Research

JAMA Pediatrics | Original Investigation

Placebo vs Amoxicillin for Nonsevere Fast-Breathing

Pneumonia in Malawian Children Aged 2 to 59 Months
A Double-blind, Randomized Clinical Noninferiority Trial
Amy Sarah Ginsburg, MD, MPH; Tisungane Mvalo, MBBS; Evangelyn Nkwopara, MS; Eric D. McCollum, MD;
Chifundo B. Ndamala, Dip; Robert Schmicker, MS; Ajib Phiri, MD; Norman Lufesi, MPhil;
Rasa Izadnegahdar, MD, MPH; Susanne May, PhD

Editorial page 14
IMPORTANCE Pneumonia is the leading infectious killer of children. Rigorous evidence Supplemental content
supporting antibiotic treatment of children with nonsevere fast-breathing pneumonia
in low-resource African settings is lacking. CME Quiz at
jamanetwork.com/learning
and CME Questions page 111
OBJECTIVE To assess whether treatment with placebo for nonsevere fast-breathing
pneumonia is substantively less effective than 3 days of treatment with amoxicillin.

DESIGN, SETTING, AND PARTICIPANTS This double-blind, 2-arm, randomized clinical

noninferiority trial with follow-up of 14 days screened 1343 HIV-uninfected children
aged 2 to 59 months with nonsevere fast-breathing pneumonia at outpatient departments
of hospitals in Lilongwe, Malawi, Africa, between June 2016 and June 2017.

INTERVENTIONS Placebo or amoxicillin dispersible tablets administered twice daily for 3 days.

MAIN OUTCOMES AND MEASURES The primary end point was the proportion of children failing
treatment by day 4 with a relative noninferiority margin of 1.5 times the failure rate in the
amoxicillin group. Primary analyses were performed based on the intention-to-treat principle.
Planned secondary analyses included treatment failure or relapse by day 14.

RESULTS In total, 1126 children were randomized to 3 days of amoxicillin (n = 564) or placebo
(n = 562) therapy. Baseline demographic and clinical characteristics were similar between the
groups. For the entire study population, the mean (SD) age was 21.3 (15.1) months, and 601
(53.4%) were female. After an interim analysis, the data safety monitoring board stopped the
study because children receiving amoxicillin had a 4.0% (22 of 552 with outcome data)
treatment failure rate by day 4, whereas children receiving placebo had a 7.0% (38 of 543)
treatment failure rate (adjusted relative risk, 1.78; 95% CI, 1.07%-2.97%; adjusted absolute
difference, 3.0%; 95% CI, 0.4%-5.7%). Among children with known day 14 outcomes,
56 of 552 (10.1%) receiving amoxicillin and 64 of 543 (11.8%) receiving placebo had either
treatment failure by day 4 or relapse by day 14 (relative risk, 1.16; 95% CI, 0.83%-1.63%;
absolute difference, 1.6%; 95% CI, −2.1% to 5.4%). There were no deaths.

CONCLUSIONS AND RELEVANCE In HIV-uninfected children aged 2 to 59 months in a

malaria-endemic region of Malawi, placebo treatment of nonsevere fast-breathing
pneumonia was significantly inferior to treatment with amoxicillin. However, by day 4,
approximately 93% of children receiving placebo were without treatment failure, and there
was no significant difference between groups in treatment failure or relapse by day 14.
The number of children with nonsevere fast-breathing pneumonia that needed amoxicillin
treatment for 1 child to benefit was 33.

TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02760420 Author Affiliations: Author

affiliations are listed at the end of this
article.
Corresponding Author: Amy Sarah
Ginsburg, MD, MPH, Save the
Children Federation, Inc, 501 Kings
JAMA Pediatr. 2019;173(1):21-28. doi:10.1001/jamapediatrics.2018.3407 Hwy E, Ste 400, Fairfield, CT 06825
Published online November 12, 2018. (aginsburg@savechildren.org).

