treatment 2 evaluation of interventions types of rct blinding

TREATMENT 2 Evaluation of interventions

Types of RCT

Blinding

OBJECTIVES(Treatment lecture 1) Describe structure of RCT Define, calculate and interpret main measures of

effect for RCTs Compare RCT design with observational study

designs

Treatment lecture 2 Explain differences between efficacy and

effectiveness Distinguish between explanatory and

management trials)

What will be covered

Experimental design RCT architecture RCT analysis (measures of effect)

Calculation examples

Types of RCT Compliance

E.g. NTD trials

Blinding

Types of RCT

Compliance explain differences between efficacy and

effectiveness distinguish between explanatory and

management trials

NTD trials used below to illustrate these concepts.

Folate and neural tube defects (NTD)

Neural tube defects (NTD) = failure of closure of neural tube (at 20-25 days gestation)

Cause(s) of NTDs? Step 1

Map occurrence of NTDs by time, place and person (descriptive epidemiology)

Step 2 Why this pattern observed? (analytic epidemiology)

Occurrence of NTDs by time, place and person Declining secular trend Geographic differences

N vs S Europe Higher in Scotland, Ireland

NTD rates higher in Low SES

Poorer diet Winter births

Low fruit/vegetable intake in spring coincides with approx. 4 weeks gestation

Dietary link with NTDs???

Neural tube defects (NTD) and folate?

NTD rates higher in Women treated with anti-epileptic drugs

Epilepsy drug = folate antagonist Women with gastric bypass

Nutritional deficiencies including B12 and folate

NTD mothers: Dietary differences Low serum folate & low red blood cell folate

Folate link with NTDs??

RCT to test this hypothesis

RCT architecture

Total patient population(reference population)

Total number of patients in trial

Treated Placebo

No. (%) of outcomese.g. deaths, cures

No. (%) of outcomes,e.g. deaths, cures

RANDOMISATION

Informed consent

RCT architecture

Total patient population:905 mothers with previous NTD

Total number of patients in trial: 111

Treated60

Control51

RANDOMISATION

RCT analysesRelative risk (RR)

= incidence in treated group incidence in control group

Odds ratio = Outcome/ no outcome in treated group Outcome/ no outcome in control group

Risk difference / Attributable risk (RD)= (incid. in treated group) - (incid. in control

group)(Absolute) Risk reduction (RRed)

= (incid. in control group) - (incid. in treated group)

Relative risk reduction (RRR) (%) = risk reduction (x100) incidence in control group= 1 - RR (x 100)

Number needed to treat (NNT) = 1/ risk reduction

Relative risk reduction (RRR):

= Risk reduction x100 Incidence in controls

= (Incidence in cntrls - Incid. in Rx group) x100

Incidence in controls

= 1 - Incidence in Rx group X 100 Incidence in controls

= 1 - RR (x 100)

If confidence limits include 0, then NOTstatistically significant reduction in risk

Laurence et al. (BMJ 9 May 1981, 1509-11) Original analysis

NTD Normal NTD Rate (%)

Folate (n=60)

0 44 0.00

Control (n=51)

6 61 8.96

Relative risk reduction =100% p=0.0441

Laurence et al. (BMJ 9 May 1981, 1509-11) Original analysis

NTD Normal NTD Rate (%)

Folate (n=60)

0 44 [44] 0.00

Control (n=51)

6 61 [67] 8.96

Relative risk reduction =100% p=0.0441

What to do with non compliers?

Should they be reassigned as in the previous table?

Should they be dropped from the analysis? Should they be retained in their original group

irrespective of whether they adhered to the treatment/control regimen?

