parallel
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Crossover Group allocation Factorial Large simple Equivalency Non-inferiority Adaptive
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Section A
Comparison Structure: Parallel, Crossover, and Group Allocation Designs
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Unequal carry-over effects Treatment during washout
Test for period by treatment interactions not powerful D ropouts more significant


Analysis may be more difficult
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

P h a s eI: - 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
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



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Parallel Design Example: NETT

N a t i onal Emphysema Treatment Trial (NETT)
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Phase III trial, unmasked
People with severe emphysema 1,200 Randomized —Lung volume reduction surgery plus medical therapy —Medical therapy (standard therapy control)
Parallel Design

S i m u ltaneous treatment and control groups Each person is randomly assigned to one treatment group R a n d omization removes treatment selection bias and promotes comparability of treatment groups S t a t i stical comparisons made between treatment groups


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Crossover Design: Examples

Evening-dose vs. morning-dosed travoprost in open-angle glaucoma for 24-hour intraocular pressure control M ontelukast vs. salmeterol as adjuvant to inhaled fluticasone for exercise-induced asthma in children Topical oil vs. placebo for neuropathic pain

I n d i vidual randomization and intervention is not feasible or is unacceptable - Tracking

Contamination
I f there is a correlation in the responses within a group, design loses some efficiency (more individuals required)
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Crossover Design: Uses

C onstant intensity of underlying disease - Chronic diseases—asthma, hypertension, arthritis S h ort-term treatment effects - Relief of signs or symptoms of disease M e t a b olic, bioavailability, or tolerability studies
Types of Trial Design
Lea Drye, PhD Johns Hopkins University
Copyright © 2013 Johns Hopkins University and Lea Drye. All Rights Reserved.
Phases of trials
Lancet. 1986 May 24;1(8491):1169-73
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Vitamin A supplementation after study
C u l sters - Villages (450) selected using survey sampling method - Each randomly allocated to one treatment


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Group Allocation Design

Also known as “cluster randomization” R a n d omization unit is a group of individuals (community, school, clinic)

Follow-up Number of recruiting centers
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.
Population Sample size Allocation to treatment Treatments
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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Group Allocation Example: Sommer Vit A trial

P o p u a l tion - Preschool children in northern Sumatra in 1982-83 Treatments - Vitamin A supplementation during study
P h a s eII: - Usually 30-100 people - Preliminary information on efficacy, additional information on safety and side effects P h a s eIII: - Usually 100+ people
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Crossover Design

R a n d omization of order in which treatments are received - AB or BA

Randomization promotes balance between treatment groups in timing of exposure