RANDOMIZED CLINICAL TRIALS. Study Designs. Randomized Clinical Trials (RCT) ASSIGN EXPOSURE Follow up Check for OUTCOME. Experimental studies

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1 RANDOMIZED CLINICAL TRIALS Study Designs Observational studies Analytic studies Descriptive studies Randomized Controlled trials Case control Cohort Cross sectional Randomized Clinical Trials (RCT) Assign Exposure Randomly POPULATION Population People without the outcome Sample of people exposed Sample of people not exposed Outcome No Outcome Outcome No outcome Assign Exposure Randomly ASSIGN EXPOSURE Follow up Check for OUTCOME

2 RCT: Two by Two Table Exposure Outcome Yes No Yes a b No c d Risk of outcome in exposed (R E ) = a / a + b Risk of outcome in non-exposed (R Ē ) = c / c + d Relative risk (RR) = (R E ) = a / a + b (R Ē ) c / c + d RCT: Example 1 Study aim: Test the performance of the drug Propranolol in the treatment of myocardial Infarction. Study sample: 91 male veterans (30-53 years of age, with MI) Alive (28 days after admission) Yes No Total Survival rate Propranolol % No Propranolol % Relative Risk (RR)= 38/45 = 0.84 = / RCT: Example 2 Study aim: Evaluate the administration of a program given to pregnant women (eating habits, smoking, alcohol..) with its aim being to reduce the incidence of low birth weight babies. Low birth weight (LBW) Yes No Total Program No program Risk of LBW in women who received the program= 0.05 Risk of LBW in women who didn t receive the program= 0.15 RR = 0.05/0.15= 0.33

3 RCT: Eligibility Criteria Safety: Exclude population that will be sensitive to the events (example: pregnant women ). Select individuals likely to comply. RCT: Control treatment Usually give the control group a placebo. Placebo is an inactive control treatment that is indistinguishable (regarding appearance, sensation, smell, and taste) from the experimental treatment. The placebo Look-alike, feel-alike, smell-alike, and taste-alike the treatment. RCT: Treatment random assignment Every subject will have the same probability of receiving a given treatment. Subjects, clinicians, or investigators do not affect the treatment received. Randomization is used so as to decrease confounding. To ensure that the randomization has been successful, investigators should always compare the treatment groups created by the randomization according to important demographic and clinical factors.

4 RCT: Methods of randomization Alphabetic rule: The first letter of the last name. Association of certain letters with certain ethnic groups could lead to an unequal distribution of ethnicity between treatment groups. Computer generated lists of random numbers Ex: 3, 5, 9, 4, 2, If even ---A If odd-----b Therefore: 1 st, 2 nd, and 3 rd receive B 4 th and 5 th receive A. Flip a coin RCT: Stratified randomization Perform stratified randomization to assure comparability for important variables. Example: Surgical (S) versus medical treatment (MT) for female cancer patients. Menopause is an important variable. To ensure equal number of (S) and (MT) among menopause and non-menopause Stratify (divide) the females into menopause and non-menopause. Within menopause: allocate randomly individuals to both treatments Within non-menopause: allocate randomly individuals to both treatments RCT: Issues in randomization Individual randomization versus group randomization Blinding: Single blinding: Subjects Double blinding: Subjects & observers Compliance

5 RCT: Analysis Efficacy: Potential effect of treatment under optimal circumstances: whether treatment can have an effect on outcome. Compare subjects according to the treatment actually received. Exclude subjects who complied poorly, switched over, or withdrew Effectiveness: Compare subjects according to the treatment actually assigned to. Actual effect of treatment in the real world of people who comply poorly, or change treatment. RCT: Ethical consideration In order for a randomized clinical trial to be ethically justifiable, none of the trial treatments should be known to have superior efficacy at the time the trial begins Randomized controlled trials Tonnesen P, Norregaard J, Simonsen K, Sawe U, A double-blind trial of a 16-hour transdermal nicotine patch in smoking cessation. N Engl J Med. 1;325(5): OBJECTIVE: to study the efficacy of a transdermal nicotine patch in smoking cessation. METHODS: a double-blind randomized study comparing the effect of a 16-hour nicotine patch (15 +/- 3.5 mg of nicotine in 16 hours) with that of a placebo patch.

6 Randomized controlled trials Random assignment of treatments Every subject will have the same probability of receiving a given treatment. Subjects, clinicians, or investigators do not affect the treatment received Placebo An inactive control treatment that is indistinguishable (regarding appearance, sensation, smell, and taste) from the experimental treatment (Look-alike, feel-alike, smell-alike, and taste-alike treatment) Double blind trial Neither the subject nor the observer know what the subject has received (treatment versus placebo) Randomized controlled trials METHODS: Of the 289 smokers who participated in the study, 145 were treated with nicotine patches and 144 with placebo patches for 16 weeks. RESULTS: Rates of sustained abstinence were significantly better with active treatment than with placebo: 53 percent of those in the nicotine-patch group were abstinent after 6 weeks as compared with 17 percent of those in the placebo-patch group (P less than ). Randomized controlled trials Abstinence No Abstinence Total Nicotine Placebo RR=3.1 CONCLUSION: The nicotine skin patch proved to be safe and efficacious,, as demonstrated by a higher rate of abstinence than with placebo.

7 RCT: Advantages Reduced potential for confounding bias. Reduced potential for sample selection bias. Reduced potential for information bias. RCT Study Hypothesis Is Hockey associated with Asthma???? RCT: Disadvantages May be unethical Often expensive May reduce generalizability

8 RCT: Abstract 1 BACKGROUND: Alternating ibuprofen and acetaminophen for the treatment of febrile children is a prevalent practice among physicians and parents, despite the lack of evidence on effectiveness or safety. OBJECTIVE: This randomized, double-blind and placebo-controlled clinical trial aims at comparing the antipyretic effectiveness and safety of alternating ibuprofen and acetaminophen doses to that of ibuprofen mono-therapy in febrile children. Alternating ibuprofen and acetaminophen in the treatment of febrile children: a pilot study. Nabulsi MM, Tamim H, Mahfoud Z, Itani M, Sabra R, Chamseddine F, Mikati M. : BMC Med Mar 4;4:4 RCT: Abstract 1 METHODS: Seventy febrile children were randomly allocated to receive either an oral dose ibuprofen and oral acetaminophen after 4 hours, or a dose of ibuprofen and placebo at 4 hours. Rectal temperature was measured at baseline and at 6 hours later. Endpoints included proportions of afebrile children at 6 hours. Intent-to-treat analysis was planned. Alternating ibuprofen and acetaminophen in the treatment of febrile children: a pilot study. Nabulsi MM, Tamim H, Mahfoud Z, Itani M, Sabra R, Chamseddine F, Mikati M. : BMC Med Mar 4;4:4 RCT: Abstract 1 RESULTS: A higher proportion of subjects in the intervention group (83.3%) became afebrile at 6 hours than in the control group (57.6%); P = Alternating ibuprofen and acetaminophen in the treatment of febrile children: a pilot study. Nabulsi MM, Tamim H, Mahfoud Z, Itani M, Sabra R, Chamseddine F, Mikati M. : BMC Med Mar 4;4:4