(Reprinted) 21

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 Research Original Investigation
A
pproximately 920 000 children die of pneumonia annu-
ally before their fifth birthday.1 There is a critical need to
provide greater access to appropriate and effective treat-
ment. Treatment of bacterial pneumonia requires an effective
antibiotic used in adequate doses for an appropriate duration.
A 3-day course of twice-daily amoxicillin is recommended by the
World Health Organization (WHO) as first-line treatment of non-
severe fast-breathing pneumonia among immune-competent
children aged 5 years or less.2 The WHO’s integrated management
of childhood illness (IMCI) guidelines identify fast-breathing
pneumonia in children with cough or difficult breathing who
demonstrate fast breathing without WHO danger signs.3 How-
ever, not all cases of fast breathing are bacterial pneumonia. In-
deed, the majority of fast-breathing pneumonia cases are likely
not pneumonia at all. There are many reasons that a child might
demonstrate fast breathing, and not all indicate disease.4-7 Thus,
isolated fast breathing may not be appropriately sensitive nor spe-
cific for diagnosing pneumonia,8 making antibiotic treatment un-
necessary. Although it is relatively well tolerated among children,
amoxicillin has side effects and causes serious but rare adverse
events.9 Furthermore, inappropriate antibiotic use may lead to
antibiotic resistance.10-15
Current case management guidelines maximize diagnos-
tic sensitivity over specificity, potentially resulting in antibi-
otic overuse.16 Existing research suggests that most fast-
breathing pneumonia cases will resolve without antibiotic
therapy. In a study evaluating fever etiology among outpa-
tient children in Tanzania, the authors found that, in the ab-
sence of critical illness and malaria, most febrile children could
be treated supportively without antibiotics.17 There is a need
to appropriately treat children with bacterial pneumonia with
antibiotics and to not unnecessarily treat children with ill-
nesses unresponsive to antibiotics.
Studies in Asia have evaluated the effectiveness of 3-day
amoxicillin treatment of fast-breathing pneumonia;2,6,18,19 how-
ever, evidence is needed to evaluate whether any antibiotic
treatment is required.20 There have been multiple calls for care-
fully designed, scientifically sound studies repeated in differ-
ent geographic regions to assess the need for antibiotic treat-
ment of fast-breathing pneumonia. Given the paucity of such
data from Africa, there is a critical need for African-specific re-
search in malaria-endemic settings to establish optimal man-
agement of fast-breathing pneumonia in children.
Methods
Study Design
The primary objective of this prospective, double-blind, 2-arm,
randomized controlled noninferiority trial was to investigate
whether treatment with placebo in HIV-uninfected children
aged 2 to 59 months with nonsevere fast-breathing pneumo-
nia in a malaria-endemic region of Malawi was (null hypoth-
esis) substantively less effective than 3 days of treatment with
amoxicillin. An innovative noninferiority design was devel-
oped based on the assertion that placebo could not be ex-
pected to be more beneficial than amoxicillin with respect to
the primary outcome of treatment failure (TF) by day 4 but
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Placebo vs Amoxicillin for Nonsevere Fast-Breathing Pneumonia in Malawian Children
Key Points
Question Are antibiotics necessary for the treatment of
nonsevere fast-breathing pneumonia in children?
Findings In this double-blind, randomized clinical noninferiority
trial that included 1126 HIV-uninfected children aged 2 to 59
months in a malaria-endemic region of Malawi, Africa, placebo
treatment of nonsevere fast-breathing pneumonia was
significantly inferior to 3 days of amoxicillin treatment with respect
to treatment failure at day 4. Fast-breathing pneumonia resolved
by day 4 in 93% of children without the use of the antibiotic.
Meaning Without amoxicillin treatment, 7% of Malawian children
with nonsevere fast-breathing pneumonia failed treatment by day
4, and treating 33 children with amoxicillin was necessary for 1
child to benefit.
could be expected to be only slightly worse than amoxicillin
(alternative hypothesis). Children aged 2 to 59 months meet-
ing the fast-breathing pneumonia case definition (eAppendix
1 in Supplement 1) at the outpatient departments of Kamuzu
Central Hospital (KCH) and Bwaila District Hospital in Lilon-
gwe, Malawi, Africa, were screened by 2 of us (T.M. and C.B.N.)
to determine eligibility (eAppendix 1 in Supplement 1). The
study was conducted in accordance with the International Con-
ference on Harmonisation, Good Clinical Practice, and the Dec-
laration of Helsinki 200821 and was approved by the Western
Institutional Review Board of Washington in the United States,
the College of Medicine Research and Ethics Committee in
Blantyre, Malawi, and the Malawi Pharmacy, Medicines and
Poisons Board. All children’s parents or legal guardians pro-
vided written informed consent to participate in this trial. The
trial protocol is provided in Supplement 2.
Procedures
On day 1 after enrollment, eligible children were randomized
in a 1:1 ratio to receive 3 days of either placebo dispersible tab-
lets (intervention) or amoxicillin dispersible tablets, 250 mg,
(control) in 2 divided doses based on age ranges (500 mg/d for
children 2-11 months of age, 1000 mg/d for children 12-35
months, and 1500 mg/d for children 36-59 months), the cur-
rent WHO-recommended therapy for HIV-uninfected children.2
Study drugs were identical in appearance, smell, taste, dis-
persion activity, and packaging. Randomization was strati-
fied by age groups (2-11, 12-35, and 36-59 months) using blocks
of size 2, 4, and 6. Other than the unblinded biostatisticians,
pharmacists, monitors, and data safety monitoring board mem-
bers, everyone on the study team was blinded to each child’s
assigned treatment group.
Enrollment was initially conducted solely at KCH (phase
1) and then transitioned on September 20, 2016, to Bwaila Dis-
trict Hospital (phase 2) after KCH introduced bypass fees, which
reduced patient volumes. Bwaila District Hospital enrollees
were transferred to KCH for additional evaluation, observa-
tion, and admission, if necessary. To maximize safety, all en-
