![Results
The mean (SD) time between the date of randomization into WHI and the
last Modified Mini-Mental State Examination (3MSE) for all WHIMS
participants was 4.05 (1.19) years. Overall, 61 women were diagnosed with
probable dementia, 40 (66%) in the estrogen plus progestin group
compared with 21 (34%) in the placebo group. The hazard ratio (HR) for
probable dementia was 2.05 (95% confidence interval [CI], 1.21-3.48; 45 vs.
22 per 10 000 person-years; P = .01). This increased risk would result in an
additional 23 cases of dementia per 10 000 women per year. Alzheimer
disease was the most common classification of dementia in both study
groups. Treatment effects on mild cognitive impairment did not differ
between groups (HR, 1.07; 95% CI, 0.74-1.55; 63 vs. 59 cases per 10 000
person-years; P = .72).
Conclusions
Estrogen plus progestin therapy increased the risk for probable dementia
in postmenopausal women aged 65 years or older. In addition, estrogen
plus progestin therapy did not prevent mild cognitive impairment in these
women. These findings, coupled with previously reported WHI data,
supportthe conclusion that the risks of estrogen plus progestin outweigh](https://image.slidesharecdn.com/rct-250209100025-80da4ae9/85/RCT-pptx-randomized-controlled-trials-ppt-34-320.jpg)
RCT.pptx randomized controlled trials ppt
- 1. EXPERIMENTAL EPIDEMIOLOGY AND RANDOMIZED CONTROLLED TRIALS BY B. ANUSHA 2k5
- 2. Definition: EXPERIMENTAL EPIDEMIOLOGY ⮚In 1920’s it meant study of epidemics among colonies of experimental animals such as rats and mice. ⮚In Modern usage it is equated with randomized controlled trials. RANDOMISED CONTROLLED TRIALS ⮚Those involving random allocation for carrying out various trials.
- 3. JAMES LIND James Lind performed a human experiment in which he added different substances to diet of 12 soldiers who were suffering from scurvy. He divided his patients into 6 pairs and supplemented the diets of each pair with cider, elixir vitriol, vinegar, sea water, and two oranges and one lemon daily. All the subjects were studied for 6 days. At the end of 6 days the LIMEYS Recovered from scurvy and were found fit for
- 4. Basic steps in conducting RCT • Drawing up a protocol • Selecting reference population • Randomization • Manipulation or intervention • Assessment of outcome
- 5. Assessment Manipulation & follow up Control group Experimental group Randomize Make necessary exclusions Select suitable sample (experimental or study population) Select a suitable population (reference or target population) Those who do not wish to give consent Those not eligible
- 6. THE PROTOCOL • It specifies: • The aims and objectives of the study. • Criteria for the selection of study and control groups. • Treatments to be applied. • Standardization of working procedures. • Schedules and responsibilities of the parties involved in the trial. • It aims at preventing bias and to reduce the sources of error in the study. • It should be strictly adhered to throughout the study.
- 7. Selecting reference and experimental populations ❑Reference or target population: • It is the population to which the findings of the trial if found successful are expected to be applicable. • It may be entire world population, geographically limited or limited to persons in specific age , sex , occupational and social groups. ❑ Experimental or study population • It is derived from the reference population. • It is the actual population that participates in the experimental study. • Ideally, it should be randomly chosen from the reference population, so that it has the same characteristics as the latter.
- 8. • They must give “informed consent”. • They should be representative of the population to which they belong and • They should be qualified or eligible for the trial. The participants must fulfill the following three criteria:
- 9. Randomization • It is a statistical procedure by which the participants are allocated into groups usually called “study” and “control” groups. • It is the “heart” of the control trial. • It ensures that the investigator has no control over allocation of participants to either study or control group, thus eliminating “selection bias”. • It is crucial that both groups should be alike with regard to certain variables that might effect the outcome of the experiment (e.g., age, sex) • It is always desirable to check that the groups formed initially are basically similar in composition. • It is best done by using a table of random numbers.
