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Table 1 Study definitions, eligibility criteria, and clinical outcomes

From: Malawian children with fast-breathing pneumonia with and without comorbidities

Study definitions

 Fast-breathing pneumonia

Cough less than 14 days or difficulty breathing AND fast breathing for age

 Chest-indrawing pneumonia

Cough less than 14 days or difficulty breathing AND visible indrawing of the chest wall with or without fast breathing for age

 Fast breathing for age

Respiratory rate ≥ 50 breaths per minute (for children 2 to < 12 months of age) or ≥ 40 breaths per minute (for children ≥12 months of age)

 Very fast breathing for age

≥70 breaths per minute (for children 2 to < 12 months of age) or ≥ 60 breaths per minute (for children ≥12 months of age)

 Severe respiratory distress

Grunting, nasal flaring, and/or head nodding

 Hypoxemia

Transcutaneous peripheral oxyhemoglobin saturation (SpO2) < 90% in room air, as assessed non-invasively by a pulse oximeter

 World Health Organization (WHO) Integrated Management of Childhood Illness (IMCI) general danger signs

Lethargy or unconsciousness, convulsions, vomiting everything, inability to drink or breastfeed

 Severe acute malnutrition

Weight for height/length < −3 SD, mid-upper arm circumference (MUAC) < 11.5 cm, or edema

 HIV exposure

Children < 24 months of age with a HIV-infected mother

ITIP1 and ITIP3 eligibility criteria

 Inclusion criteria

• 2–59 months of age

• Cough < 14 days or difficulty breathing

• Fast breathing for age

• ITIP3 fast-breathing pneumonia cohort: excluded from enrollment in ITIP1 clinical trial due to the presence of any of the following:

 ▪ Severe respiratory distress

 ▪ Hypoxemia

 ▪ Hemoglobin < 8.0 g/dL, if a positive malaria rapid diagnostic test (mRDT)

 ▪ Severe acute malnutrition

 ▪ Severe malaria (i.e., positive mRDT with any WHO IMCI general danger sign, stiff neck, abnormal bleeding, clinical jaundice, or hemoglobinuria)

 ▪ HIV seropositivity or HIV exposure

• Ability and willingness of child’s caregiver to provide informed consent and to be available for follow-up for the planned duration of the study, including accepting a home visit if he/she fails to return for a scheduled study follow-up visit

 Exclusion criteria

• Chest indrawing

• Stridor when calm

• Resolution of fast breathing after bronchodilator challenge (trial of rapid-acting inhaled bronchodilator for up to 3 times, 15–20 min apart) among those with audible or auscultatory wheeze at screening

• Possible tuberculosis (coughing for more than 14 days)

• Hemoglobin < 8.0 g/dL, if a negative mRDT

• Known allergy to penicillin or amoxicillin

• Receipt of an antibiotic treatment in the 48 h prior to the study

• Living outside the study area

• Any medical or psychosocial condition or circumstance that, in the opinion of the investigators, would interfere with the conduct of the study or for which study participation might jeopardize the child’s health

• Participation in a clinical study of an investigational product within 12 weeks prior to enrollment or planning to begin participation during this study

• Prior participation in any ITIP study during a previous pneumonia diagnosis

• ITIP1 cohort only:

 ▪ Severe respiratory distress

 ▪ Hypoxemia

 ▪ Hemoglobin < 8.0 g/dL, if a positive mRDT

 ▪ Severe acute malnutrition

 ▪ Severe malaria (i.e., positive mRDT with any WHO IMCI general danger sign, stiff neck, abnormal bleeding, clinical jaundice, or hemoglobinuria)

 ▪ HIV seropositivity or HIV exposure

ITIP1 and ITIP3 clinical outcomes

 Treatment failurea

For both ITIP1 and ITIP3, development of very fast breathing, chest indrawing, severe respiratory distress, hypoxemia, WHO IMCI general danger signs, fever, or change in antibiotics:

 • For ITIP1, prior to or on Day 4 (i.e., anytime between Days 2, 3, or 4)

 • For ITIP3, on Day 6 only

For ITIP1 only, missing two or more doses due to vomiting, or hospitalization due to pneumonia (including prolonged hospitalization or re-admission) prior to or on Day 4

Death:

 • For ITIP1, prior to or on Day 4

 • For ITIP3, prior to or on Day 6

 Clinically curedb

For both ITIP1 and ITIP3, absence of fast-breathing pneumonia, very fast breathing for age, chest indrawing, severe respiratory distress, hypoxemia, WHO IMCI general danger signs, and fever by Day 14:

 • Cured but failed initial antibiotic treatment regimen

 • Cured and did not fail initial antibiotic treatment regimen

 Not clinically curedb

Day 14:

 • Deteriorating

 • Stable (not improving or deteriorating, prognosis unclear)

On or prior to Day 16:

 • Death

  1. aChildren with treatment failure in ITIP1 may have had their Day 4 visit 1 day later (on Day 5) and children with treatment failure in ITIP3 may have had their Day 6 visit 1 day later (on Day 7)
  2. bClinically cured status is assessed from the last visit that may have occurred 2 days earlier to 2 days later than the scheduled day (i.e., on actual Days 12 through 16)