Basic Study Design Friday Lecture PDF

OL3 BASIC STUDY DESIGN Carlos Cordero García, MD, PhD Head of PM&R Department. Juan Ramón Jiménez University Hospital. Huelva, Spain. Senior Teaching Assistant PPCR 2023 April 26th 2024 Carlos Corder...

OL3 BASIC STUDY DESIGN Carlos Cordero García, MD, PhD Head of PM&R Department. Juan Ramón Jiménez University Hospital. Huelva, Spain. Senior Teaching Assistant PPCR 2023 April 26th 2024 Carlos Cordero has no conflict of interest related with the content of this presentation. DOUBTS, QUESTIONS, PPT PRESENTATION… [email protected] [email protected]  AGENDA Case Discussion Some Questions Quiz – Multiple choice questions  FIRST PART - CASE DISCUSSION Dr. Garden – Challenges for a study design in Dermatology PARALLEL DESIGNS  PARALLEL DESIGNS Each subject receives only one of the treatments for a predetermined time. The responses in groups of subjects are then compared. Two or more arms Most common used design in Phase II and Phase III trials.  PARALLEL DESIGNS Direct tests (No standard therapy) Experimental therapy (E) vs Placebo (P) Active control (Standard therapy) E vs Standard treatment (S) Direct tests in the context of standard therapies S + E vs S + P Amount, timing of E - Low dose vs high dose of E - E initially vs E delayed - E intermittently vs E continuously  PARALLEL DESIGNS Advantages Disadvantages Simple Ethical concern if direct tests vs placebo Easy to interpret for reviewers If there are many groups, analysis can be complicated Less complex assumptions Many treatments comparations can be made CROSSOVER DESIGN  CROSSOVER DESIGN Repeated measurements design in which each experimental unit (patient) receives different treatments at different times of the study. Each patient acts as his/her own control Often used for assessment of chronic and stable diseases A wash-out period could be needed Critical point: carry-over effect (effect of the treatment from the previous time period on the response at the current time period)  CROSSOVER DESIGN Advantages Disadvantages Eliminate between-subjects variability Carry-over effects Ethical issues Drop out after the first intervention Easier recruitment Order effect Powerful (each patient serves as own control) Long wash out periods can increase the duration of the trial Requires less patients FACTORIAL DESIGN  FACTORIAL DESIGN Evaluate two interventions compared to a control in a single experiment to increase efficiency OR To test the interaction effects between two independent interventions (2x2 – simplest case)  FACTORIAL DESIGN Physician’s health study trial – test aspirin for prevention of cardiovascular diseases and beta-carotene for prevention of cancer “The remaining 22,071 physicians were then randomly assigned to receive active aspirin and active beta-carotene (n=5,517), active aspirin and beta-carotene placebo (n=5,520), aspirin placebo and active beta-carotene (n=5,519), or aspirin placebo and beta-carotene placebo (n=5,515). A total of 11,037 physicians were randomized to aspirin and 11,034 to aspirin placebo; a total of 11,034 physicians were randomized to beta-carotene and 11,037 to beta-carotene placebo.” N Engl J Med 1989; 321:129-135  FACTORIAL DESIGN Advantages Disadvantages Can perform two experiments with less patients than Assumption of no interaction – Efficacy of each regimen performing two separate experiments does not depend of the presence of the other Efficient – Allow to test two hypothesis at the same time Poor power to detect an interaction Complexity SECOND PART MORE QUESTIONS….. Placebo…when?? Efficacy vs Effectiveness?? Real World Data vs RCTs  PLACEBO Write in the chat examples in which a placebo arm would be appropiate and examples in which the use of placebo would not be appropiate EFFICACY VS EFFECTIVENESS  EFFICACY(RCT) VS EFFECTIVENESS (RWE) Table included in: Singal AG, Higgins PDR, Waljee AK. Clinical and Translational Gastroenterology 2014; 5: e45  RWD VS RCTS RWD RCTS Collected under real-life practice Controlled environment circumstances Interventional Observational Ascertains efficacy in limited population Provides a measure of effectiveness in sizes. the unrestricted population  RWD VS RWE RWD RWE Raw data collected outside constraints of Insights obtained by analyzing RWD RCT Information aimed at decision making Fact-based insights Shaped information; includes RWD as Component of RWE; non informative subset without RWE  THIRD PART: QUIZ – MULTIPLE CHOICE QUESTIONS  QUESTION 1 Researchers investigated the efficacy and side effects of the synthetic cannabinoid nabilone in comparison with those of the weak