- 10. • The essential difference between a randomized control trial and an analytical study is that in the latter, there is no randomization because a differentiation into diseased and non diseased groups has already taken place. RCT AND ANALYTICAL STUDY
- 11. Manipulation • This is to intervene or manipulate the study group by the deliberate application or withdrawal or reduction of the suspected causal factor. • This manipulation creates an independent variable (e.g., drug, vaccine) whose effect is then determined by measurement of the final outcome, which constitutes the dependent variable (e.g., incidence of disease, survival time)
- 12. Follow up • This implies examination of the experimental and control group subjects at definite intervals of time, in a standard manner. • The follow up may be short or may require many years depending upon the study undertaken. • Some losses to follow up are inevitable due to factors , such as death, migration, and loss of interest. This is known as attrition.
- 13. Assessment • The final step is assessment of the outcome of the trial in terms of 1. Positive results: benefits of the experimental measures such as reduced incidence or severity of the disease 2. Negative results: severity and frequency of side effects and complications ,if any ,including death Bias may arise from errors of assessment of the outcome due to human element. They may be from three sources: a) Bias on the part of participants known as “subject variations” . b) “Observer bias” due to the investigator. c) Bias in evaluation • In order to reduce these problems ,a technique known as “blinding” is adopted.
- 14. Blinding • Blinding can be done in three ways – A.SINGLE BLIND TRIAL: the trial is so planned that the participant is not aware whether he belongs to the study group or control group. B.DOUBLE BLIND TRIAL: here neither the doctor nor the participant is aware of the group allocation and the treatment received. C.TRIPLE BLIND TRIAL: the participant, the investigator and the person analyzing the data are all “blind”. • Ideally ,triple blinding should be used; but the double blinding is the most frequently used method.
- 15. Some study designs 1. CONCURRENT PARELLEL STUDY DESIGN: In this situation , comparisons are made between two randomly assigned groups, one group exposed to specific treatment, and the other group not exposed. ❖ Patients remain in the study group or the control group for the duration of the investigation.
- 16. Design of concurrent parallel therapeutic trials Exposed to specific treatment Unexposed to specific treatment Random assignment Patients Compare outcome
- 17. 2.CROSS OVER TYPE • Each patient serves as his own control . • The study group receives the treatment under consideration . • The control group receives some alternate form of active treatment or placebo. The two groups are observed over time. • Then the patients in each group are taken off their medication or placebo, and vice versa. • This type of study offers a number of advantages.
- 18. Cross over controlled therapeutic trials Exposed to specific treatment Unexposed to specific treatment Random assignment Patients Compare outcome & Unexposed to treatment
- 19. 1. CLINICAL TRIALS: These are concerned with evaluating therapeutic agents, mainly drugs. 2. Some of the recent examples include _ evaluation of beta blockers in reducing cardiovascular mortality, trials of beta carotene on cancer incidence etc. 3. Many ethical, administrative and technical problems are involved in the conduct of clinical trials. TYPES OF RANDOMIZED CONTROLLED TRIALS
- 20. 2.PREVENTIVE TRIALS • These are purported to prevent or eliminate disease on an experimental basis. • The most frequently occurring type of preventive trials are the trials of vaccines and chemo prophylactic drugs.
- 21. 3.RISK FACTOR TRIALS • The investigator intervenes to interrupt the usual sequence in the development of disease for those individuals who have “risk factor” for developing the disease. • Risk factor trials can be “single factor” or “multi-factor” trials.
- 22. • The study was conducted inn 3 centres in Europe. • The design was double blind and randomization was successfully achieved. • The mean observation was 9.6 years. • The trial showed a significant reduction in non fatal cardiac infarction, but unfortunately, there were 25% more deaths in the clofibrate –treated group than in the control group possibly due to long term toxic effect of the drug. •The WHO promoted a trial on primary prevention of coronary heart disease using clofibrate to lower serum cholesterol, which was accepted as a significant risk factor for CHD. •This study is the largest preventive trial conducted yet conducted, comprising of 15,000 men of whom one-third received clofibrate and two-third received olive oil as control treatment.
- 24. CESSATION EXPERIMENTS • Here an attempt is made to evaluate the termination of a habit which is considered to be causally related to a disease. • The familiar example is cigarette smoking and lung cancer. • If in a RCT, one group of cigarette smokers continue to smoke and the other group has given up, the demonstration of a decrease in the incidence of lung cancer in the study group greatly strengthens the hypothesis of a causal relationship.
