Randomized trial of amoxicillin vs. placebo for pneumonia in Pakistan

BACKGROUND World Health Organization (WHO) recommends oral amoxicillin in fast breathing pneumonia while recent trial evidence indicates that non-treatment might be non-inferior. METHODS A double blind randomized parallel placebo-controlled non-inferiority trial was conducted in slums of Karachi, Pakistan. Children 2-59 months at primary health care centres fulfilling WHO criteria for fast-breathing pneumonia without danger signs were randomized to three days of placebo (test treatment) or amoxicillin using WHO weight bands. Primary outcome was cumulative treatment failure from randomization to completion of 3 days of treatment. A priori non-inferiority margin was set based on treatment failure of 3.5% in amoxicillin and 1.75% in placebo arm (NI margin of 1.75%). RESULTS Between November 9 2014 and November 30 2017, 4002 children were randomized; placebo (n=1999) and amoxicillin (n=2,003). Per protocol failure rates for placebo group were 4.9 % (995/ 1927) and amoxicillin group were 2.6 %( 51/1929); difference 2.23 %( Upper bound of 95 % CI 3.24; P Value <0.001), also similar by intention to treat analysis. Fever, anaemia and wheeze predicted treatment failure. Number-Needed-to-Treat to prevent each failure was 44 (95 % CI 31-80). Mortality rates were 0.05% with one death per group. Relapse rates were 2.2 % and 3.1 % in the placebo and standard arms respectively. CONCLUSIONS Non-inferiority was not established for placebo over amoxicillin in fast breathing pneumonia as difference in treatment failure was 2.3%, above the pre-specified margin of 1.75%. Low failure rates in placebo and high number needed to treat suggests that implications may be context specific. Trial Registration Number: ClinicalTrials.gov number NCT02372461


Supplementary materials
1. 4 months old male baby, weight 5.975, active alert, feeding well, no previous history of illness, 7 th baby of the family delivered through normal vaginal delivery at home, cried immediately after birth, no significant family history of convulsions or any other illness, baby was exclusively breast feed.
After randomisation, received 5ml of study drug at 1120 hours and dropped home after explaining and providing number of on call physician. It was also explained when to return in case of any emergency. On Sunday, November 13, 2016 at 1100 hours baby developed high grade fever with convulsions, involving his right upper and lower limb with uprolling of the eyes, and frothing from mouth. He was taken to a local GP who referred him to Indus hospital by that GP without giving any medication. Patient became unconscious while on the way to Indus Hospital. He reached at 1300 to Indus Hospital. Doctors at Indus Hospital gave him some IV fluids, injectable drugs ( not given any documented paper, they do not know the names of the medication) and oxygen therapy. Meanwhile mother was told that baby became stiff at that moment and was then referred to NICH at 1430 hours. At NICH patient was again given injectable drugs (names not known), IV fluids and then was intubated. The family was given ambu bag to ventilate the baby because of shortage of space in the Intensive Care Unit. He was kept in the emergency the whole time and expired at 0400 hours on November 14, 2016.
It was enquired why mother didn't contact on call physician and hospital number that was provided to her. She replied that she was confused to see the condition of the baby and forgot to call anyone. According to the mother they did not receive any discharge papers or treatment details.The death certificate mentioned cause of death is cardiopulmonary arrest secondary to pneumonia and sepsis.
She was enrolled with complaints of cough for 2 days and fever for 1 day. Respiratory rate was 49 breaths per minute (first reading), 46 breaths per minute (second reading), O2 saturation 95%, temperature 40 o C sponging done and Paracetamol given at the PHC, 2 nd reading 38.6 o C, (physician gave him Syp paracetamol 4hrly for home). After randomization, received 5ml of study drug at 1120 hours and dropped home after explaining and providing number of on call physician and local collector Data collector of the study site. It was also explained when to return in case of any emergency.
On Day 0, February 4, 2017 at 1811 hours evening follow up was conducted by CHW. On examination child had cough, RR was 44/46, Temp 36.7C, O2 92% in air. She was well according to parents. Evening dose, 5 ml of study drug was given by CHW the child vomited out and this was repeated which she tolerated. Father complained that the child had cough so requested CHW for nebulization, so the CHW nebulized the child with normal saline at the PHC, and then dropped them back at home, after explaining to call in case of any emergency. Evening physician took update from the CHW who informed about the vomiting.
According to the father, after 2 hours of nebulization, the child developed high grade fever (not documented), and another bout of cough so parents took her to a local health care provider (GP) who prescribed injections ceftriaxone and amikacin along with oral ventolin syrup. After the injectable, according to the father, the child was better for some time but between 0100-0200 hours on February 15 th 2017, he had two episodes of small watery loose stool. Within 5 to 10 minutes of the episode, the baby got stiff and unresponsive. The father felt like the child had already died but for confirmation, they took him to Sultan Hospital from where child was referred to Chinniot Hospital where the doctor declared death on arrival. Later, we asked the father why the on call physician was not contacted, to which they replied that they forgot to call. Based on the father's narrative, the child had died around 0200 hours at home. Eligibility criteria for participants (detailing whether participants in the non-inferiority or equivalence trial are similar to those in any trial(s) that established efficacy of the reference treatment) and the settings and locations where the data were collected.

