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Introduction to Randomized Clinical Trials

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Title: Introduction to Randomized Clinical Trials


1
Introduction toRandomized Clinical Trials
  • Stephen Bent
  • Associate Professor of Medicine
  • University of California, San Francisco

2
Randomized Trials
  • Rationale
  • Basic designs
  • Participants
  • Intervention
  • Blinding
  • Outcomes
  • Adherence
  • Follow-up

3
Take Home Messages
  • 1. RCTs really only do one thing
  • But, its a very important thing.
  • 2. RCTs are the BEST study design for evaluating
    efficacy.
  • RCTs compare mean responses
  • Not always what wed like to know
  • RCTs take a long time and cost

4
Take Home Messages
  • What is bias?
  • What is confounding?

5
Rationale
  • Why do a randomized blinded trial
  • minimize confounding!!!
  • minimize co-interventions
  • minimize biased outcome ascertainment
  • Why not do a randomized trial
  • major ethical issues
  • narrow research question
  • expensive
  • long time from idea to paper
  • Generally reserved for mature questions

6
Basic Trial Design
Population
Intervention
Randomization
Sample
7
Randomization
  • Participants are assigned to treatment groups by
    chance with a known probability
  • Random number table or computer
  • Tamper-proof system
  • ordered, sealed envelopes
  • centralized system (phone, fax, web)

8
Value of Randomization
  • Balances baseline characteristics of the
    treatment groups
  • eliminates confounding due to measured and
    unmeasured factors
  • provides an unbiased comparison between groups
  • Does NOT maintain balance after randomization

9
Variations of Randomization
  • Fixed Allocation - probability fixed
  • Simple - flip a coin
  • Blocked - randomize consecutive small batches
  • Stratified - separate randomization in strata
  • Clustered - randomize groups
  • Adaptive - probability changes

10
Cross-over Design
Population
Intervention
Randomization
Sample
Placebo
11
Factorial Design
Int A and Int B
Population
Int A and Pbo B
Sample
Pbo A and Int B
Pbo A and Pbo B
12
Participants
  • Inclusion criteria to maximize
  • rate of outcomes (old, weak)
  • likely benefit from intervention
  • generalizability
  • ease of recruitment

13
Exclusion Criteria
  • Intervention unsafe
  • Intervention unlikely to be effective
  • Unlikely to adhere to the intervention
  • Run in
  • Unlikely to complete follow-up
  • Practical problems

Practice Parsimony Preserve Generalizability
14
Choice of Intervention
  • Maximize
  • effectiveness (highest tolerable dose)
  • safety (lowest effective dose)
  • generalizability
  • trial design/conduct
  • recruitment
  • compliance
  • blinding

15
Choice of Control
  • Inert placebo usually best
  • Active therapy or standard of care

16
Cointerventions
  • Unintended effective interventions
  • participants use other therapy or change behavior
  • study staff, medical providers, family or friends
    treat participants differently
  • Nondifferential - decreases power
  • Differential - causes bias

17
Biased Outcome Ascertainment
  • If group assignment is known
  • participants may report symptoms or outcomes
    differently
  • physicians or investigators may elicit symptoms
    or outcomes differently

18
Canadian Cooperative MS Trial
  • 165 patients with multiple sclerosis
  • plasma exchange cyclo pred
  • sham plasma exchange placebo meds
  • Outcome structured neurologic exam by blinded
    and unblinded neurologists
  • More improvement with plasma exchange by
    unblinded, but not blinded assessment

Noseworthy, Neurology, 1994
19
Biased Outcome Adjudication
  • Study staff who decide if a change or outcome has
    occurred may
  • classify similar events differently in treatment
    groups
  • Problematic with soft outcomes
  • investigator judgement
  • participant reported symptoms, scales

20
Why Not Blind?
  • Impossible
  • surgery
  • exercise
  • diet
  • education
  • Possible, but
  • dangerous
  • painful
  • cumbersome

21
Is It Really Blinded?
  • Difficult even for drugs
  • identical placebo difficult to prepare
  • drug may smell, taste, feel different
  • drug may cause side effects
  • test results may unblind
  • participants may test drug

22
What if You Cant Blind?
  • Do the best you can
  • minimize differential cointervention
  • blind those measuring outcome
  • use hard outcomes
  • Measure degree of unblinding

