Indiaclen Short course of Amoxicillin in treatment of Pneumonia

(ISCAP)

3 versus 5 days amoxicillin for treatment of non-severe pneumonia in young children: a

double blind, placebo controlled multi-centric randomized trial

Funding AgencyFunding Agency

USAID through IndiaClen/INCLEN

Study Location

- Mumbai - Mumbai - Lucknow- Lucknow - Nagpur- Nagpur - New Delhi - New Delhi - Chandigarh - Chandigarh

- Trivandrum- Trivandrum - Vellore- Vellore

C

N.DL

N

M

VT

C=Chandigarh N.D= N. Delhi, L=Lucknow, N=Nagpur, M=Mumbai, T=Trivendrum, V=Vellore

BACKGROUNDBACKGROUND

• ARI is the biggest killer of under 5 children in developing

countries including India.

• ARI Control Programme in India recommends

cotrimoxazole as first line drug for non-severe pneumonia.

• Reports of significant in vivo and in vitro resistance to

cotrimoxazole.

• Clinical studies showing high treatment failure with

cotrimoxazole.

Objectives

PrimaryPrimary

To compare the proportions of children To compare the proportions of children

recoveringrecovering on 3-day versus 5-day treatment on 3-day versus 5-day treatment

with oral amoxicillin in children aged 2-59 with oral amoxicillin in children aged 2-59

months presenting with non-severe pneumonia, months presenting with non-severe pneumonia,

with or without wheezewith or without wheeze

Objectives

SecondarySecondaryTo compareTo compare Proportion who relapse within the next 6-14 days of Proportion who relapse within the next 6-14 days of

observation observation Proportion who had resistant strains of Proportion who had resistant strains of S.pneumoniaeS.pneumoniae

and and H.influenzae H.influenzae in nasopharyngealin nasopharyngeal cultures at the time cultures at the time of enrollment and at 12-14 days follow-up of enrollment and at 12-14 days follow-up

Direct medical cost of treatment of clinical failures and Direct medical cost of treatment of clinical failures and relapses in both groups (Data not shown)relapses in both groups (Data not shown)

Outcome Measures

Clinical Cure- on day 6Clinical Cure- on day 6 Clinical failure- Till day 6Clinical failure- Till day 6 Clinical relapse days 7-14Clinical relapse days 7-14

DEFINITIONSDEFINITIONS

Clinical cure:Clinical cure:

Return of respiratory rate to age specific WHO cut Return of respiratory rate to age specific WHO cut

off.off.

Clinical Failure:Clinical Failure:

Development of chest indrawing with danger signs Development of chest indrawing with danger signs

or persistence of fast breathing at day 3 or later or persistence of fast breathing at day 3 or later

leading to therapy change.leading to therapy change.

RelapseRelapse::

Development of signs of pneumonia between day 6 Development of signs of pneumonia between day 6

-14. -14.

Inclusion CriteriaInclusion Criteria

Children aged 2Children aged 2 - 59 months - 59 months with non-severe pneumoniawith non-severe pneumonia (WHO defined)(WHO defined) Written informed consent Written informed consent

Exclusion criteria Exclusion criteria severe pneumonia or very severe disease (WHO defined)severe pneumonia or very severe disease (WHO defined) severe malnutritionsevere malnutrition other infectious conditions requiring antibiotics therapyother infectious conditions requiring antibiotics therapy clinically recognized congenital heart diseaseclinically recognized congenital heart disease known or clinically recognized chronic systemic disorderknown or clinically recognized chronic systemic disorder history of repeated wheezing including physicians history of repeated wheezing including physicians

diagnosed asthmadiagnosed asthma hospitalization in past 2 weekshospitalization in past 2 weeks use of antibiotics in previous 2 daysuse of antibiotics in previous 2 days measles within the last monthmeasles within the last month known history of penicillin allergy known history of penicillin allergy prior enrollment in the studyprior enrollment in the study

