Zinc study

A CRITICAL APPRAISAL

Presented at

Workshop on RANDOMIZED CONTROL TRIALS- DESIGN,

ANALYSIS AND REPORTING

Indian Institute of Public Health (Delhi)

Anuradha Bansal – Veena R. Parmar – Srikant Basu – Jasbinder Kaur

– Suksham Jain – Abhijeet Saha – Deepak Chawla

1. Summary of the article

2. Basic Study Design

3. Section-wise critical appraisal

Title and abstract

Introduction

Material and Methods

Results

Discussion

Conclusion

4. Internal Validity and External Validity

Objectiv

e

To evaluate the efficacy of zinc supplementation on

duration of illness in children with severe ALRTI

PChildren age group 2-24 months with severe ALRTI (Inclusion

criteria)

In a teaching referral hospital in North India

I20mg of elemental zinc per day for 5 days

CControl group received an equal amount of placebo with

appropriate taste, smell, color and consistency similar to zinc

mixture

OPrimary - Time to be asymptomatic (Composite)

Secondary – Duration on hospital stay,

Resolution of danger signs, respiratory distress, tachypnea

and hypoxia in room air

TSuperiority objective

Randomized Control Trial, prospective in nature

Assessed for

eligibility

N=120

14

excluded (parental refusal

or exclusion

criteria)

106

Randomized

53 - zinc

group

52 analyzed

53 -control

group

Enrollment

Process

Randomization

Intervention

Follow up

52 - zinc group(1 left against medical

advice)

53 received

placebo

52 analyzed

(1 lost to follow

up)

ITT?

The study claims to have followed an intention to

treat analysis whereas actually the trial profile

shows a minor inconsistency

In the intervention arm, one patient left after being

randomized – the final result has EXCLUDED the

patient and considered n=52 in this arm

In the control arm, the loss to follow up has been

INCLUDED in the size of the control group as n=53

here.

(The n given in the baseline and outcome tables

is different)

TITLE

Mentions study design, intervention and population

Does not mention the area from which the population has been studied

ABSTRACT

Objectives, methods, findings and conclusions have been well summarised

No mention of the method of randomization

INTRODUCTION

Justification for the

need for study and

area mentioned (North India) has been clearly outlined and reflects clinical equipoise

MATERIAL AND METHODS

Method Description Comment

RANDOMIZATION TECHNIQUE

Simple Randomization through a random number table

Suspicious as exactly same size of control and intervention arm has been achieved

ALLOCATIONCONCEALMENT

Achieved by dispensing the drug and placebo in identically looking bottles

Justified- but no mention of who dispensed the drug to the patient

PREPARATION OF PLACEBO

Placebo prepared to give similar taste, smell, color and consistency compared to original zinc mixture

Mentioned sources and details

BLINDING Repeated mention of the trial being of a ‘triple blind design’

No mention of ‘WHO’ exactly was blinded

DISCHARGE CRITERIA FOR PATIENTS

Asymptomatic for at least 24 hours. Objective in nature

SAMPLE SIZE CALCULATION

Pilot study revealed that for 80% power and 0.05 two sided alpha, a sample of 400 was needed which was brought down to 106 due to time constraints

No detailed mention of way of arriving at sample size -effect size-change in primary outcome

SAMPLE SIZE OF THE STUDY

N=106 Identified by the study as a limitation

Small to give any decisive result, does not resolve the inconsistency of results established by studies before –Precision compromised therefore WIDE CONFIDENCE INTERVAL OBTAINED.

Time to be asymptomatic

Median hours with IQR – range more or less same, statistically insignificant

No. of children symptomatic

Similar and statistically insignificant value

Duration of hospital stay

Shorter by 9 hours in the zinc group – result insignificant

Time to resolution of respiratory distress, tachypnea, dangers signs and hypoxia

Similar in both the groups, results statistically insignificant.

Sub Group Analysis Post Hoc is questionable, should have been a

priori

Multiplicity problem Secondary outcomes are correlated

Primary and secondary also correlated

Duration of stay- degree of subjectivity, not mentioned about blinded also

Components of composite endpoint have equal importance in terms of relevance to the patient -more or less the same, least important is duration of stay

Zinc supplementation did not reduce recovery

time and duration of hospital stay

Not enough evidence found to reject null

hypothesis

The conclusions are plausible.

Internal Validity Selection bias – Doubtful since the number in both

the arms has been found to be equal despite simple randomisation

Performance bias – Triple blind claimed but no mention of who all were blinded

Attrition bias – no problem

Detection bias – no mention of who assessed the outcome and who did what?

Reporting bias – inconclusive

External Validity

Given the inclusion and exclusion criteria which is

generally applicable

Inclusion of both wheezy and non wheezy

children

Very less proportion of population of slum areas,

less even in intervention group -Pragmatism?

Good proportion of anaemic patients,

confounding variable

Small sample size

Group 2 :

Dr Sabyasachi Das, Aleesha Mary Joseph, Jalnidh

Kaur, Anjali Sinha, Mr Suraj Parab, Dr Sunny

Chaudhary, Dr Bhawna Shukla, Dr Rupal Shah