23
Be Courageous
  • Laparoscopic lysis of adhesions for pelvic pain
  • Internal mammary ligation for angina
  • Orthoscopic debridement for OA
  • Sham burr holes for fetal tissue implants for
    Parkinsons

24
Do the Best You Can
  • Exercise to prevent coronary events
  • exercise - supervised exercise to 80 maximum
    capacity 30 min 3/wk
  • control - supervised exercise to 40 maximum
    capacity 30 min 3/wk
  • Psychotherapy for schizophrenia
  • therapy - psychotherapy weekly
  • control - advice about diet, exercise, and
    smoking weekly

25
Use a Hard Outcome
  • Death
  • Measurements
  • test results
  • MVO2 vs.. self-reported exercise ability
  • Doppler evaluation vs.. swollen leg for DVT
  • scales and diaries vs. investigator judgment
  • Geriatric Depression Scale vs. improved
  • 7-day urinary diary vs. dry

26
Adherence
  • Intervention cannot work if it isnt used
  • Adherence measures
  • intervention
  • pill count, diaries, biologic measure, measuring
    device in dispenser
  • visits
  • study measurements

27
Womens Health Initiative
  • RQ Does calcium plus vitamin D reduce risk of
    fractures in postmenopausal women?
  • Design Randomized trial
  • Subjects 36,282 PM women enrolled in WHI
  • Intervention 1 gm calcium 400 IU vitamin D
  • Outcome clinical fractures
  • Adherence at end of trial 60 and about 60 of
    placebo group was taking calcium

28
Outcomes in Clinical Trials
  • Efficacy Outcomes
  • Primary
  • Secondary
  • Surrogate
  • Composite
  • Adverse Effects
  • rare
  • common

29
Adverse Events and Side Effects
  • Anticipated
  • use specific questions
  • Unanticipated
  • ask about general adverse experiences
  • Rare
  • sample size inadequate
  • Common
  • multiple differences between groups

30
A Randomized Controlled Trial of a Chinese Herbal
Remedy to Increase Energy, Memory, Sexual
Function, and Quality of Life in Elderly Adults
in Beijing, China
  • Stephen Bent, MD
  • Osher Center for Integrative Medicine
  • University of California, San Francisco

31
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32
Longevity Treasure
  • Proprietary extract
  • 10 Chinese herbs
  • Believed to increase Yang
  • Marketed to improve
  • Energy, Memory, Sexual Function, Qi
  • Widespread use in China
  • US sales of over 1 million

33
Research Question
  • Does the daily use of Longevity Treasure lead to
    changes in energy, memory, sexual function, qi,
    or quality of life?

34
Methods
  • Design Randomized Controlled Trial
  • Participants
  • Chinese residents of Beijing, age gt 60
  • Self-reported decreased energy, memory, or sexual
    interest
  • Recruitment word of mouth

35
Exclusion Criteria
  • High Yang
  • Serious medical illness
  • Currently taking Longevity Treasure

36
Intervention
  • Random assignment to
  • Longevity Treasure, 4 capsules three times a day
    (30 days)
  • Identical placebo, 4 capsules, three times a day
    (30 days)

37
Outcomes
  • Assessed at baseline and 30 days
  • Primary
  • Change in quality of life, SF-12 questionnaire
  • Change in quality of life, Qi scale

38
Secondary Outcome Measures
  • Energy questionnaire
  • Energy physical tests
  • 6 minute walk
  • Step test
  • Grip strength
  • Chair stands
  • Foot tap
  • Memory word and picture recall
  • Sexual function 3-item questionnaire

39
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40
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43
Study Flow
44
Baseline Characteristics
Characteristic Placebo Herbs P-value
Age 65.6 66.4 0.23
Women () 62.2 64.4 0.72
Decreased energy () 21.0 25.4 0.42
Decreased memory () 81.5 86.4 0.30
Decr. sexual interest () 97.5 94.1 0.19
Qi score 13.8 15.8 0.01
45
Results Primary Outcomes
  • SF-12, Mental Component (Baseline 53)
  • Herbs 4.4
  • Placebo 2.5
  • Difference 1.9 points (95 CI, 0.1 to 3.6)
  • SF-12, Physical Component (Baseline 50)
  • Herbs 1.6
  • Placebo 1.7
  • Difference -0.1 (95 CI, -1.7 to 1.5)