opioid dihydrocodeine for treating chronic neuropathic pain. A randomized, double blind, crossover trial was used. In total 96 participants with chronic neuropathic pain aged 23-84 years were recruited. Treatments were delivered in an escalating manner so that by the end of a six week treatment period the participants were receiving a maximum daily dose of 240 mg dihydrocodeine or 2 mg nabilone. The trial lasted for 14 weeks, comprising two treatment periods each of six weeks’ duration, separated by a two week washout period. The main outcome measure was pain as measured on a visual analogue scale over the final two weeks of each treatment period. The researchers reported that dihydrocodeine provided better pain relief than nabilone and had slightly fewer side effects. Which one of the following statements best describes how trial participants were allocated to treatment group? a) Participants were randomized to nabilone or dihydrocodeine and received the same drug for both treatment periods. b) Participants received both drugs—nabilone and dihydrocodeine—with treatment order for each participant decided at random. c) All participants received both drugs in the same order, with the treatment order determined at random (either they all received nabilone in the first treatment period and dihydrocodeine in the second or vice versa)  QUESTION 1 Researchers investigated the efficacy and side effects of the synthetic cannabinoid nabilone in comparison with those of the weak opioid dihydrocodeine for treating chronic neuropathic pain. A randomized, double blind, crossover trial was used. In total 96 participants with chronic neuropathic pain aged 23-84 years were recruited. Treatments were delivered in an escalating manner so that by the end of a six week treatment period the participants were receiving a maximum daily dose of 240 mg dihydrocodeine or 2 mg nabilone. The trial lasted for 14 weeks, comprising two treatment periods each of six weeks’ duration, separated by a two week washout period. The main outcome measure was pain as measured on a visual analogue scale over the final two weeks of each treatment period. The researchers reported that dihydrocodeine provided better pain relief than nabilone and had slightly fewer side effects. Which one of the following statements best describes how trial participants were allocated to treatment group? a) Participants were randomized to nabilone or dihydrocodeine and received the same drug for both treatment periods. b) Participants received both drugs—nabilone and dihydrocodeine—with treatment order for each participant decided at random. c) All participants received both drugs in the same order, with the treatment order determined at random (either they all received nabilone in the first treatment period and dihydrocodeine in the second or vice versa)  QUESTION 2 Researchers investigated the effects of two separate interventions—dietary advice and knee strengthening exercises—on knee pain and function using a factorial randomized controlled trial of two years of duration.Trial participants were overweight or obese adults in the community recruited at their general practice. The dietary intervention consisted of individualized advice on healthy eating. The knee strengthening exercise intervention was a home based self managed program. For both interventions, the control arm was an advice leaflet based on the Arthritis Research Campaign (United Kingdom) leaflet for osteoarthritis of the knee. Which one of the following options is false? a) The trial permitted the simultaneous investigation of dietary advice and knee strengthening exercises b) Trial participants received the dietary, exercise, and control intervention in a random order c) Trial participants had a one in four probability of receiving control treatment—the advice leaflet  QUESTION 2 Researchers investigated the effects of two separate interventions—dietary advice and knee strengthening exercises—on knee pain and function using a pragmatic factorial randomized controlled trial of two years of duration.Trial participants were overweight or obese adults in the community recruited at their general practice. The dietary intervention consisted of individualized advice on healthy eating. The knee strengthening exercise intervention was a home based self managed program. For both interventions, the control arm was an advice leaflet based on the Arthritis Research Campaign (United Kingdom) leaflet for osteoarthritis of the knee. Which one of the following options is false? a) The trial permitted the simultaneous investigation of dietary advice and