rollees were observed for at least 2 to 8 hours before dis-
charge. Children with no fever and a respiratory rate (RR) below
the enrollment threshold were discharged after 2 hours; other
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 Placebo vs Amoxicillin for Nonsevere Fast-Breathing Pneumonia in Malawian Children
children remained under observation. Children aged less than
6 months, children with moderate malnutrition (11.5-13.5 cm
mid–upper arm circumference), or febrile children with a nega-
tive malaria rapid diagnostic test result were hospitalized over-
night and assessed for discharge on day 2.
During observation, if a child’s condition deteriorated (new
WHO IMCI danger sign, hypoxemia, RR 10 breaths higher than
that at enrollment, or severe respiratory distress), the child was
hospitalized and counted as a TF (eAppendix 1 in Supple-
ment 1). During discharge, an oxygen saturation less than 93%
or very fast breathing required continued hospital monitor-
ing but was not considered a TF. If discharge criteria were not
met by day 3, the child’s status was considered a TF.
Caregivers received phone calls on days 1 to 3 and were evalu-
ated in the clinic or home on days 2 to 4 and day 14. During follow-
up, all children were assessed for TF or relapse (eAppendix 1 in
Supplement 1) and study drug adherence at all scheduled and un-
scheduled visits. Most children with TF or relapse were hospi-
talized and treated with second-line intravenous antibiotics. Once
second-line antibiotics were started, the child was considered
nonadherent to the randomized treatment.
Outcomes
The primary end point was the proportion of children with day
4 TF (eAppendix 1 in Supplement 1). Secondary end points were
proportions of children with relapse (days 5-14 among chil-
dren without TF before or on day 4), with day 4 TF or relapse
by day 14, with TF among those with baseline malaria, and by
age group. All adverse events were assessed and managed per
KCH standard clinical practice, documented, followed up, and
treated until resolution or stabilization. All serious adverse
events (eAppendix 1 in Supplement 1) were reported for re-
view within 24 hours.
Statistical Analysis
The statistical analysis plan is provided in eAppendix 2 in
Supplement 1. A relative noninferiority margin of 1.5 times the
TF rate in the amoxicillin group was chosen based on an an-
ticipated TF rate in the amoxicillin group of 4% to 10%. This
noninferiority margin was selected after extensive discus-
sions among the investigators (including A.S.G. and S.M.) re-
garding the TF rate for placebo that would be acceptable to cli-
nicians, considering the anticipated potential TF rate in the
amoxicillin group and potential for enrollment in the study.
Adjusting for 2 formal interim analyses (the O’Brien-Fleming
boundary for early noninferiority22 and the Pocock boundary
for early inferiority23), enrolling 2000 children (1000 per group)
provided 84.2% power when the TF rate was 7% in the amoxi-
cillin group and 64.8% power when the TF rate was 4% in the
amoxicillin group, assuming equal TF rates in both groups.
These power calculations took into account a dropout rate of
5% and assumed a 1-sided α of .025 for a test of a difference in
proportions. The test was initially conceptualized as 1-sided
because of the assertion that placebo could not be more ben-
eficial than amoxicillin regarding TF; however, 2-sided 95% CIs
are also presented because placebo was inferior to amoxicil-
lin (the harmful direction). Primary analyses were performed
based on the intention-to-treat principle using linear regres-
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Original Investigation Research
Figure. CONSORT Diagram by Treatment Group
1343 Assessed for eligibility
217 Excluded
166 Not meeting inclusion
criteriaa
61 Declined to participate
1126 Randomizeda
564 Allocated to and received 562 Allocated to and received
amoxicillin placebo
552 Analyzed 543 Analyzed
12 Excluded from analysis 19 Excluded from analysis
6 Lost to follow-up 11 Consent withdrawn
3 Consent withdrawn 7 Lost to follow-up
3 Missing day 4 follow-up 1 Missing day 4 follow-up
a
Of the 166 ineligible children, 10 were enrolled. CONSORT indicates
Consolidated Standards of Reporting Trials.
sion adjusted for age groups, study phase, and sex and using
robust standard errors based on the Huber-White sandwich
estimator.24,25 Given that its use would be justified because the
sample size was sufficiently large, linear regression analysis
was conducted for this binary outcome to model differences
in rates.26 Relative risks are also presented. Sensitivity analy-
ses were performed using multiple imputations27 and tipping
point analyses. Analyses of secondary end points used robust
standard errors unadjusted for interim analyses or any other
factor. Further analysis details are provided in eAppendix 6 in
Supplement 1. Statistical analyses were conducted using R, ver-
sions 3.2.5 and 2.14.1 (the R Foundation).
Results
Enrollment started June 7, 2016, with formal interim analysis con-
ducted after one-third of the children were enrolled. In the in-
terim analysis, the early inferiority boundary was crossed, and
after review of additional data, the data safety monitoring board
members recommended pausing enrollment and analyzing data
from the children already enrolled at the time of the review. Af-
ter subsequent review, the board recommended stopping the
study. The last visit was completed June 20, 2017.
In total, 1343 children were screened, of which 61 were eli-
gible but refused enrollment consent and 166 were ineligible
(eAppendix 3 in Supplement 1); however, 10 of these 166 were
enrolled (Figure). Thus, a total of 1126 children were en-
rolled, with 564 receiving amoxicillin and 562 receiving pla-
cebo. The primary outcome was available for 552 children
(97.9%) in the amoxicillin group and 543 children (96.6%) in
the placebo group. Baseline demographic and clinical charac-
teristics were similar between the groups (Table 1). There were
no substantive differences between the treatment groups in
the distribution of RR by age groups.
By day 4, amoxicillin recipients had a TF rate of 4.0% (22 of
552 with day 4 outcome), and placebo recipients had a TF rate
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 Research Original Investigation Placebo vs Amoxicillin for Nonsevere Fast-Breathing Pneumonia in Malawian Children

