Conditions: Otitis Media Infections, Respiratory Tract Respiratory Tract Infections
Keywords: Acute otitis media Augmentin Extra Strength Amoxicillin-clavulanic acid Pediatric Beta-lactamase
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 310
Healthy volunteers: no

Brief summary:
Augmentin (ES)-600 is a high-dose amoxicillin/clavulanic acid 14:1 formulation that allows administration at 90/6.4 milligrams (mg)/kilograms (kg)/day in two divided doses. Most physicians in India use the standard Augmentin (amoxicillin:clavulanic acid 7:1) (45/6.4 mg/kg/day) formulation and double the dose to achieve higher dose of amoxicillin/clavulanic acid at 90 mg/kg/day in pediatric acute otitis media (AOM) due to non-availability of Augmentin (ES)-600. Using the 7:1 formulation causes unnecessary exposure to higher proportionate dose of clavulanic acid (12.8 mg/kg/day) as a unit dose of 6.4 mg/kg/day of clavulanic acid is only required for efficacy against beta-lactamase producing AOM pathogens. Hence, there is an unmet need for availability of Augmentin (ES)-600 in India. This is an open label, single arm, multicenter, non-comparative study in participants aged 6 months to 12 years with AOM. It aims to assess the safety and clinical efficacy of Augmentin (ES)-600 administered in two divided doses, every 12 hours in pediatric population in India. AUGMENTIN is a registered trademark of the GlaxoSmithKline group of companies.

Detailed description:

Arms:
arm 1: Eligible participants will receive Augmentin (ES)-600 at 90/6.4 mg/kg/day administered in two divided doses, every 12 hours with food for 10 days.

Interventions: intervention 1: Augmentin (ES)-600
Intervention descriptions: intervention 1: Augmentin ES will be administered as reconstituted oral suspension containing Amoxicillin and Potassium Clavulanate 600 mg/42.9 mg per 5 milliliters.

Protocol document:
Prot_000.pdf: 
 
 
 
 
Protocol 
 
Study ID: 213514 
 
Official Title of Study: A Multicentre, Open-label, Non-comparative Phase IV Clinical Study to 
Evaluate the Safety and Clinical Efficacy of Augmentin Extra Strength (ES)-600 
(amoxicillin/potassium clavulanate 14:1 combination) in Children with Acute Respiratory 
Tract Infections (ARTIs) in India 
 
NCT Number-NCT04600752 
 
Approval Date of Document: 19-May-2021 
 
 


T M F -1 3 3 2 8 2 5 0  
C O N FI D E N TI A L  
 
Gl a x o S mit h Kli n e gr o u p of c o m p a ni e s  
 
2 1 3 5 1 4  
 
1  
 
TI T L E P A G E  
Pr ot oc ol Title: A M ultic e ntre, O pe n -la bel, N o n-c o m parati ve P hase I V Cli nical St u d y t o 
E val uate t he Safet y a n d Cli nical Efficac y of A u g me nti n E xtra Stre n gt h ( E S) -6 0 0 
(a m o xicilli n /p otassi u m cla v ula nate  1 4 : 1 c o m bi nati o n) i n C hil dre n wit h Ac ute Res pirat or y 
Tract I nfecti o ns ( A R TIs)  i n I n dia 
Pr ot oc ol N u m ber : 2 1 3 5 1 4/ A me n d me nt 0 1 
C o m p o u n d N u m ber or N a me:  B R L 2 5 0 0 0  
St u d y P h ase:  P hase I V  
S h ort Title : A P hase I V St u d y t o E v al uate t he Safet y a n d Efficac y of A u g me nti n E xtra 
Stre n gt h ( E S) -6 0 0 (a m o xicilli n /p otassi u m cla v ula nate 1 4 : 1 c o m bi nati o n) i n C hil dre n wit h 
Ac ute Res pirat or y Tract I nfecti o ns ( A R TIs)  i n I n dia 
S p o ns or N a me a n d Le g al Re gistere d A d dress:  
Gla x o S mit h Kli ne Researc h & D e vel o p me nt Li mite d  
9 8 0 Great W est R oa d  
Bre ntf or d  
Mi d dlese x, T W 8 9 G S  
U K  
Gla x o S mit h Kli ne Researc h & D e vel o p me nt Li mite d  
2 5 2, Dr. A n nie Besa nt R oa d  
W orli, M u m bai 4 0 0 0 1 8  
I n dia 
Me dic al M o nit or N a me a n d C o nt act I nf or m ati o n   
Re g ul at or y A ge nc y I de ntif yi n g N u m ber(s):  N ot A p plica ble  
A p pr o v al D ate:  1 9 -M A Y -2 0 2 1  
C o p yri g ht 2 0 2 1  t he Gla x o S mit h Kli ne gr o u p of c o m pa nies. All ri g hts r eser ve d.  
U na ut h orise d c o p yi n g or use of t his i nf or mati o n is pr o hi bite d.  
P P D


