1. 1 Exploring Alternative Antibiotic Treatment Regimens: Methodology and Implications Dr. Tabish Hazir MASCOT Study Group 2 nd ICIUM Conference 2004

2. 2 BACKGROUND  To reduce ARI mortality WHO introduced standardised case management guidelines. management guidelines.  Amoxicillin and cotrimoxazole are recommended as first line treatment for non-severe pneumonia. treatment for non-severe pneumonia.  The currently recommended duration of therapy is 5 days.  This recommendation is not based on strong scientific evidence.  Shorter antibiotic courses have shown to be effective in the treatment of otitis media, sinusitis and tonsillopharyngitis. treatment of otitis media, sinusitis and tonsillopharyngitis.  If effective, shorter antibiotic course for treatment of pneumonia will have important policy implications. pneumonia will have important policy implications.

3. 3  Patients tend to stop treatment once they are better which results in non-adherence. results in non-adherence.  Shorter course antibiotic therapy for non-severe pneumonia would have many advantages: would have many advantages: a. Reduce the cost of treatment a. Reduce the cost of treatment b. Enhance patient compliance. b. Enhance patient compliance. c. Contribute towards containment of antimicrobial resista c. Contribute towards containment of antimicrobial resista BACKGROUND Contd.

4. 4 METHODOLOGY It was an equivalence, randomized, double blind, placebo- It was an equivalence, randomized, double blind, placebo- controlled trial. controlled trial. Carried out in the outpatient departments of 6 hospitals in Carried out in the outpatient departments of 6 hospitals in Gilgit, Islamabad, Lahore, Multan and Rawalpindi. Gilgit, Islamabad, Lahore, Multan and Rawalpindi. All children with cough and/or difficult breathing were All children with cough and/or difficult breathing were screened by specially hired and trained study physicians at screened by specially hired and trained study physicians at each site. each site. Children diagnosed to have WHO defined “non-severe Children diagnosed to have WHO defined “non-severe pneumonia” were enrolled. pneumonia” were enrolled. Randomization scheme was developed at WHO, Geneva for each site using uneven blocks of 2, 4, 6 for both groups in ratio of 1:1. Randomization scheme was developed at WHO, Geneva for each site using uneven blocks of 2, 4, 6 for both groups in ratio of 1:1.

5. 5 Each of the study patients received two medicine bottles, Each of the study patients received two medicine bottles, labeled ‘Green’ containing active drug for first 3 days and labeled ‘Green’ containing active drug for first 3 days and ‘Red’ containing either placebo or active drug for next 2 days. ‘Red’ containing either placebo or active drug for next 2 days. Follow-ups were done on day 3, 6, and 14. Follow-ups were done on day 3, 6, and 14. Antibiotic was changed to oral Chloramphenicol in children Antibiotic was changed to oral Chloramphenicol in children who did not show improvement. who did not show improvement. Children who showed deterioration at any stage were Children who showed deterioration at any stage were admitted for injectible antibiotics. admitted for injectible antibiotics. All children were followed up by study physicians till they All children were followed up by study physicians till they were cured. were cured. METHODOLOGY

6. 6 INCLUSION CRITERIA Age 2-59 months. Age 2-59 months. History of cough and/or difficult breathing. History of cough and/or difficult breathing. Diagnosis of WHO defined non - severe pneumonia. Diagnosis of WHO defined non - severe pneumonia. EXCLUSION CRITERIA Signs of WHO defined severe pneumonia or very severe disease. Signs of WHO defined severe pneumonia or very severe disease. Known penicillin allergy. Known penicillin allergy. Complicating acute non-pulmonary or chronic illness. Complicating acute non-pulmonary or chronic illness. Living outside the municipal limits of city. Living outside the municipal limits of city. Taken the appropriate doses of WHO recommended antimicrobial drugs Taken the appropriate doses of WHO recommended antimicrobial drugs for 48 hours prior to presentation. for 48 hours prior to presentation. Prior history of wheezing or bronchial asthma and wheezing now. Prior history of wheezing or bronchial asthma and wheezing now. Previously enrolled patients in the present study. Previously enrolled patients in the present study. Whose parents/guardian refuse to give consent. Whose parents/guardian refuse to give consent.

7. 7 SAMPLE SIZE Sample size was calculated to show a point estimate of Sample size was calculated to show a point estimate of clinical failure rate. clinical failure rate. We assume the two modes of therapy to be equal, if the We assume the two modes of therapy to be equal, if the failure rate between the two regimens is within 5%. failure rate between the two regimens is within 5%. For an alpha of 0.03 and a power of 90% the required sample size was 845 in each group. For an alpha of 0.03 and a power of 90% the required sample size was 845 in each group. With inclusion of 15% loss to follow-up the total estimated sample size was 1954. With inclusion of 15% loss to follow-up the total estimated sample size was 1954.

8. 8 METHODOLOGICAL ISSUES GENERAL GENERAL SPECIFIC SPECIFIC 1.Irritants 2.Affecting data quality a.Trial specific b.Site specific

9. 9 SPECIFIC METHODOLOGICAL ISSUES 1.TRAINING: a.Site study physicians. b. Lady Health Workers (LHWs). 2. HOME FOLLOW-UPS. 3. 14 DAY FOLLOW-UP: Delay in communication and feedback 4. STANDARDIZATION OF RADIOLOGICAL INTERPRETATION. 5. MICROBIOLOGY.