Table 1. Child Demographic and Clinical Characteristics at Enrollment by Treatment Group

Children, No. (%)

Characteristic Amoxicillin (n = 564) Placebo (n = 562) Overall (n = 1126)
Age, mo
2-11 196 (34.8) 196 (34.9) 392 (34.8)
12-35 255 (45.2) 254 (45.2) 509 (45.2)
36-59 113 (20.0) 112 (19.9) 225 (20.0)
Sex
Male 271 (48.0) 254 (45.2) 525 (46.6)
Female 293 (52.0) 308 (54.8) 601 (53.4)
Height/weight z scorea
<−3 0 1 (0.2) 1 (0.1)
−2 to −3 5 (0.9) 9 (1.6) 14 (1.2)
>−2 558 (98.9) 552 (98.2) 1110 (98.6)
Mid–upper arm circumference, cma
<11.5 0 0 0
11.5-13.5 32 (5.7) 45 (8.0) 77 (6.8)
>13.5 531 (94.1) 517 (92.0) 1048 (93.1)
Respiratory rate, mean (SD), breaths/minb
Age 2-11 mo
<50 1 (0.2) 0 1 (0.1)
50-59 133 (23.6) 146 (26.0) 279 (24.8)
≥60 62 (11.0) 50 (8.9) 112 (9.9)
Age 12-59 mo
<40 0 0 0
40-49 234 (41.5) 233 (41.5) 467 (41.5)
≥50 134 (23.8) 133 (23.7) 267 (23.7)
Oxygen saturation, %b
<90 0 0 0
90-92 0 0 0
≥93 564 (100) 562 (100) 1126 (100)
Axillary temperature, °Cb
<38 386 (68.4) 405 (72.1) 791 (70.2)
≥38 178 (31.6) 157 (27.9) 335 (29.8)
Heart rate, mean (SD), beats/mina 142.3 (18.1) 142.4 (17.2) 142.4 (17.6)
Pneumococcal vaccine
Received 3 doses 298 (52.8) 321 (57.1) 619 (55.0)
Received <3 doses or unknown 266 (47.2) 241 (42.9) 507 (45.0)
Pentavalent vaccine
Received 3 doses 301 (53.4) 319 (56.8) 620 (55.1)
Received <3 doses or unknown 263 (46.6) 243 (43.2) 506 (44.9)
Caregiver assessment at enrollment
Fevera
Yes 476 (84.4) 469 (83.5) 945 (83.9)
No. of days, mean (SD) 2.7 (1.1) 2.8 (1.4) 2.7 (1.2)
Cougha
Yes 546 (96.8) 547 (97.3) 1093 (97.1)
No. of days, mean (SD) 2.9 (1.2) 3.1 (1.5) 3.0 (1.4)
a
Difficult breathinga Data not available for all randomized
children.
Yes 180 (31.9) 180 (32.0) 360 (32.0)
b
Larger value between screening and
No. of days, mean (SD) 2.5 (0.9) 2.6 (1.3) 2.5 (1.1)
enrollment visits.

of 7.0% (38 of 543), resulting in an adjusted TF relative risk of 1.78 dren (6.4%) had relapse by day 14 in the amoxicillin group com-
(95% CI, 1.07%-2.97%) and an absolute TF rate difference pared with 26 of 505 children (5.1%) in the placebo group, rep-
(intention-to-treat primary analysis) of 3.0% (95% CI, 0.4%-5.7%) resenting a relative risk of 0.80 (95% CI, 0.49%-1.32%). When
(Table 2). Among the children without TF by day 4, 34 of 530 chil- considering both TF before or by day 4 and relapse by day 14, 56

