Please select the eligibility criteria that correspond to the clinical trial below.
Title: Randomized Double Blind Placebo Controlled Trial of Amoxycillin in the Treatment of Non-Severe Pneumonia With Wheeze in Children Aged 2- 59 Months of Age: A Multi-Centric Study
Brief Summary: Background: The current Integrated management of childhood infections (IMCI) algorithm prescribes that children with wheeze and fast breathing presenting to first level health facilities are given antibiotics if they continue to have fast breathing after two doses of bronchodilator. The primary purpose of the algorithm is to prevent mortality due to bacterial pneumonia. However, an unknown proportion of children managed in this fashion will have a viral related wheezing illness or asthma rather than pneumonia. Although it is unlikely that wheezing syndromes are a significant cause of mortality for children in developing countries, these algorithms are likely to result in unnecessary administration of antibiotics as well as inadequate treatment of recurrent wheezing illness. We do not have clear evidence about whether antibiotics can be withheld in some categories of children with wheeze. It is clear that wheeze can occur in bacterial infection and in addition co-infection with virus and bacteria has been well demonstrated in several studies of pneumonia etiology in children. Although some studies have found that children with more severe disease or who are blood culture positive are more likely to be febrile at presentation, this sign is not sufficiently sensitive or specific to determine whether antibiotics should be administeredSetting: The study will be conducted in eight medical colleges situated in Lucknow, Nagpur, New Delhi, Mumbai, Chennai, Trivandrum, Vellore, and Chandigarh. Design: This will be a multicentric, randomized, double blind efficacy trial. . Hypothesis: The primary hypothesis is that the use of oral amoxycillin for three days would be as effective, in terms of clinical cure on day 4 as compared to use of oral placeboMain objective: To compare the proportion of children aged 2 to 59 months presenting with non-severe pneumonia with wheeze whose respiratory rate does not fall below the age specific cut-off after three doses of nebulized salbutamol, that achieve clinical cure on day 4 on 3 day of treatment with oral amoxycillin versus placebo.Inclusion criteria: Children aged 2-59 months with non-severe pneumonia based on WHO criteria of respiratory rate above the age specific cut-off, audible / ausculatory wheeze. Exclusion criteria: Children with severe disease, received any documented antibiotic treatment in the past 48 hours, diagnosed asthmatic on maintenance therapy, complicating acute non-pulmonary or chronic illness, known drug allergy, hospitalization in the past 2 weeks, history of measles within the last month, known immunodeficiency disorder, prior enrollment in the study, residing in areas not accessible for follow-up or whose guardian refuses to consent for the study. Sample size: Has been calculated to test the null hypothesis. There will be 950 children in each arm. Thus each site is required to recruit a minimum of 225 cases over 18 months.


Options:
A: Inclusion Criteria:

* History of cough \<14 days or difficult breathing with fast breathing (for children 2 to \<12 months of age, \>50 breaths/minute and for children \>12 months of age, \> 40 breaths/minute).
* Ability and willingness of children'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 to Kamuzu Central Hospital (KCH) with the child for a scheduled study follow-up visit.

Exclusion Criteria:

* If fast breathing observed at screening resolves after bronchodilator challenge.
* Chest-indrawing.
* Severe respiratory distress, classified by World Health Organization (WHO) pocketbook guidelines (e.g., grunting, nasal flaring, head nodding, crackles on auscultation, or very severe chest-indrawing).
* Presence of WHO Intergrated Management of Childhood Illness (IMCI) danger signs including: lethargy or unconsciousness, convulsions, vomiting everything, or inability to drink or breastfeed.
* Hypoxia (SaO2 \< 90% on room air, as assessed by a Lifebox pulse oximeter).
* Stridor when calm.
* HIV-1 seropositivity or HIV-1 exposure, assessed as follows:

  * An HIV-positive result upon rapid antibody test will exclude any child from this study. If a child is less than 12 months or age or breastfeeding with a positive rapid test result, the child will be referred to receive additional confirmatory HIV testing (e.g., dried blood spot filter paper test) and follow-up from KCH staff, as per standard of care. Even if the confirmatory HIV testing subsequently shows that child is HIV-negative, he or she will remain excluded from the study.
  * If a child is less than 12 months of age or breastfeeding and has an HIV-negative result upon rapid antibody test, the child's biological mother's HIV status will need to be assessed. If the mother is HIV-positive, the child will be excluded. If the mother has a documented HIV-negative test result from within the past 3 months, the child will be included. If the mother does not have documentation of an HIV-negative test result, she will be tested via rapid antibody testing to determine the child's eligibility for this study.
  * If a child is over 12 months of age and not breastfeeding, an HIV-negative rapid antibody test is required for inclusion in the study.
  * Note: If a child has documentation of an HIV-negative test result from within the past 3 months, that test result will be used for the child's eligibility assessment.
* Severe acute malnutrition (weight for height/length \< -3 SD, mid-upper arm circumference \<115 mm, or edema).
* Possible tuberculosis (coughing for more than 14 days).
* Severe anemia, classified by WHO pocketbook guidelines (i.e., severe palmar pallor or hemoglobin \<8.0 g/dL).
* Severe malaria, classified by WHO pocketbook guidelines (i.e., positive mRDT with any danger sign, stiff neck, abnormal bleeding, clinical jaundice, or hemoglobinuria).
* Known allergy to penicillin or amoxicillin.
* Receipt of an antibiotic treatment in the 48 hours prior to the study based on caregiver's self-report and/or documentation in child's medical record.
* Hospitalized within 14 days prior to the study.
* Living outside Lilongwe urban area, the study catchment 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.
* Any non-pneumonia acute medical illness which requires antibiotic treatment per local standard of care.
* Participation in a clinical study of another investigational product within 12 weeks prior to randomization or planning to begin participation during this study.
* Prior participation in an Innovative Treatments in Pneumonia study during a previous pneumonia diagnosis.
B: Inclusion Criteria:

* Children aged 2-59 months with non-severe pneumonia based on WHO criteria of respiratory rate above the age specific cut-off, audible / ausculatory wheeze, accessible to follow up, whose guardians give written informed consent.

