•Correction to the higher amoxicillin dose from 70-120mg/kg to 70-90mg/kg • Trial Assessment Schedule: o Inclusion of an additional phone call at day 4. o Clarification regarding the physical exam at the final visit o Change to duration of the symptom diary • Section 3 - clarifications and changes to the inclusion and exclusion criteria. • Section 6.1.2 – clarification on procedures for face to face visits • Section 6.2.1 – additional detail regarding the collection of nasopharyngeal swabs • Section 6.3.1 – additional detail regarding the collection of EDTA blood sample • Section 6.7.1 – additional information regarding storing parent/guardians email address and phone number and additional phone call at day 4. • Section 10.3 – addition of methodology sub-study. Amendments to all PISs and consent forms, as below: • Clarification regarding storage of contact details • Change in duration of symptom diary • Clarifications regarding sample collection and storage • Update to trial schedule • Addition of methodology sub-study • Clarification regarding storage of participant data GP Letter, version 3.0 12Aug16 • Corrected higher dose of amoxicillin CAP-IT Symptom Diary, version 2.0 12Aug16 • Change in duration of symptom diary • Updated schedule • Change to severity categories for symptoms • Change to wellbeing scale CAP-IT Wellbeing Questionnaire (EQ-5D-Y), version 2.0 12Aug16 • Correction of typo on visit label CAP-IT Study Medicine Information Sheet for Parents, version 2.0 12Aug16 • Change ‘syrup’ to ‘medicine’ throughout Addition of 15 new sites and change of PI to one site. Updated IMP details

Updated child trial diary - Minor formatting changes. New Trial Patient-parent card - To be given to parents/guardians of the CAP-IT participants at the time of study enrolment

New wording: Previous PED and WARD specific patient information sheet, summary information sheet and consent forms have been merged together into CAP-IT patient information sheet, summary information sheet and consent form. These will replace the PED and WARD specific documents. Patients from both groups will be now consented using the same CAP-IT information sheets. CAP-IT Protocol, Version 3.0 30Aug2017: • Throughout - minor typographical corrections and amendments for consistency and clarity. • Throughout - version and date updated to v3.0, 30-Aug-2017. • Throughout – addition of CTA number “17141803” • Page iii-iv – trial contact details updated • Trial assessment schedule updated: - Addition of blood sample sub-study in PED group. - Addition of optional medical history, physical examination, symptom review, nasopharyngeal swab, saliva sample, haematology, biochemistry, virology, chest x-ray and stool sample taken at pre-randomisation n WARD group. - Nasopharyngeal and saliva samples added to randomisation (d1) for WARD group • Section 1 - background re-ordered and partially re-worded in parts for clarity and reference to recent literature added. In addition, previously unavailable results from CAP-IT feasibility work (service evaluation) have been included. • Section 3 – clarifications and changes to the inclusion and exclusion criteria • Section 3/9.6 – change of pilot timeframe from initial 6 months of the study to 3 months during the first winter of recruitment • Section 5.6.1 – additional instruction added for cases of tolerability issues. Section 6.2.1 - The nasopharyngeal sample for WARD patients will be collected at randomisation to ensure availability of a baseline sample for comparison with the final sample. An optional additional sample may be taken prior to antibiotic treatment at admission. Appendices updated Updated IMP details

Addition of CAP-IT information poster to be displayed in A&E departments targeted towards parents of potential CAP-IT participants to give a brief overview of the research.

The IMP dossier for the placebo used in the CAP-IT study has been updated with i) a broader release specification for viscosity, ii) up to date stability data. In the IMPD placebo version 1, the release specification for viscosity is 150-400mPA. In version 3.0, this has been widened to 150-550mPA. The broadening of the release specification is supported by a declaration from the manufacturer of the placebo, which contains data confirming that the difference in viscosity in the range of 239 to 556mPa*s are not visibly distinguishable and therefore should not affect IMP blinding. Based on our overall assessment, the broadening of the viscosity specification will allow shelf life extension of the placebo according to ICH guideline (i.e. maximum of 12 months extrapolation from last analysed time-point) without comprising the safety or integrity of the clinical trial.

As part of the written informed consent for the CAP-IT study, parents/ guardians give consent for their child’s GP to provide information on any antibiotic prescriptions given during the planned 29 day duration of the study for that patient. Where a participant is lost to follow up, information on antibiotic prescriptions during this period will be elicited through contact with the participant’s GP. In the case of a parent/guardian decision to withdraw from the study, parent/guardians will be asked whether they consent to further data collection through hospital notes and NHS records. If consent is given, information on antibiotic prescriptions during the planned 29 day duration of the study for that patient will be elicited through contact with the participant’s GP. A template GP letter and form has been designed for use by sites to collect this data and approval is requested for this. In addition, several new investigator sites are being added to the protocol and a change of PI at a current site has occurred.

Summary of changes to protocol: •Statistical changes: Joint analysis of the PED & WARD groups, change to the primary endpoint definition, change to the non-inferiority margin (4-8%) and a consequent reduction in sample size from 2400 to 800 children. •Addition of an Endpoint Review Committee (ERC). •Addition of a procedure for collecting primary endpoint data from primary care for patients who are lost to follow-up or withdrawn. •Modification of the WARD criteria to allow outpatient systemic antibacterial treatment prior to presentation as long as total treatment is <48 hours before randomisation. •Removal of saliva sample collection information as this has been stopped. Summary of changes to the PIS and summary PIS: •Removal of reference to the saliva samples, which are no longer being collected •Additional information about the stool sub-study •Additional and modified wording of section relating to patient data Summary of changes to the symptom diary: •Removal of reference to the Wellbeing Questionnaire as this is performed as part of telephone follow-up calls