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 Placebo vs Amoxicillin for Nonsevere Fast-Breathing Pneumonia in Malawian Children Original Investigation Research

Table 2. Outcomes by Treatment Group

Children, No./Total No. (%)

Amoxicillin
Outcome (n = 564) Placebo (n = 562) Relative Risk (95% CI) Difference, % (95% CI)
Primary
Treatment failure on or prior to day 4a 22/552 (4.0) 38/543 (7.0) 1.78 (1.07 to 2.97) 3.0 (0.4 to 5.7)
Secondary a priori
Relapse on or prior to day 14 if cured by day 4b 34/530 (6.4) 26/505 (5.1) 0.80 (0.49 to 1.32) 1.3 (−4.1 to 1.6)
Treatment failure or relapse on or prior to day 14 56/552 (10.1) 64/543 (11.8) 1.16 (0.83 to 1.63) 1.6 (−2.1 to 5.4)
As treated referent ≥80 amoxicillin dosesc 14/541 (2.6)
Partial adherence to amoxicillin (0 < adherence < 80) 3/6 (50.0) 19.3 (7.45 to 50.1) 47.0 (6.8 to 87.1)
Adherent to placebod 36/541 (6.7) 2.57 (1.40 to 4.71) 4.1 (1.6 to 6.6)
Multiple imputatione 1.76 (1.06 to 2.94) 3.2 (0.4 to 5.9)
Subgroups a priori
Age groups, mo
2-11 10/189 (5.3) 15/187 (8.0) 1.52 (0.70 to 3.29) 2.7 (−2.3 to 7.8)
12-35 9/252 (3.6) 17/245 (6.9) 1.87 (0.75 to 4.69) 3.4 (−0.6 to 7.3)
36-59 3/111 (2.7) 6/111 (5.4) 2.21 (0.79 to 6.16) 2.7 (−2.5 to 7.9)
Fast breathing, RRf
2-11 mo
50-59 5/131 (3.8) 12/140 (8.6) 2.25 (0.81 to 6.20) 4.8 (−0.9 to 10.4)
60-69 4/52 (7.7) 3/46 (6.5) 0.85 −1.2
≥70 1/5 (20.0) 0/1 (0) 0 −20.0
12-23 mo
40-49 3/78 (3.8) 4/73 (5.5) 1.42 1.6
50-59 2/64 (3.1) 6/49 (12.2) 3.92 9.1
≥60 2/13 (15.4) 1/8 (12.5) 0.81 −2.9
24-59 mo
40-49 4/153 (2.6) 8/155 (5.2) 1.97 (0.61 to 6.42) 2.5 (−1.8 to 6.9)
50-59 1/50 (2.0) 3/66 (4.5) 2.27 2.5
≥60 0/5 (0) 1/5 (20.0) ND 20.0
Mid–upper arm circumference, cmf
<11.5 0 0 ND ND
11.5-13.5 1/32 (3.1) 6/43 (14.0) 4.46 10.8
>13.5 21/519 (4.0) 32/500 (6.4) 1.58 (0.92 to 2.71) 2.4 (−0.4 to 5.1)
Malaria
Positive 0/72 (0) 1/65 (1.5) ND 1.5
Negative 22/480 (4.6) 37/478 (7.7) 1.69 (1.01 to 2.82) 3.2 (0.1 to 6.2)
d
Abbreviations: ND, not determined; RR, respiratory rate. All children in the placebo group were considered adherent to placebo in the
a
Difference and 95% CI adjusted for stratification variables age and phase. as-treated analysis.
e
b
Of those without treatment failure on or prior to day 4. Covariates used in imputation were treatment group, age group, sex,
c
and mother’s educational level.
Excluding treatment failures within 2 hours; difference and CI adjusted for age
f
group, sex, and study phase. Data not available for all randomized children.

of 552 children (10.1%) in the amoxicillin group and 64 of 543 chil-
dren (11.8%) in the placebo group met criteria (relative risk, 1.16;
95% CI, 0.83%-1.63%). Additional secondary outcome results are
provided in Table 2. The higher TF rate in the placebo group was
consistent across prespecified subgroups defined by age group,
RR, malnutrition, malaria, or by whether a child was known to
have received 3 doses of pneumococcal conjugate vaccine or pen-
tavalent vaccine or not (Table 2; eAppendix 4 in Supplement 1).
The amount of missing primary outcome data was low (overall,
31 data points [2.8%]: 12 data points in the amoxicillin group and
19 in the placebo group). Estimates derived from multiple impu-
tations for missing outcome data were similar to the results from
the complete case analysis. The results of a tipping point analy-
sis indicated that TF rates among those with missing data would
need to be in the opposite direction of that observed (ie, higher
TF rates in the amoxicillin than in the placebo groups) for the
complete data to change the differences in the TF rate from sig-
nificant to nonsignificant.
The percentage of children with at least 1 serious adverse
event between enrollment and day 14 was higher in the pla-
cebo group (54 of 562, 9.6%) than in the amoxicillin group (44
of 564, 7.8%) (Table 3). This outcome was primarily caused by
a higher proportion of children with pneumonia-related seri-
ous adverse events in the placebo group. There were no deaths.