Hampton RCT chart - NTD study



Treated 60 Control 51

Continued 441

Withdrawn 162

0 (0%) NTD No. (%) NTD

Continued3

Withdrawn4

No. (%)NTD No. (%) NTD

RANDOMISATION

No. of NTD(%) No. of NTD (%)

'As treated'

Coronary Drug Project Trial Died Living Proportion

dying (%)

Compliant patients

297 1516 16.4 297/(297+1516)

Non-compliant patients

228 654 25.9 228/(228+654)

Relative risk reduction = 1 – RR(x100) = 1 - 16.4% / 25.9%(x100) = 37%

p << 0.0005, CI (95%) = 24 – 50%

Laurence et al.“Pure” analysis

NTD Normal NTD Rate(%)

All Folate(n=60)

2 58 [60] 3.33

All Control(n=51)

4 47 [51] 7.84

Risk reduction = 58% Not significant (p=0.27)




Treated 60 Control 51

Continued1

Withdrawn2

No. (%) NTD No. (%) NTD

Continued3

Withdrawn4


RANDOMISATION

2 NTD (3 .3%) 4 NTD (7.8%)

EFFICACY

EFFECTIVENESS (1+2 vs 3+4)




Treated Control

Continued1

Withdrawn2

No. (%) NTD No. (%) NTD

Continued3

Withdrawn4


RANDOMISATION

No. of NTD(%) No. of NTD (%)

EFFICACY (1 vs 3)

EFFECTIVENESS

Explanatory trial Efficacy: Compare outcome in compliers in

treatment group with outcome in compliers in control group

Non compliers omitted from analysis What if large number of non compliers?!

Management /intention to treat/pragmatic trial Effectiveness: Compare outcome according to

group to which assigned (irrespective of compliance) What if large number of non compliers?!

Intention-to-treat vs explanatory trials Both types of trial have their place, depending on

the trial objectives. Explanatory trials

show whether an intervention can work preferred by drug companies as it’s easier to show an

effect of a drug etc. Management trials

show whether an intervention does work more realistic, more likely to show what is likely to happen

in real life clinical situations

Use results from management trials to make your clinical decisions!!

Fletcher & Fletcher 4th edn Clinical Epidemiology, Chapter 8,Treatment, p136-8. Explanation of explanatory trials misleading Figs 8.7 & 8.8 not helpful

Characteristics of explanatory and management trials

EXPLANATORY Can it work? Intention

mechanisms efficacy

Restricted recruitment Idealised application Restricted eligibility of

events Type I ( )error

MANAGEMENT Does it work? Intention

all consequences effectiveness

All comers recruited Pragmatic All events eligible

Type II ( )error

Error types associated with management & explanatory trials

Conclusion from RCT

The Truth

A better A no better

A better than B **

A no better than B *

* Error associated with management trials (effectiveness)** Error associated with explanatory trials (efficacy)

BLINDING

Students often confused about this so some explanatory notes provided in the next sides.

Definitions Single blind

Patient not aware of whether on treatment on not. Double blind

Neither patient nor doctor knows who is on treatment on not.

Treble blind Neither patient nor doctor nor laboratory know who is on

treatment on not.

vs open treatment allocation (not blind, patient and doctor aware of whether in treatment group or not)

‘Double’ blinding Requires making the actual treatment and the

control indistinguishable – hence use of placebo Dummy (inert) substance or intervention which is

indistinguishable in appearance from the treatment (drug or other intervention)

Required to counteract the placebo effect Feel better because believing something will work

See example in next 2 slides Helps ensure similar behaviour by patients and

similar treatment of patients in both treatment and control groups

Avoids assessment bias observer and patient

Participants’ guesses regarding whether they received nicotine or placebo, assessed at the 6-month follow-up survey

Assigned versus perceived placebo effects in nicotine replacement therapy for smoking reduction in Swiss smokers.

R. Dar, F. Stronguin & J-F Etter, J Consult & Clin Psychol. 2005, 73, 350-3

Response Received nicotine

N=247

Received placebo

N=244

% guessed nicotine 35.8 16.4

% guessed placebo 26.3 54.5

% did not know 35.2 29.1

Mean reduction in cigarettes smoked per day as a function of actual and perceived treatment

Response Received nicotine, n=247

Received placebo, n=244

Total n=491

Guessed nicotine 14.0 13.8 13.9CI 11.8-16.2 10.6-16.9

Guessed placebo 8.1 8.1 8.1CI 5.4-10.7 6.4-9.8

Did not know 10.7 8.9 9.9CI 8.4-13.0 6.6-11.3

Total 11.3 9.3 10.3

CI = 95% confidence intervals for group means

J Consult & Clin Psychol. 2005, 73, 350-3

treatment 2 evaluation of interventions types of rct blinding

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