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SPONSOR SIGNATORY: 
Protocol Title: A Multicentre, Open-label, Non-comparative Phase IV Clinical Study to 
Evaluate the Safety and Clinical Efficacy of Augmentin Extra Strength (ES)-600 
(amoxicillin/potassium clavulanate 14:1 combination) in Children with Acute Respiratory 
Tract Infections (ARTIs) in India 
Protocol Number: 213514/Amendment 01 
Compound Number or Name: BRL25000 
 
 
 
Dr Puja Kochhar 
Medical Director Infectious Diseases 
Classic & Established Products. 
 
Date 
 
The signed page is a separate document. 
 
 
 
Medical Monitor Name and Contact Information can be found in the Study Reference 
Manual. 
 
 
 


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date 
DNG Number 
Amendment 1 
19-MAY-2021 
TMF-13328250 
Original Protocol 
21-AUG-2020 
2020N430706_00 
 
Amendment 1 [19-May-2021] 
Overall Rationale for the Amendment: 
The rationale for this amendment is to address Subject Expert Committee (SEC) 
recommendation of revising the Phase IV study protocol to include all indications 
approved by CDSCO in the Marketing Authorization of Augmentin ES. Therefore, the 
indication is being revised to Acute Respiratory Tract Infections (ARTIs) i.e. inclusion of 
CABP and ABRS in addition to AOM 


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Section # and 
Name 
Description of Change 
Brief Rationale 
Throughout the 
protocol 
Acute otitis media is replaced with 
Acute respiratory tract infection. 
To broaden the indication and include 
acute respiratory tract infections.  
Acute respiratory tract infection 
meaning addition of CABP and ABRS 
in addition to AOM. 
Section 1.1: 
Synopsis  
Section 3: 
Objectives and 
Endpoints 
Added an additional secondary 
endpoint of Early clinical response 
at on-therapy visit (Day 3 to 5). 
Added tables providing definitions 
of primary and secondary clinical 
response. 
To assess if there is any clinical 
response early during the treatment 
period. 
 
To clarify the definitions of different 
responses as part of clinical response. 
Section 1.2: 
Schema 
Changed the study schema. 
Updated as per the changed study 
design. 
Section 1.3: 
Schedule of 
Activities 
Added an additional column for 
interim visit between OT visit and 
EOT visit 
Added a row for radiographic 
evaluations and the respective 
foot note 
Added early clinical response at 
OT 
Updated as per the changed study 
design. 
Section 2.2: 
Background 
Added background information 
about ARTIs 
Since the indication is changed from 
AOM to ARTIs updated this section to 
include information about ARTIs. 
Section 2.3.1: 
Risk Assessment  
Added the risk of exposure to 
ionizing radiation from X ray and 
its mitigation strategy 
Since X ray is included at Preliminary 
Visit (if required as per investigator’s 
discretion), the related risk is included. 
Section 4.1: 
Overall Design 
Updated details about OT visit. 
Added the details of additional 
interim visit. 
Updated as per the changed study 
design. 
Section 5: Study 
Population 
Added inclusion criteria for patient 
with ABRS and CABP. 
Updated the exclusion criteria 
To include the patients with ABRS and 
CABP. 
Section 5.4: 
Study Procedures 
Updated details of OT visit and 
added details of the Interim visit 
Updated as per the changed study 
design. 


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Section # and 
Name 
Description of Change 
Brief Rationale 
Added radiological evaluation at 
preliminary visit 
Section 8.1: 
Efficacy 
assessment 
Added evaluation of early clinical 
response at OT visit. 
Added evaluation of primary 
clinical response at Interim visit. 
Updated as per the changed study 
design. 
Section 8.2: 
Safety 
Assessment  
Added section on Radiographic 
Evaluations (Section 8.2.4) 
To include information about the X ray. 
Section 1.1: 
Synopsis 
Section 9.2: 
Sample Size 
Determination 
Sample size is changed from 200 
to 270 (without dropouts) and 310 
(including dropouts) 
Sample size is changed to 
accommodate the patients with ABRS 
and CABP along with the AOM 
patients. 
Section 9.4.3: 
Secondary 
Endpoint 
Added details on estimand 
Update estimand strategy  
Section 9.2:  
A new subsection (Section 9.2.1: 
Sample Size Sensitivity) is added 
To provide details regarding the 
calculation of the precision of sample 
size  
Appendix 3 
Added radiographic evaluations 
along with the Laboratory 
evaluations 
To include information about the X ray. 


