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 Agency USAID through IndiaClen/INCLEN

Study Location - Mumbai - Lucknow - Lucknow - Nagpur - Nagpur - New Delhi - New Delhi - Chandigarh - Chandigarh - Trivandrum - Trivandrum - Vellore - Vellore C N.D L N M V T C=Chandigarh N.D= N. Delhi, L=Lucknow, N=Nagpur, M=Mumbai, T=Trivendrum, V=Vellore

BACKGROUND 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 Primary To compare the proportions of children recovering on 3-day versus 5-day treatment with oral amoxicillin in children aged 2-59 months presenting with non-severe pneumonia, with or without wheeze

Objectives Secondary To compare  Proportion who relapse within the next 6-14 days of observation  Proportion who had resistant strains of S.pneumoniae and H.influenzae in nasopharyngeal cultures at the time of enrollment and at days follow-up  Direct medical cost of treatment of clinical failures and relapses in both groups (Data not shown)

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

DEFINITIONS Clinical cure: Return of respiratory rate to age specific WHO cut off. Clinical Failure: Development of chest indrawing with danger signs or persistence of fast breathing at day 3 or later leading to therapy change. Relapse : Development of signs of pneumonia between day

Inclusion Criteria  Children aged months  with non-severe pneumonia (WHO defined)  Written informed consent

Exclusion criteria Exclusion criteria  severe pneumonia or very severe disease (WHO defined)  severe malnutrition  other infectious conditions requiring antibiotics therapy  clinically recognized congenital heart disease  known or clinically recognized chronic systemic disorder  history of repeated wheezing including physicians diagnosed asthma  hospitalization in past 2 weeks  use of antibiotics in previous 2 days  measles within the last month  known history of penicillin allergy  prior enrollment in the study

Sample Size  Calculated to test equivalence hypothesis to detect difference of 4.5% using one sided t- test and 90% power, assuming 12% failure rate with amoxycillin  Required number of patients was 950 in each group

Intervention  Scored amoxicillin dispersible tablet (125 mg/tablet) for the first three days 4-6 kg ½ tablet per dose 4-6 kg ½ tablet per dose 7-10 kg 1 tablet per dose 7-10 kg 1 tablet per dose kg 1 ½ tablets per dose kg 1 ½ tablets per dose kg 2 tablets per dose kg 2 tablets per dose Effective dose per kg body weight – 31 to 54 mg/day  For the next two days they received either amoxicillin or placebo

FINAL OUTCOME 3 days = 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 = st follow-up 2 nd follow-up 3 rd follow-up

Results Table 1: Loss to follow-up Absolute difference, C.I Total N % 5 day AMX N % 3 day AMX N % 0.2 (-2.2, 2.5) LTF Day (-1.5, 2.4) LTF Day (-1, 2.0) LTF Day 4

Results Table 2: Adherence to treatment types Adherence at 5 day Adherence at 3 day p-valueTotal n% 5-day AMX n % 3-day AMX n %

Results Table 3: Outcome Measures (Per Protocol) 3-day AMX N % 5-day AMX N % Absolute Difference 95% C.I Total recruited Cure on day (-0.9, 2.8) Relapse (-1.2, 1.85)

Results Table 4: Risk factors associated with failures by logistic analysis Unadjusted OR C.I Adjusted OR C.I Variable 2.1 (.9, 4.9) 1.95 (1.0, 3.8) RSV positivity (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 P value =0.01

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