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 Research Original Investigation Placebo vs Amoxicillin for Nonsevere Fast-Breathing Pneumonia in Malawian Children

Table 3. Serious Adverse Events by Treatment Group

Children, No. (%)

Serious Adverse Eventa Amoxicillin (n = 564) Placebo (n = 562) Overall (n = 1126)
Children with at least 1 serious adverse eventb 44 (7.8) 54 (9.6) 98 (8.7)
Pneumoniac 34 (6.0) 42 (7.5) 76 (6.7)
Fast-breathing pneumoniad 7 (1.2) 12 (2.1) 19 (1.7)
Chest-indrawing pneumonia 17 (3.0) 18 (3.2) 35 (3.1)
Danger sign pneumonia 5 (0.9) 9 (1.6) 14 (1.2)
Chest radiograph–confirmed pneumoniae 4 (0.7) 4 (0.7) 8 (0.7)
Pneumoniaf 1 (0.2) 0 1 (0.1)
Nonrespiratory 12 (2.1) 13 (2.3) 25 (2.2)
Acute gastroenteritis 4 (0.7) 4 (0.7) 8 (0.7)
Fever 1 (0.2) 4 (0.7) 5 (0.4)
Malaria 2 (0.4) 1 (0.2) 3 (0.3)
Convulsion 1 (0.2) 1 (0.2) 2 (0.2)
Urinary tract infection 0 2 (0.4) 2 (0.2)
Vomiting 2 (0.4) 0 2 (0.2)
Anemia 0 1 (0.2) 1 (0.1)
Epistaxis 1 (0.2) 0 1 (0.1)
Febrile convulsion 1 (0.2) 0 1 (0.1)
a
Children may have more than 1 serious adverse event. failures (in the placebo group) on day 4 and met additional treatment failure
b
Occurring any time after study drug is administered to child up to 14 days after criteria. The remaining 15 serious adverse events were recurrences
enrollment. of fast-breathing pneumonia and, therefore, relapses after day 4.
e
c
One child in the placebo group had a danger sign pneumonia serious adverse Chest radiograph–confirmed pneumonia serious adverse events did not
event before day 4 and a fast-breathing pneumonia serious adverse event demonstrate fast breathing, chest indrawing, or any danger signs; however,
after day 4. pneumonia was diagnosed through positive results on chest radiographs.
f
d
Of the 19 fast-breathing pneumonia serious adverse events, 4 were treatment For 1 child, no type of pneumonia was specified.

Caregiver-reported adherence was high, with 517 of 564 (91.7%)
reporting adherence with all doses in the amoxicillin group and
509 of 562 (90.6%) reporting adherence with all doses in the
placebo group (eAppendix 5 in Supplement 1).
Discussion
We evaluated 3 days of oral placebo administration vs oral amoxi-
cillin treatment among 1126 HIV-uninfected children aged 2 to
59 months presenting with WHO–defined nonsevere fast-
breathing pneumonia in a malaria-endemic region of Malawi,
Africa. Our results showed that, compared with children who re-
ceived placebo, children who received amoxicillin had a signifi-
cantly lower TF rate on or before day 4. The direction of the es-
timated effect was the same across prespecified subgroups and
in an as-treated analysis. In a post hoc analysis examining dif-
ferent RRs, the direction of difference in the TF rate was consis-
tent in children presenting with the lowest fast-breathing RR and
regardless of number of pneumococcal conjugate or pentavalent
vaccine doses. However, by day 4, approximately 93% of chil-
dren were without TF in the placebo group. Although there was
no significant difference between the groups at 14 days, our study
could not rule out meaningful differences in TF or relapse by day
14, which were estimated to be less than 12% in both groups. The
number of nonsevere fast-breathing pneumonia cases needed
to treat with amoxicillin for 1 child to benefit was 33. It might be
argued that such a large number needed to treat to benefit 1 child
is acceptable relative to the low risks associated with taking an-
tibiotics. However, it might also be argued that efforts should fo-
cus on identifying and providing antibiotics to those children who
truly need them to prevent TF or relapse or focus on identifying
and providing only supportive care to those children who recover
without antibiotics.
Although placebo was inferior to amoxicillin for treat-
ment of nonsevere fast-breathing pneumonia, the vast major-
ity of children in the placebo group recovered without amoxi-
cillin. As in previous studies,7 this observation suggests that
true bacterial pneumonia among children with fast breathing
in the present study appeared to have been low, implying that
fast breathing might be neither an appropriately sensitive nor
specific sign of bacterial pneumonia. It also suggests that in a
small subgroup of children receiving a diagnosis of WHO-
defined nonsevere fast-breathing pneumonia, antibiotics ap-
peared to reduce the absolute rate of TF by a 3.0% adjusted
difference (relative risk of TF, 1.78 for the comparison of chil-
dren who received placebo vs those who received amoxicil-
lin). Thus, in a small subset of fast-breathing children, amoxi-
cillin seemed to be of benefit, but it was unclear whether the
benefit was derived from the appropriate treatment of bacte-
rial pneumonia or the treatment of some other infection or non-
antibacterial inflammatory process.
The results of the present study suggest that it may be ad-
visable to schedule a follow-up visit on day 4 for reevaluation and
treatment if necessary for low-risk children who are available for
follow-up. For those whose follow-up cannot be assured—and