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TABLE OF CONTENTS 
PAGE 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 3 
1. 
PROTOCOL SUMMARY ........................................................................................ 10 
1.1. 
Synopsis ..................................................................................................... 10 
1.2. 
Schema ...................................................................................................... 15 
1.3. 
Schedule of Activities (SoA) ........................................................................ 17 
2. 
INTRODUCTION .................................................................................................... 20 
2.1. 
Study Rationale .......................................................................................... 20 
2.2. 
Background ................................................................................................ 21 
2.3. 
Benefit/Risk Assessment ............................................................................ 23 
2.3.1. 
Risk Assessment ......................................................................... 23 
2.3.2. 
Benefit Assessment ..................................................................... 28 
2.3.3. 
Overall Benefit: Risk Conclusion .................................................. 28 
3. 
OBJECTIVES AND ENDPOINTS ........................................................................... 28 
4. 
STUDY DESIGN .................................................................................................... 30 
4.1. 
Overall Design ............................................................................................ 30 
4.2. 
Scientific Rationale for Study Design .......................................................... 32 
4.2.1. 
Participant Input into Design ........................................................ 33 
4.3. 
Justification for Dose .................................................................................. 33 
4.4. 
End of Study Definition ............................................................................... 33 
5. 
STUDY POPULATION ........................................................................................... 34 
5.1. 
Inclusion Criteria ......................................................................................... 34 
5.2. 
Exclusion Criteria ........................................................................................ 36 
5.3. 
Lifestyle modifications ................................................................................. 37 
5.4. 
Study Procedure ......................................................................................... 37 
5.4.1. 
Schedule of Assessments ............................................................ 37 
5.4.2. 
Screening, Enrolment and Baseline Assessments ....................... 37 
5.4.3. 
On Therapy .................................................................................. 38 
5.4.3.1. 
Day 1 .......................................................................... 38 
5.4.3.2. 
On-therapy Visit (Days 3 to 5) .................................... 38 
5.4.3.3. 
Interim Visit (Within 24 Hours of Notification) .............. 39 
5.4.4. 
End of Therapy Visit (Day 12 to 14) ............................................. 39 
5.4.5. 
Post Therapy ............................................................................... 40 
5.4.5.1. 
Interim Visit (Day 15 to 21) ......................................... 40 
5.4.5.2. 
Follow up Visit (Day 22-28)........................................... 40 
5.4.6. 
Reason of Concluding Study........................................................ 41 
5.5. 
Screen Failures........................................................................................... 41 
6. 
STUDY INTERVENTION ........................................................................................ 42 
6.1. 
Study Intervention(s) Administered ............................................................. 42 
6.1.1. 
Medical Devices ........................................................................... 43 
6.2. 
Preparation/Handling/Storage/Accountability .............................................. 43 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................... 44 
6.4. 
Study Intervention Compliance ................................................................... 44 
6.5. 
Concomitant Therapy.................................................................................. 45 


