The idea of randomisation, first introduced in the design of agricultural experiments by R.A.Fisher, ensured that true treatment effect could be separated from other effects arising from differences in experimental conditions or differences in the subjects studied. Randomisation did not feature in clinical trials until Bradford Hill introduced it formally in a trial of streptomycin for tuberculosis in 1948. Today randomisation is regarded as an essential feature of a well conducted clinical trial.
Article presentation on clinical trial
Dr. Priyamadhaba BeheraJunior ResidentARTICLE PRESENTATION ONCLINICAL TRIAL12/04/20131
Evaluation of Atorvastatin for the Treatment ofPatients With Asthma: A Double-Blind RandomizedClinical TrialAbdollatif Moini, Ghasem Azimi, Abdolhay Farivar Impact Factor 1.913
Outline of presentation1.Summary of article (1-18)–introduction– objectives– Methodology– Results– Discussion2.Epidemiology and biostatics concepts related toarticle (19-22)3.Critical appraisal (23-30)
Introduction• Asthma is a global health problem. Despite theavailability of effective treatment, somepatients develop a type of asthma that isinsensitive to corticosteroid• The anti-inflammatory and immunomodulatoryeffects of satins are well-documented
Objective• the potential therapeutic effects ofatorvastatin were investigated in asthmaticpatients
METHODLOGYStudy Setting Hospital -basedStudy site asthma clinics of Arak University ofMedical Sciences , Rahahan, Arak,IranType of Study Randomised clinical trialSample Size 62Study Subjects 18-70 years(grade2/grade3)asthmatic patientsScales used Asthma Control Test Questionnaire(For primary out-come) 6
• Inclusion criteria –mild persistent/moderatepersistent asthmatic (grade 2/grade 3) aged inbetween 18 to 70 years• Exclusion criteria1. taking satins at the time of study2. h/o of sensitive to satins3. severe asthma leading to hospitalization within a monthprior to study4. Smoking5. hepatitis or active liver disease, myopathy or myositis,6. pregnancy
Methodologymild persistent to moderate persistent asthma (grades 2 and 3 of severity criteriafor asthma) aged 18 to 70 years who presented at asthma clinics of ArakUniversity of Medical Sciences from 24 October 2010 to 10 April 201173 agreed to participateVolunteer patients were alternately allocated to the interventionand control group based on timing of entering study
ASTHMA CONTROL TEST• The ACT is a 5-item patient-administered survey forassessing asthma control• Each of the 5 questions is given a score from 1 to 5.• Responses from the ACT are summed to yield a scorethat ranges from 5 (poor control) to 25 (completecontrol).• A cut-off score of 19 or less identifies patients withpoorly controlled asthma.
Ethical clearance• The research protocol was approved by theScientific Ethics Committee of Arak Universityof Medical Sciences, and written informedconsent was obtained from the volunteers
STATISTICAL ANALYSIS• Statistical analysis carried out with software SPSS 16.0• Chi-squared test and student t-test were used to comparethe treatment and control group• independent and dependent t-test were used for thecomparison of groups and subgroups13
DISCUSSION One probable reason for the lack of a significant clinicalresponse to satins in this study, as well as in otherhuman studies, is that the therapeutic effects observedin vitro and in mice do not necessarily occur in humans Favourable clinical response requires a higher drugdosage or a longer period of treatment, or that thevariables selected in this study were insufficientlysensitive to show improved asthma control atorvastatin is not effective for the treatment of mild tomoderate asthma 17
Limitations• Did not have access to more sensitivequantitative methods for evaluating airwayhyper-responsiveness and inflammation.eg: using a peak flow meter, methacholinechallenge test, CRP assay, number of salivaeosinophils, the fraction of exhaled nitric oxide,or alveolar nitric oxide.18
RandomizationRandomization gives each participant a known (usually equal)chance of being assigned to any of the groups. Successfulrandomization requires that group assignment cannot bepredicted in advance.Basic Benefits of Randomization• Eliminates assignment basis• Tends to produce comparable groups• Produces valid statistical tests (valid false positive errorrates)
Why Randomize?• If, at the end of a clinical trial, a difference in outcomesoccurs between two treatment groups (say, interventionand control) possible explanations for this differencewould include:• the intervention exhibits a real effect;• the outcome difference is solely due to chance• there is a systematic difference (or bias) between thegroups due to factors other than the intervention.Randomization aims to obviate the third possibility.
Forms of Randomization• Simple Randomization• Permuted Block Randomization• Stratified Block Randomization• Dynamic (adaptive) random allocation
Alternative allocation vs.Randomisation• Some investigators incorrectly believe that analternating assignment of participants to theintervention and the control groups (eg-ABABAB…..)is a randomization• No random components exits in this type ofallocation except the first participant• A single-blind or unblinded study, the investigatorsknow the next assignment that lead to bias• In double-blind study, if the the blind is broken atone participant then entire sequence of assignmentis known
CRITICAL APPRAISALCONSORT (CONsolidated Standards of ReportingTrials)
CRITICAL APPRAISAL-1• Title and abstract are clear with study design,balanced summary of what was found• Background explains the scientific rationale for thestudy• In objectives they mention that the study, thepotential therapeutic effects of atorvastatin wereinvestigated in asthmatic patients ,but they haveonly considered grade-2/3 asthmatic patients in thestudy24
CRITICAL APPRAISAL-2• Inclusion and exclusion criteria for participants are clear• Settings and locations where the data were collected arementioned• The interventions for each group with sufficient details toallow replication, including how and when they were actuallyadministered• Completely defined pre-specified primary and secondaryoutcome measures, including how and when they wereassessedHow sample size was determined is explained
CRITICAL APPRAISAL-3• Detail description of randomisation is not given• Alternately allocation doesnt survey the purpose ofrandomisation• Statistical methods used to compare groups forprimary and secondary outcomes are mentioned• A table showing baseline demographic and clinicalcharacteristics for each group• Participant flow diagram is given but steps ofrandomisation and voluntary data missing is notclear
CRITICAL APPRAISAL-4• Silent about possible bias• Internal validity is questionable d/o selectionbais• Generalisability of this result is not possible toall asthmatic patient as it uses grade-2/3asthma in sampling• Silent about funding27