Introduction to Randomized Clinical Trials

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					      Introduction to
 Randomized Clinical Trials

            Stephen Bent
   Associate Professor of Medicine
University of California, San Francisco
Randomized Trials

 –Basic designs
     Take Home Messages

• 1. RCT’s really only do one thing
  –But, it’s a very important thing.
• 2. RCT’s are the BEST study
  design for evaluating efficacy.
• RCT’s compare mean responses
  –Not always what we’d like to know
• RCT’s take a long time and cost $
     Take Home Messages

• What is bias?
• What is confounding?

• 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
  –long time from idea to paper
• Generally reserved for mature questions
                Basic Trial Design

Population          Intervention           Outcome

       Sample   Randomization   +   Blinding

                    Control                Outcome

• 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)
   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
       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
                Cross-over Design

Population       Intervention   Washout   Placebo

   Sample    Randomization

                 Placebo        Washout   Intervention

                         Outcome              Outcome
              Factorial Design

               Int A and Int B    Outcome
               Int A and Pbo B    Outcome

               Pbo A and Int B    Outcome

                Pbo A and Pbo B   Outcome

• Inclusion criteria to maximize:
  –rate of outcomes (old, weak)
  –likely benefit from intervention
  –ease of recruitment
             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
       Choice of Intervention

• Maximize
  –effectiveness (highest tolerable dose)
  –safety (lowest effective dose)
  –trial design/conduct
     • recruitment
     • compliance
     • blinding
          Choice of Control

• Inert placebo usually best
• Active therapy or “standard of care”

• Unintended effective interventions
  –participants use other therapy or change
  –study staff, medical providers, family or
   friends treat participants differently
• Nondifferential - decreases power
• Differential - causes bias
Biased Outcome Ascertainment
• If group assignment is known
  – participants may report symptoms
    or outcomes differently
  – physicians or investigators may
    elicit symptoms or outcomes
   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
  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
Why Not Blind?

• Impossible
  – surgery
  – exercise
  – diet
  – education
• Possible, but
  – dangerous
  – painful
  – cumbersome
       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
What if You “Can’t” Blind?

Do the best you can
  –minimize differential cointervention
  –blind those measuring outcome
  –use “hard” outcomes
Measure degree of unblinding
           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 Parkinson’s
        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
     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”

• Intervention cannot work if it isn’t used
• Adherence measures
    • pill count, diaries, biologic measure,
      measuring device in dispenser
  –study measurements
      Women’s 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
Outcomes in Clinical Trials

 • Efficacy Outcomes
 • Adverse Effects
Adverse Events and Side Effects

• Anticipated
  – use specific questions
• Unanticipated
  – ask about general adverse experiences
• Rare
  – sample size inadequate
• Common
  – multiple differences between groups
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
    University of California, San
      Longevity Treasure

• Proprietary extract
• 10 Chinese herbs
• Believed to increase “Yang”
• Marketed to improve
  –Energy, Memory, Sexual Function,
• Widespread use in China
• US sales of over $1 million
      Research Question

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

• Design: Randomized Controlled
• Participants
  –Chinese residents of Beijing, age >
  –Self-reported decreased energy,
   memory, or sexual interest
• Recruitment – “word of mouth”
        Exclusion Criteria

• High Yang
• Serious medical illness
• Currently taking Longevity Treasure

• Random assignment to

  –Longevity Treasure, 4 capsules
   three times a day (30 days)

  –Identical placebo, 4 capsules, three
   times a day (30 days)

• Assessed at baseline and 30 days

• Primary
  –Change in quality of life, SF-12
  –Change in quality of life, Qi scale
  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
  Study Flow
       Assessed for eligibility

Excluded (n=82)
High Yang (65)
   HTN (12)
   Other (5)


 Placebo (119)         Herbs (118)

 Withdrew (n=4)      Withdrew (n=10)
 Side effect (2)      Side effect (8)
  Left area (2)        Left area (2)

Analyzed (n=115)    Analyzed (n=108)
           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
 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)
      Primary Outcome: Qi scale

1.5                               Placebo
        Unadjusted   Adjusted
      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
           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
• Longevity Treasure may improve mental
  –2 point increase on SF-12 mental health
  –Similar improvement on SF-36 subscale
• The benefit, if any, is small
• Longevity Treasure does not improve
  –Sexual Function
  –Energy or Qi

• Longevity Treasure cannot be
  strongly recommended without
  further supportive evidence

• RCTs of Chinese herbs are

• More work is needed to explore
  Chinese concepts of quality of
  life and qi
A randomized controlled trial of saw
palmetto for the treatment of benign
       prostatic hyperplasia

     Stephen Bent, MD         John Neuhaus, PhD
     Christopher Kane, MD    Harley Goldberg, DO
     Katsuto Shinohara, MD 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)
   Saw palmetto (serenoa repens)

• Many patients seek an alternative to drug

• Used daily by 1.1% of the US adult population

• Widely used in Europe
• Randomized, double-blind, placebo-controlled
• Patients recruited from Kaiser Permanente,
  Northern California and San Francisco VAMC
  – Inclusion:
     • Age > 50
     • AUASI > 8 (range 0-35)
     • Peak flow > 4 and < 15 mls/sec
  – Exclusion:
     • Prior prostate cancer or prostate surgery
     • Using alpha-antagonist, 5-ARI, or saw palmetto (washout
     • Severe concomitant illness

• 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
              STEP Study Flow Chart

                                   Saw palmetto 160 mg twice a day

                                     Placebo capsule twice a day
Enrollment Run-in
   Visit    Visit


      -6     -4     0 wks.    1         3           6            9    12
     wks.   wks.             mo.       mo.         mo.          mo.   mo.
    Screening Randomizatio                     Randomized
   Period Visits n Visit                     Treatment Period
    Baseline Characteristics

  Characteristic       Saw Palmetto   Placebo
                         (N=112)      (N=113)
      Age (yr)             62.9         63.0

       White               84%         79%

AUA Symptom Index          15.7        15.0

Prostate Volume (ml)       34.7        33.6

Maximal Urinary Flow       11.4        11.6
    Rate (ml/s)
 Serum PSA (ng/dl)         1.8          1.6
                       Results: AUASI

        0                   5               10             15
            Randomization           Month

                            Saw palmetto         Placebo

                                                           p = 0.99
    Results: Maximum Flow Rate
Maximum Urine Flow Rate

                                 0                   5              10             15
                                     Randomization          Month

                                                     Saw Palmetto        Placebo

                                                                                   p = 0.37

• No evidence of benefit in AUASI,
  Qmax, or other measured
• No evidence of harm; no safety
• Discrepancy between our
  findings and others’ results
  needs exploration
     Internet-Based RCT’s

• Exciting potential
• Reach unlimited # of patients
• Lower cost
• Much shorter time to completion
• Participate from home,
  Kava and Valerian for Anxiety and
An Internet-based Randomized Blinded
Figure 1.
        REMOTE Study

• Tolterodine ER (Detrol) for OAB
• 1st Internet-based RCT of drug
• Great idea, but many barriers
     Take Home Messages

• 1. RCT’s really only do one thing
  –But, it’s a very important thing.
• 2. RCT’s are the BEST study
  design for evaluating efficacy.
• RCT’s compare mean responses
  –Not always what we’d like to know
• RCT’s take a long time and cost $
     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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