Study Designs. Randomized Clinical Trials (RCT) RCT: Example 1. RCT: Two by Two Table. Outcome. Exposure. Yes a b No c d

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1 Study Designs Randomized Clinical Trials (RCT) Assign Exposure Randomly Experimental studies Analytic studies Observational studies Descriptive studies POPULATION Population People without the outcome Sample of people exposed Sample of people not exposed Outcome No Outcome Outcome No outcome Randomized Controlled trials Case control Cohort Cross sectional Assign Exposure Randomly ASSIGN EXPOSURE Follow up Check for OUTCOME RCT: Two by Two Table RCT: Example 1 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 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 = /

2 RCT: Example 2 RCT: Eligibility Criteria 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 Safety: Exclude population that will be sensitive to the events (example: pregnant women ). Select individuals likely to comply. 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 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.

3 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 RCT: Analysis Individual randomization versus group randomization Blinding: Single blinding: Subjects Double blinding: Subjects & observers Compliance Relief of headache Yes No Total A 100 B 100 A: 5 did not take any medication, 2 took B B: 3 did not take any medication and 3 took A

4 RCT: Analysis EFFECTIVENESS Relief of headache Yes No Total A 100 B 100 A: 5 did not take any medication, 2 took B B: 3 did not take any medication and 3 took A RCT: Analysis EFFICACY Relief of headache Yes No Total A 96 B 96 A: 5 did not take any medication, 2 took B B: 3 did not take any medication and 3 took A RCT: Analysis RCT: Ethical consideration 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. 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

5 Experimental studies 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. Experimental studies 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) Experimental studies 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 ). Experimental studies Randomized controlled trials Nicotine Placebo RR=3.1 Abstinence No Abstinence Total CONCLUSION: The nicotine skin patch proved to be safe and efficacious,, as demonstrated by a higher rate of abstinence than with placebo.

6 RCT: Advantages RCT Study Reduced potential for confounding bias. Reduced potential for sample selection bias. Hypothesis Is Hockey associated with Asthma? Reduced potential for information bias.??? RCT: Disadvantages RCT: Abstract 1 May be unethical Often expensive May reduce generalizability 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

7 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 RCT: Abstract 2 BACKGROUND: The optimum duration of antimicrobial prophylaxis in elective gastric cancer surgery is still open to question. This multicentre randomized clinical trial compared a single-dose with a multiple-dose regimen of antimicrobial prophylaxis for prevention of surgical-site infection. METHODS: Between May 2001 and December 2004, 501 patients undergoing elective surgery for gastric cancer in ten centres were allocated randomly to single- or multiple-dose antimicrobial prophylaxis. The primary outcome measure was the incidence of surgical-site infection, analyzed by intention to treat. RCT: Abstract 2 RESULTS: Some 243 patients who received a single dose and 243 who received multiple doses of antibiotics were included in the final analysis. The surgical-site infection rate was 9.5 per cent (23 of 243) and 8.6 per cent (21 of 243) respectively (difference 0.9 (95 per cent confidence interval to 5.9) per cent). Antimicrobial prophylaxis had no major adverse effects. Randomized clinical trial of single- versus multiple-dose antimicrobial prophylaxis in gastric cancer surgery. Mohri Y, Tonouchi H, Kobayashi M, Nakai K, Kusunoki M; on behalf of the Mie Surgical Infection Research Group. Br J Surg May 18;94(6): Randomized clinical trial of single- versus multiple-dose antimicrobial prophylaxis in gastric cancer surgery. Mohri Y, Tonouchi H, Kobayashi M, Nakai K, Kusunoki M; on behalf of the Mie Surgical Infection Research Group. Br J Surg May 18;94(6):

8 Sequence in the discovery of a causal association Clinical observation of a possible causal association between a factor and a disease Descriptive epidemiologic analysis establishing the association on a population level Analytic epidemiologic studies establishing the association on an individual level Sequence in the discovery of a causal association Experimental reproduction of the disease by the risk factor and/or elucidation of the pathogenic mechanism of the factor in the disease. Observation that removal of the risk factor (or modification of the host response to it) decreases the incidence of the disease. Example: Lung cancer and smoking Venous thromboembolism and O.C