46
Primary Outcome Qi scale
47
Secondary Outcome Measures
Measure (range) Baseline Herb Placebo P-value
Memory (0-39) 21.3 4.5 4.2 0.51
Physical test (-16 to 8) 0.3 -0.1 -0.1 0.8
Sexual function (0-26) 4.1 -0.5 -0.9 0.17
SF-36 Vitality 74.8 6.1 5.0 0.39
SF-36 Mental Health 81.0 7.0 5.2 0.04
48
Adverse Events
Event Placebo () Herb () P-value
Diarrhea 3.4 1.7 0.41
URI 1 1 1.00
Headache 0 1 0.31
Dry mouth 5.9 12.7 0.07
Total 19 29 0.24
49
Summary
  • Longevity Treasure may improve mental health
  • 2 point increase on SF-12 mental health score
  • Similar improvement on SF-36 subscale
  • The benefit, if any, is small
  • Longevity Treasure does not improve
  • Memory
  • Sexual Function
  • Energy or Qi

50
Conclusions
  • Longevity Treasure cannot be strongly recommended
    without further supportive evidence
  • RCTs of Chinese herbs are feasible
  • More work is needed to explore Chinese concepts
    of quality of life and qi

51
A randomized controlled trial of saw palmetto for
the treatment of benign prostatic hyperplasia
  • Stephen Bent, MD
  • Christopher Kane, MD
  • Katsuto Shinohara, MD

John Neuhaus, PhD Harley Goldberg, DO Andrew L.
Avins, MD, MPH
University of California, San Francisco Kaiser
Permanente Northern California, Division of
Research
Funded by the National Institute of Diabetes,
Digestive and Kidney Diseases (NIDDK) and the
National Center for Complementary and Alternative
Medicines (NCCAM)
52
Saw palmetto (serenoa repens)
  • Many patients seek an alternative to drug therapy
  • Used daily by 1.1 of the US adult population
  • Widely used in Europe

53
Methods
  • Randomized, double-blind, placebo-controlled
    trial
  • Patients recruited from Kaiser Permanente,
    Northern California and San Francisco VAMC
  • Inclusion
  • Age gt 50
  • AUASI gt 8 (range 0-35)
  • Peak flow gt 4 and lt 15 mls/sec
  • Exclusion
  • Prior prostate cancer or prostate surgery
  • Using alpha-antagonist, 5-ARI, or saw palmetto
    (washout permitted)
  • Severe concomitant illness

54
Interventions
  • Saw palmetto 160mg bid for one year
  • Indena (extract, 92 free fatty acids)
  • Cardinal Health (encapsulation)
  • Rexall Sundown (packaging)
  • Placebo polyethylene glycol-400 and brown
    coloring agent

55
STEP Study Flow Chart
Saw palmetto 160 mg twice a day
Washout
Placebo capsule twice a day
Run-in Visit
Enrollment Visit
Randomized Treatment Period Visits
Randomization Visit
Screening Period Visits
56
Baseline Characteristics
57
Results AUASI
18
17
16
AUASI
15
14
0
5
10
15
Randomization
Month
Saw palmetto
Placebo
p 0.99
58
Results Maximum Flow Rate
12.5
12
11.5
Maximum Urine Flow Rate
11
10.5
0
5
10
15
Randomization
Month
Saw Palmetto
Placebo
p 0.37
59
Conclusions
  • No evidence of benefit in AUASI, Qmax, or other
    measured outcome
  • No evidence of harm no safety concerns
  • Discrepancy between our findings and others
    results needs exploration

60
Internet-Based RCTs
  • Exciting potential
  • Reach unlimited of patients
  • Lower cost
  • Much shorter time to completion
  • Participate from home, convenient

61
Kava and Valerian for Anxiety and InsomniaAn
Internet-based Randomized Blinded Trial
62
Figure 1.
63
REMOTE Study
  • Tolterodine ER (Detrol) for OAB
  • 1st Internet-based RCT of drug
  • https//oab.mytrus.com/home
  • Great idea, but many barriers currently

64
Take Home Messages
  • 1. RCTs really only do one thing
  • But, its a very important thing.
  • 2. RCTs are the BEST study design for evaluating
    efficacy.
  • RCTs compare mean responses
  • Not always what wed like to know
  • RCTs take a long time and cost

65
Take Home Messages
  • Bias a systematic deviation of an observation
    from the true clinical state
  • Confounder a variable that is related to the
    predictor and a cause of the outcome
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