Sample SizeSample Size

Calculated to test equivalence hypothesis tCalculated to test equivalence hypothesis to detect o detect difference of 4.5% using one sided difference of 4.5% using one sided t-t- test and 90% test and 90% power, assuming 12% failure rate with amoxycillinpower, assuming 12% failure rate with amoxycillin

Required number of patients was 950 in each groupRequired number of patients was 950 in each group

Intervention Scored amoxicillin dispersible tablet (125 mg/tablet) for the Scored amoxicillin dispersible tablet (125 mg/tablet) for the

first three daysfirst three days

4-6 kg ½ tablet per dose4-6 kg ½ tablet per dose

7-10 kg 1 tablet per dose7-10 kg 1 tablet per dose

11-15 kg 1 ½ tablets per dose11-15 kg 1 ½ tablets per dose

16-20 kg 2 tablets per dose16-20 kg 2 tablets per dose

Effective dose per kg body weight – 31 to 54 mg/day Effective dose per kg body weight – 31 to 54 mg/day

For the next two days they received either amoxicillin or For the next two days they received either amoxicillin or

placeboplacebo

FINAL OUTCOMEFINAL OUTCOME

3 days = 1095 5 days = 1093

Failure = 68 Resolved = 1027 Failure =73 Resolved = 1020

Failure= 47 Resolved = 980 Failure= 37 Resolved = 983

Relapse=32 Cured = 948 Relapse= 29 Cured = 954

1st follow-up

2nd follow-up

3rd follow-up

ResultsTable 1: Loss to follow-up

Absolute difference,

C.I

Total

N %

5 dayAMX

N %

3 day AMX

N %

0.2(-2.2, 2.5)

190 8.794 8.696 9.8LTF Day 12-14

0.4(-1.5, 2.4)

129 5.967 6.162 5.7LTF Day 6

0.5(-1, 2.0)

80 3.743 3.937 3.4LTF Day 4

ResultsTable 2: Adherence to treatment types

0.66186585.2

92884.9

937 85.6

Adherence at 5 day

0.78205794

1026 93.9

1031 94.2

Adherence at 3 day

p-valueTotal n%

5-day AMX n %

3-day AMX n %

ResultsTable 3: Outcome Measures (Per Protocol)

3-dayAMX

N %

5-dayAMX

N %

Absolute Difference

95% C.I

Total recruited 1033 1026

Cure on day 6 980 94.9 983 95.8 0.9(-0.9, 2.8)

Relapse 32 3.3 29 3.0 0.3(-1.2, 1.85)

ResultsTable 4: Risk factors associated with failures by logistic analysis

Unadjusted ORC.I

Adjusted ORC.I

Variable

2.1(.9, 4.9)

1.95 (1.0, 3.8)

RSV positivity

-11.57(7.4, 18.0)

Non-Adherence at 5 days

2.8

(1.5, 5.2)

2.82 (1.8, 4.45)

Excess Respiratory Rate more than 10 bmp

13.1 (8.5, 20.2)

Resistance pattern of isolates in two treatment types

66.6

66.7

54.4

57.466

.1 78.2

61.2

62.2

020406080

100

SP resistantTime 0

SP resistantTime 2

HI resistantTime 0

HI resistantTime 2

3 day AMX 5 day AMX

P v

alue

=0.

01

CONCLUSIONSCONCLUSIONS

1. Oral amoxicillin for 3 days is as

effective clinically as 5 days in the

treatment of children 2-59 months

old suffering from non severe

pneumonia.

2. In S. pneumoniae on day 12 – 14

an increased in-vitro resistance to

cotrimoxazole with 5 day treatment

seen.

For the treatment of non-For the treatment of non-severe pneumonia in severe pneumonia in children 2 to 59 months of children 2 to 59 months of age the National ARI age the National ARI Control Programmes Control Programmes already using amoxicillin already using amoxicillin as first line drug should as first line drug should consider 3 day antibiotic consider 3 day antibiotic therapytherapy

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