- 25. 5.TRIAL OF AETIOLOGICAL AGENTS ⚫One of the aims of experimental epidemiology is to confirm or refute an etiological hypothesis. ⚫The best known example of an etiological agent relates to retrolental fibroplasia.
- 26. ▣ RCT have been extended to assess the effectiveness and efficiency of health services. ▣ An excellent example of such an evaluation is controlled trials in the chemotherapy of tuberculosis in India, which demonstrated that “domiciliary treatment” of pulmonary TB was as effective as the more costlier “hospital or sanatorium” treatment. ▣ The results have gained international acceptance and ushered in a new era-the era of domiciliary treatment, in the treatment of TB. 6.Evaluation of health services
- 27. HEALTH SERVICES RESEARCH STUDIES • Studies have shown that many of the health care delivery tasks traditionally performed by physicians can be performed by nurses and other paramedical workers, thus saving physicians time.
- 29. Topiramate for Migraine Prevention • Context Small open-label and controlled trials suggest that the antiepileptic drug topiramate is effective for migraine prevention. • Objective To assess the efficacy and safety of topiramatefor migraine prevention in a large controlled trial. • Design, Setting, and Patients A 26-week, randomized, double-blind, placebo-controlled study was conducted during outpatient treatmentat 52 North American clinical centers. Patients were aged 12to 65 years and had a 6- month history of migraine (International Headache Society criteria) and 3 to 12 migraines a month butno more than 15 headache days a month during a 28-day prospectivebaseline phase.
- 30. Interventions: After a washout period, patients meeting entry criteria were randomized to topiramate (50, 100, or 200mg/d) or placebo. Topiramate was titrated by 25 mg/wk for 8weeks to the assigned or maximum tolerated dose, whichever was less. Patients continued receiving that dose for 18 weeks. Main Outcome Measures: The primary efficacy measure was change from baseline in mean monthly migraine frequency. Secondary efficacy measures included responder rate (proportion of patients with 50% reduction in monthly migraine frequency), reductions in mean number of monthly migraine days, severity, duration, and days a month requiring rescue medication, and adverse events. The month of onset of preventive treatment action was assessed.
- 31. • Results: Of 483 patients randomized, 468 provided at least 1 post baseline efficacy assessment and comprised the intent-to- treat population. Mean monthly migraine frequency decreased significantly for patients receiving topiramate at 100 mg/d (-2.1, P = .008) and topiramate at 200 mg/d (-2.4, P<.001) vs placebo (- 1.1). Statistically significant reductions (P<.05) occurred within the first month with topiramate at 100 and 200 mg/d. The responder rate was significantly greater with topiramate at 50 mg/d (39%, P = .01), 100 mg/d (49%, P<.001), and 200 mg/d (47%, P<.001) vs. placebo (23%). Reductions in migraine days were significant for the 100-mg/d (P = .003) and 200-mg/d (P<.001) topiramate groups. Rescue medication use was reduced in the 100-mg/d (P = .01) and 200-mg/d (P = .005) topiramate groups. Adverse events resulting in discontinuation in the topiramate groups included paresthesia, fatigue, and nausea. Conclusion: Topiramate showed significant efficacy in migraine prevention within the first month of treatment, an effect maintained for the duration of the double-blind phase.
- 32. Estrogen Plus Progestin and the Incidence of Dementia and Mild Cognitive Impairment in Postmenopausal Women The Women's Health Initiative Memory Study: A Randomized Controlled Trial Context Postmenopausal women have a greater risk than men of developing Alzheimer disease, but studies of the effectsof estrogen therapy on Alzheimer disease have been inconsistent. On July 8, 2002, the study drugs, estrogen plus progestin, in the Women's Health Initiative (WHI) trial were discontinued because of certain increased health risks in women receiving combined hormone therapy. Objective To evaluate the effect of estrogen plus progestin on the incidence of dementia and mild cognitive impairment comparedwith placebo.