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 Placebo vs Amoxicillin for Nonsevere Fast-Breathing Pneumonia in Malawian Children Original Investigation Research

this may be the majority of children in routine settings in sub-
Saharan Africa—treatment with amoxicillin may be warranted;
it is unclear whether those children would require a longer course
of amoxicillin. More research is needed regarding the duration
of the amoxicillin treatment given the 6% relapse vs the 4% TF
rates among children with nonsevere fast-breathing pneumonia
who received 3 days of amoxicillin.
The WHO recommendations to use antibiotics to treat fast
breathing in a child with cough or difficulty breathing are based
on low-quality evidence.28 A 2016 Cochrane review assessing an-
tibiotic treatment of undifferentiated acute respiratory infection
in children less than 5 years of age found that there is insufficient
evidence for antibiotic use as a means of preventing suppurative
complications, such as pneumonia.29 In the United States, clini-
cal practice guidelines established by the Pediatric Infectious Dis-
eases Society and the Infectious Diseases Society of America note
that, for outpatients, “antimicrobial therapy is not routinely re-
quired for preschool-aged children with community-acquired
pneumonia, because viral pathogens are responsible for the great
majority of clinical disease (strong recommendation; high-quality
evidence).”30(pe30) While Haemophilus influenzae type b (Hib) and
pneumococcal conjugate vaccines are being scaled up—the Hib
conjugate vaccine was introduced in Malawi in 2002 as part of
the Expanded Programme for Immunization, and the pneumo-
coccal conjugate vaccine was added to the national strategy in
2011—the etiology and epidemiology of community-acquired
pneumonia is changing. For example, a recent pneumococcal
conjugate vaccine effectiveness study in Malawi found a reduc-
tion in the severest forms of clinical and hypoxemic pneumonia
alongside a seemingly paradoxical increase in fast-breathing
pneumonia cases. The authors speculated that this likely repre-
sented a vaccine-induced shift away from more severe combined
viral and pneumococcal disease to less severe pneumococcal-
free viral disease that still met the fast-breathing pneumonia
definition.31 In 2015, the Expanded Programme for Immuniza-
tion in Malawi reported 88% coverage for both Hib and pneumo-
coccal conjugate vaccines.
Limitations
The limitations to our study included strict inclusion and exclu-
sion criteria, the absence of laboratory or radiology testing, and
the close monitoring and follow-up, which limits the generaliz-
ability of our results to routine programmatic care settings. Pneu-
monia is frequently considered a single entity rather than a clini-
cal syndrome encompassing several underlying factors. This
makes interpretation of the results challenging. Without etiologic
information, we could only note the effect of the intervention
on the clinical syndrome of pneumonia.
Follow-up care and monitoring of enrolled children gen-
erally exceeded local standards of care; thus, the TF rate may
have been influenced by both the high quality of care pro-
vided and by the high awareness and vigilance for identify-
ing TF. It may be that those children identified as failing treat-
ment would have recovered without antibiotics had we taken
a watchful waiting approach and not intervened with antibi-
otic treatment. However, opportunities for follow-up and ac-
cess to care are often issues in low-resource settings. In addi-
tion, treatment approaches vary widely among countries and
regions. The routine pediatric HIV testing included in this study
protocol, although recommended, is not rigorously imple-
mented during routine care in low-resource, HIV-endemic
settings.32 In areas where HIV endemicity is high or where se-
vere acute malnutrition or other predisposing conditions for
bacterial disease is common, it may be reasonable to expect a
higher TF rate among those not treated with antibiotics. As
such, our results might not be generalizable across different
regions, settings, or nontrial conditions. Specifically, the per-
centages of TF and relapse rates observed in the present study
might underestimate true TF and relapse rates.
Conclusions
In our population of HIV-uninfected children with nonsevere
fast-breathing pneumonia in Malawi, Africa, placebo admin-
istration was inferior to 3 days of amoxicillin treatment. How-
ever, 93% of children with WHO-defined fast-breathing pneu-
monia and without antibiotic treatment were without TF by
day 4. There were no deaths. In addition, the number needed
to treat was 33, which is considered high. Further research is
needed to better define which children would truly benefit
from antibiotic therapy.