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Interventions 4 Precise details of the interventions intended for each group detailing whether the reference treatment in the non-inferiority or equivalence trial is identical (or very similar) to that in any trial(s) that established efficacy, and how and when they were actually administered.

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Objectives 5 Specific objectives and hypotheses, including the hypothesis concerning non-inferiority or equivalence.

Outcomes 6
Clearly defined primary and secondary outcome measures detailing whether the outcomes in the non-inferiority or equivalence trial are identical (or very similar) to those in any trial(s) that established efficacy of the reference treatment and, when applicable, any methods used to enhance the quality of measurements (e.g., multiple observations, training of assessors).

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Sample size 7 How sample size was determined detailing whether it was calculated using a non-inferiority or equivalence criterion and specifying the margin of equivalence with the rationale for its choice. When applicable, explanation of any interim analyses and stopping rules (and whether related to a noninferiority or equivalence hypothesis).

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Randomization --Sequence generation 8 Method used to generate the random allocation sequence, including details of any restrictions (e.g., blocking, stratification)

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Randomization --Allocation concealment 9 Method used to implement the random allocation sequence (e.g., numbered containers or central telephone), clarifying whether the sequence was concealed until interventions were assigned.
Blinding (masking) 11 Whether or not participants, those administering the interventions, and those assessing the outcomes were blinded to group assignment. If done, how the success of blinding was evaluated.
Statistical methods 12 Statistical methods used to compare groups for primary outcome(s), specifying whether a one or two-sided confidence interval approach was used. Methods for additional analyses, such as subgroup analyses and adjusted analyses.

Participant flow
13 Flow of participants through each stage (a diagram is strongly recommended). Specifically, for each group report the numbers of participants randomly assigned, receiving intended treatment, completing the study protocol, and analyzed for the primary outcome. Describe protocol deviations from study as planned, together with reasons.

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Recruitment 14 Dates defining the periods of recruitment and follow-up. 12 Baseline data 15 Baseline demographic and clinical characteristics of each group. Table 1 Numbers analyzed 16 Number of participants (denominator) in each group included in each analysis and whether the analysis was "intention-to-treat" and/or alternative analyses were conducted. State the results in absolute numbers when feasible (e.g., 10/20, not 50%).

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Outcomes and estimation 17 For each primary and secondary outcome, a summary of results for each group, and the estimated effect size and its precision (e.g., 95% confidence interval). For the outcome(s) for which non-inferiority or equivalence is hypothesized, a figure showing confidence intervals and margins of equivalence may be useful. Table 2 Ancillary analyses 18 Address multiplicity by reporting any other analyses performed, including subgroup analyses and adjusted analyses, indicating those pre-specified and those exploratory. Adverse events 19 All important adverse events or side effects in each intervention group. Table 2 DISCUSSION Interpretation 20 Interpretation of the results, taking into account the noninferiority or equivalence hypothesis and any other study hypotheses, sources of potential bias or imprecision and the dangers associated with multiplicity of analyses and outcomes.

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Generalizability 21 Generalizability (external validity) of the trial findings. 19 Overall evidence 22 General interpretation of the results in the context of current evidence.