- 33. Design, Setting, and Participants The Women's Health Initiative Memory Study (WHIMS), a randomized, double-blind, placebo-controlled clinical trial, began enrolling participants from the Women's Health Initiative (WHI) estrogen plus progestin trial in May 1996. Of the 4894 eligible participants of the WHI study, 4532 (92.6%) postmenopausal women free of probable dementia, aged 65 years or older, and recruited from 39 of 40 WHI clinical centers were enrolled in the WHIMS. Intervention Participants received either 1 daily tablet of 0.625 mg of conjugated equine estrogen plus 2.5 mg of medroxyprogesterone acetate (n = 2229), or a matching placebo (n = 2303). Main Outcome Measures Incidence of probable dementia (primaryoutcome) and mild cognitive impairment (secondary outcome) were identified through a structured clinical assessment.
- 34. Results The mean (SD) time between the date of randomization into WHI and the last Modified Mini-Mental State Examination (3MSE) for all WHIMS participants was 4.05 (1.19) years. Overall, 61 women were diagnosed with probable dementia, 40 (66%) in the estrogen plus progestin group compared with 21 (34%) in the placebo group. The hazard ratio (HR) for probable dementia was 2.05 (95% confidence interval [CI], 1.21-3.48; 45 vs. 22 per 10 000 person-years; P = .01). This increased risk would result in an additional 23 cases of dementia per 10 000 women per year. Alzheimer disease was the most common classification of dementia in both study groups. Treatment effects on mild cognitive impairment did not differ between groups (HR, 1.07; 95% CI, 0.74-1.55; 63 vs. 59 cases per 10 000 person-years; P = .72). Conclusions Estrogen plus progestin therapy increased the risk for probable dementia in postmenopausal women aged 65 years or older. In addition, estrogen plus progestin therapy did not prevent mild cognitive impairment in these women. These findings, coupled with previously reported WHI data, supportthe conclusion that the risks of estrogen plus progestin outweigh
- 35. Behavioral and Pharmacological Therapies for Late-Life Insomnia Context Insomnia is a prevalent health complaint in older adults. Behavioral and pharmacological treatments have their benefits and limitations, but no placebo-controlled study has compared their separate and combined effects for late-life insomnia. Objective To evaluate the clinical efficacy of behavioral and pharmacological therapies, singly and combined, for late-life insomnia. Design and Setting Randomized, placebo-controlled clinical trial, at a single academic medical center. Outpatient treatment lasted 8 weeks with follow-ups conducted at 3, 12, and 24 months. Subjects Seventy-eight adults (50 women, 28 men; mean age, 65 years) with chronic and primary insomnia. Interventions Cognitive-behavior therapy (stimulus control, sleep restriction, sleep hygiene, and cognitive therapy) (n=18), pharmacotherapy (temazepam) (n=20), or both (n=20) compared with placebo (n=20).
- 36. Conclusions Behavioral and pharmacological approaches are effective for the short- term management of insomnia in late life; sleep improvements are better sustained over time with behavioral treatment. Main Outcome Measures Time awake after sleep onset and sleep efficiency as measured by sleep diaries and polysomnography; clinical ratings from subjects, significant others, and clinicians. Results The 3 active treatments were more effective than placebo at post treatment assessment; there was a trend for the combined approach to improve sleep more than either of its 2 single components (shorter time awake after sleep onset by sleep diary and polysomnography). For example, the percentage reductions of time awake after sleep onset was highest for the combined condition (63.5%), followed by cognitive- behavior therapy (55%), pharmacotherapy (46.5%), and placebo (16.9%). Subjects treated with behavior therapy sustained their clinical gains at follow-up, whereas those treated with drug therapy alone did not. Long- term outcome of the combined intervention was more variable. Behavioral treatment, singly or combined, was rated by subjects, significant others, and clinicians as more effective than drug therapy alone. Subjects were also more satisfied with the behavioral approach.
- 37. REFERENCES --Parks text book of preventive and social medicine -www.who.int -AUTHOUR AFFILIATIONS ❑Michigan head pain and neurological institute, Ann arbor ❑Dep't of public health sciences (Drs. schumaker and legault) ❑Medical college of Virginia
Editor's Notes
- #19: dministrative