ARTICLE INFORMATION
Accepted for Publication: August 1, 2018.
Published Online: November 12, 2018.
doi:10.1001/jamapediatrics.2018.3407
Open Access: This is an open access article
distributed under the terms of the CC-BY License.
© 2018 Ginsburg AS et al. JAMA Pediatrics.
Author Affiliations: Save the Children Federation,
Inc, Fairfield, Connecticut (Ginsburg, Nkwopara);
University of North Carolina Project, Lilongwe
Medical Relief Fund Trust, Tidziwe Centre,
Lilongwe, Malawi (Mvalo, Ndamala); Eudowood
Division of Pediatric Respiratory Sciences,
Department of Pediatrics, Johns Hopkins School of
Medicine, Baltimore, Maryland (McCollum);
Department of International Health, Johns Hopkins
Bloomberg School of Public Health, Baltimore,
Maryland (McCollum); Department of Biostatistics,
University of Washington Clinical Trial Center,
Seattle (Schmicker, May); Department of Pediatrics
and Child Health, College of Medicine, University of
Malawi, Chichiri, Blantyre (Phiri); Acute Respiratory
Infection and Emergency Triage Assessment and
Treatment, Malawi Ministry of Health, Lilongwe
(Lufesi); Bill & Melinda Gates Foundation, Seattle,
Washington (Izadnegahdar).
Author Contributions: Drs Ginsburg and May had
full access to all of the data in the study and take
responsibility for the integrity of the data and the
accuracy of the data analysis.
Concept and design: Ginsburg, McCollum, Phiri,
Lufesi, Izadnegahdar, May.
Acquisition, analysis, or interpretation of data:
Ginsburg, Mvalo, Nkwopara, McCollum, Ndamala,
Schmicker, Phiri, May.
Drafting of the manuscript: Ginsburg, Ndamala,
Phiri, May.
Critical revision of the manuscript for important
intellectual content: Ginsburg, Mvalo, Nkwopara,
McCollum, Schmicker, Phiri, Lufesi, Izadnegahdar,
May.
Statistical analysis: Schmicker, May.
Obtained funding: Ginsburg, May.
Administrative, technical, or material support:
Ginsburg, Mvalo, Nkwopara, Lufesi, Izadnegahdar.
Supervision: Ginsburg, Nkwopara, McCollum,
Ndamala, Phiri, May.
Conflict of Interest Disclosures: Dr Ginsburg and
Ms Nkwopara reported receiving grants from the
Bill & Melinda Gates Foundation. Messrs Ndamala
and Schmicker and Drs Mvalo, Phiri, and May
reported receiving grants from Save the Children
Federation, Inc. Dr Izadnegahdar is employed by
the Bill & Melinda Gates Foundation. Dr May
reported receiving grants from the National Heart,
Lung, and Blood Institute; the Department of

jamapediatrics.com (Reprinted) JAMA Pediatrics January 2019 Volume 173, Number 1 27

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 Research Original Investigation
Defense; and the National Institute of Allergy and
Infectious Diseases and receiving personal fees
from Novo Nordisk, the National Institute of
Neurological Disorders and Stroke, and various
academic and for-profit entities. No other
disclosures were reported.
Funding/Support: This trial was funded by grant
OPP1105080 from the Bill & Melinda Gates
Foundation.
Role of the Funder/Sponsor: The Bill & Melinda
Gates Foundation had no role in the design and
conduct of the study; collection, management,
analysis, and interpretation of the data;
preparation, review, or approval of the manuscript;
and decision to submit the manuscript for
publication.
Additional Contributions: Gwen Ambler, MPH,
PATH, provided substantial help with planning for
study implementation. The study staff at the
University of North Carolina Project, Lilongwe
Medical Relief Fund Trust provided patient care.
Triclinium Clinical Development facilitated data
management and safety monitoring. All of the
aforementioned contributors were financially
compensated for the stated contribution. We thank
the Malawi Ministry of Health for their support and
the members of the data safety monitoring board,
including Shamim A. Qazi, Christopher T. Roberts,
Grace J. Malenga, and Harry Campbell. We also
thank the trial participants, their caregivers, and the
local community in Lilongwe, Malawi, for their
participation and support.
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