knee strengthening exercises b) Trial participants received the dietary, exercise, and control intervention in a random order c) Trial participants had a one in four probability of receiving control treatment—the advice leaflet  QUESTION 3 Researchers investigated whether a systematic approach to the treatment of pain reduced agitation in people with moderate to severe dementia living in nursing homes. A cluster randomized controlled trial study design was used. The intervention comprised a stepwise protocol for the treatment of pain for eight weeks, with additional follow-up lasting four weeks from the end of treatment. The control group received the usual treatment and care. A sample of 352 residents living in 60 nursing home units across five municipalities of western Norway was identified. Each nursing home unit was independent, with no crossover of staff, and defined as a natural cluster for the purpose of the trial. Residents were eligible if they were aged 65 or older and had moderate to severe dementia and clinically significant behavioural disturbances. In total, 175 residents living in 33 clusters were randomized to intervention, and 177 residents living in 27 clusters were randomized to control. The primary outcome was agitation as measured on the Cohen-Mansfield agitation inventory. The researchers reported that the systematic approach to pain management significantly reduced agitation in residents of nursing homes with moderate to severe dementia. Which one of the following statements is false? a) All the residents in each nursing home unit received the same treatment – intervention or control – that their nursing home had been allocated b) All residents within a nursing unit had an equal probability of being randomized to intervention or control. c) The cluster of residents—the independent nursing home unit—was the unit of observation.  QUESTION 3 Researchers investigated whether a systematic approach to the treatment of pain reduced agitation in people with moderate to severe dementia living in nursing homes. A cluster randomized controlled trial study design was used. The intervention comprised a stepwise protocol for the treatment of pain for eight weeks, with additional follow-up lasting four weeks from the end of treatment. The control group received the usual treatment and care. A sample of 352 residents living in 60 nursing home units across five municipalities of western Norway was identified. Each nursing home unit was independent, with no crossover of staff, and defined as a natural cluster for the purpose of the trial. Residents were eligible if they were aged 65 or older and had moderate to severe dementia and clinically significant behavioural disturbances. In total, 175 residents living in 33 clusters were randomized to intervention, and 177 residents living in 27 clusters were randomized to control. The primary outcome was agitation as measured on the Cohen-Mansfield agitation inventory. The researchers reported that the systematic approach to pain management significantly reduced agitation in residents of nursing homes with moderate to severe dementia. Which one of the following statements is false? a) All the residents in each nursing home unit received the same treatment – intervention or control – that their nursing home had been allocated b) All residents within a nursing unit had an equal probability of being randomized to intervention or control. c) The cluster of residents—the independent nursing home unit—was the unit of observation.  QUESTION 4 Researchers assessed the efficacy of varenicline (a licensed cigarette smoking cessation aid) in helping users of smokeless tobacco to quit. A double blind placebo controlled parallel group randomized controlled trial study design was used.The intervention was varenicline 1 mg twice daily.Treatment was delivered for 12 weeks, with 14 weeks’ follow-up afterwards. Participants were aged 18 years or more.They were also users of smokeless tobacco who wished to quit and had no abstinence period longer than three months during the year before recruitment. In total, 431 participants were recruited and randomized to varenicline (n=213) or placebo (n=218). All participants were offered brief behavioural support or counselling at the discretion of the investigators. The primary endpoint was continuous abstinence for four weeks at the end of treatment (weeks 9-12) confirmed by cotinine concentration. A significantly higher rate of abstinence was reported in the varenicline group compared with placebo (59% v 39%; relative risk 1.6, 95% confidence interval 1.32 to 1.87; P