Exclusion Criteria:

* Children with severe disease, received any documented antibiotic treatment in the past 48 hours, diagnosed asthmatic on maintenance therapy, complicating acute non-pulmonary or chronic illness, known drug allergy, hospitalization in the past 2 weeks, measles or history of measles within the last month, known immunodeficiency disorder, prior enrollment in the study, residing in areas not accessible for follow-up or whose guardian refuses to consent for the study. Radiological Pneumonia on X-Ray.
C: Inclusion Criteria:

* Male or female, 2 to 59 months of age.
* History of cough \<14 days or difficult breathing with chest-indrawing.
* 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 to Kamuzu Central Hospital (KCH) for a scheduled study follow-up visit.

Exclusion Criteria:

* If chest-indrawing observed at screening resolves after bronchodilator challenge, among those with wheeze at screening.
* Severe respiratory distress (e.g., grunting, nasal flaring, head nodding, or severe chest-indrawing).
* Presence of World Health Organization (WHO) Integrated Management of Childhood Illness (IMCI) danger signs including: lethargy or unconsciousness, convulsions, vomiting everything, or inability to drink or breastfeed.
* Hypoxia (SaO2 \< 90% on room air, as assessed by a Lifebox pulse oximeter).
* Stridor when calm.
* HIV-1 seropositivity or HIV-1 exposure, assessed as follows:

  * An HIV-positive result upon rapid antibody test will exclude any child from this study.
  * If a child is less than 12 months or age with a positive rapid test result, the child will be referred to receive additional confirmatory HIV testing (e.g., dried blood spot filter paper test) and follow-up from KCH staff, as per standard of care. Even if the confirmatory HIV testing subsequently shows that child is HIV-negative, he or she will remain excluded from the study.
  * If a child is less than 24 months of age and has an HIV-negative result upon rapid antibody test, the child's biological mother's HIV status will need to be assessed. If the mother is HIV-positive, the child will be excluded. If the mother has a documented HIV-negative test result from within the past 6 weeks, the child will be included. If the mother does not have documentation of an HIV-negative test result, she will be tested via rapid antibody testing to determine the child's eligibility for this study.
  * If a child is over 24 months of age, an HIV-negative rapid antibody test is required for inclusion in the study.
  * Note: If a child has documentation of an HIV-negative test result from within the past 6 weeks, that test result will be used for the child's eligibility assessment according to the algorithm described above.
* Severe acute malnutrition (i.e., weight for height/length \< -3 SD, mid-upper arm circumference \<115 mm, or edema).
* Possible tuberculosis (coughing for more than 14 days).
* Severe anemia, classified by WHO pocketbook guidelines (i.e., severe palmar pallor or hemoglobin \<8.0 g/dL)
* Severe malaria, classified by WHO pocketbook guidelines (e.g., positive malaria rapid diagnostic test (mRDT) with any danger sign, stiff neck, abnormal bleeding, clinical jaundice, or hemoglobinuria)
* Known allergy to penicillin or amoxicillin.
* Receipt of an antibiotic treatment in the 48 hours prior to the study based on caregiver's self-report and/or documentation in child's medical record.
* Hospitalized within 14 days prior to the study.
* Living outside Lilongwe urban area, the study catchment 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.
* Any non-pneumonia acute medical illness which requires antibiotic treatment per local standard of care.
* Participation in a clinical study of another investigational product within 12 weeks prior to randomization or planning to begin participation during this study.
* Prior participation in an Innovative Treatments in Pneumonia (ITIP) study during a previous pneumonia diagnosis.
D: Inclusion Criteria:

* 6 months of age or younger at randomization (child must be randomized on or before their 6-month birthday)
* Male or female Native American
* General state of good health
* Written informed consent obtained from the participant's parent(s) or legal guardian

Exclusion Criteria:

* Gestational age less than or equal to 35 weeks
* Chronic lung disease of prematurity
* A bleeding diathesis that would preclude IM injections
* Hospitalization at the time of randomization (unless discharge is anticipated within 10 days)
* Active RSV infection (a child with signs/symptoms of respiratory infection must have negative RSV testing) or known prior history of RSV infection
* A documented wheezing episode before enrollment
* Known renal impairment
* Known hepatic dysfunction
* Clinically significant congenital anomaly of the respiratory tract
* Chronic seizure or evolving or unstable neurologic disorder
* Congenital heart disease (CHD) (children with uncomplicated CHD \[e.g., Patent ductus arteriosus, small septal defect\] and children with complicated CHD who are currently anatomically and hemodynamically)
* Known immunodeficiency
* Mother with human immunodeficiency virus infection (unless the child has been proven to be not infected)
* Known allergy to Ig products
* Receipt of palivizumab, Respiratory syncytial virus immunoglobulin, intravenous (RSV-IGIV), or other RSV-specific monoclonal antibody, or any other polyclonal antibody (for example, hepatitis B immunoglobulin, IVIG) within 3 months prior to randomization
* Anticipated use of palivizumab or IVIG during the study (blood transfusions permitted)
* Previous receipt of RSV vaccines
* Participation in other investigational drug product studies
* Any medical or social condition which, in the opinion of the investigator, would adversely affect monitoring the infant
* Inability to complete the study follow-up period through up to 5 years of age

Answer: B