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6.5.1. 
Rescue Medicine ......................................................................... 45 
6.6. 
Dose Modification ....................................................................................... 45 
6.7. 
Intervention after the End of the Study ........................................................ 45 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................... 45 
7.1. 
Discontinuation of Study Intervention .......................................................... 45 
7.2. 
Participant Discontinuation/Withdrawal from the Study ............................... 45 
7.3. 
Lost to Follow Up ........................................................................................ 46 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 47 
8.1. 
Efficacy Assessments ................................................................................. 47 
8.2. 
Safety Assessments ................................................................................... 50 
8.2.1. 
Physical Examinations ................................................................. 50 
8.2.2. 
Vital Signs .................................................................................... 50 
8.2.3. 
Clinical Safety Laboratory Assessments ...................................... 51 
8.2.4. 
Radiographic Evaluations (X Ray) ............................................... 51 
8.3. 
Adverse Events and Serious Adverse Events ............................................. 51 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE 
Information ................................................................................... 51 
8.3.2. 
Method of Detecting AEs and SAEs ............................................. 52 
8.3.3. 
Follow-up of AEs and SAEs ......................................................... 52 
8.3.4. 
Regulatory Reporting Requirements for SAEs ............................. 52 
8.3.5. 
Pregnancy ................................................................................... 53 
8.3.6. 
Cardiovascular and Death Events ................................................ 53 
8.3.7. 
Disease-Related Events and/or Disease-Related 
Outcomes Not Qualifying as SAEs............................................... 54 
8.3.8. 
Adverse Events of Special Interest .............................................. 54 
8.3.9. 
Medical Device Deficiencies ........................................................ 54 
8.3.9.1. 
Time Period for Detecting Medical Device 
Deficiencies ................................................................ 54 
8.3.9.2. 
Follow-up of Medical Device Deficiencies ................... 54 
8.3.9.3. 
Prompt Reporting of Medical Device 
Deficiencies to Sponsor .............................................. 55 
8.3.9.4. 
Regulatory Reporting Requirements for 
Medical Device Incidents ............................................ 55 
8.4. 
Treatment of Overdose ............................................................................... 55 
8.5. 
Pharmacokinetics ....................................................................................... 55 
8.6. 
Pharmacodynamics .................................................................................... 55 
8.7. 
Genetics ..................................................................................................... 56 
8.8. 
Biomarkers ................................................................................................. 56 
8.9. 
Immunogenicity Assessments ..................................................................... 56 
8.10. 
Health Economics OR Medical Resource Utilization and Health 
Economics. ................................................................................................. 56 
9. 
STATISTICAL CONSIDERATIONS ........................................................................ 56 
9.1. 
Statistical Hypotheses................................................................................. 56 
9.2. 
Sample Size Determination ........................................................................ 56 
9.2.1. 
Sample Size Sensitivity ................................................................ 57 
9.3. 
Populations for Analyses ............................................................................ 57 
9.4. 
Statistical Analyses ..................................................................................... 57 
9.4.1. 
General Considerations ............................................................... 58 


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9.4.2. 
Primary Endpoint(s) ..................................................................... 58 
9.4.3. 
Secondary Endpoint(s) ................................................................ 58 
9.4.4. 
Other Safety Analyse(s) ............................................................... 60 
9.5. 
Interim Analyses ......................................................................................... 60 
9.6. 
Data Monitoring Committee (DMC) or Other Review Board ........................ 60 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................... 61 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ............................................................................................ 61 
10.1.1. 
Regulatory and Ethical Considerations ........................................ 61 
10.1.2. 
Financial Disclosure ..................................................................... 61 
10.1.3. 
Informed Consent Process .......................................................... 62 
10.1.4. 
Data Protection ............................................................................ 62 
10.1.5. 
Committees Structure .................................................................. 63 
10.1.6. 
Dissemination of Clinical Study Data ........................................... 63 
10.1.7. 
Data Quality Assurance ............................................................... 63 
10.1.8. 
Source Documents ...................................................................... 64 
10.1.9. 
Study and Site Start and Closure ................................................. 65 
10.1.10. Publication Policy ......................................................................... 65 
10.2. 
Appendix 2: Clinical Laboratory and Radiographic Tests ............................ 66 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ....................................... 67 
10.3.1. 
Definition of AE ............................................................................ 67 
10.3.2. 
Definition of SAE .......................................................................... 68 
10.3.3. 
Definition of Cardiovascular Events ............................................. 69 
10.3.4. 
Recording and Follow-Up of AE and SAE .................................... 70 
10.3.5. 
Reporting of SAE to GSK ............................................................. 72 
10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information .................................................................................................. 73 
10.4.1. 
Definitions: ................................................................................... 73 
10.4.2. 
Contraception Guidance .............................................................. 74 
10.4.3. 
Collection of Pregnancy Information: ........................................... 75 
10.5. 
Appendix 5: Medical Device Adverse Events (AEs), Adverse Device 
Effects (ADEs), Serious Adverse Events (SAEs) and Device 
Deficiencies: Definition and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ............................................................................ 77 
10.5.1. 
Definition of AE and ADE ............................................................. 77 
10.5.2. 
Definition of SAE, SADE and USADE .......................................... 77 
10.5.3. 
Definition of Device Deficiency ..................................................... 78 
10.5.4. 
Recording and Follow-Up of AE and/or SAE and Device 
Deficiencies ................................................................................. 78 
10.5.5. 
Reporting of SAEs ....................................................................... 80 
10.5.6. 
Reporting of SADEs ..................................................................... 81 
10.6. 
Appendix 6: COVID-19 Considerations ....................................................... 82 
10.6.1. 
Overall Rationale for This Appendix ............................................. 82 
10.6.2. 
Study Procedures During Covid-19 Pandemic ............................. 82 
10.7. 
Appendix 7: Abbreviations and Trademarks ................................................ 84 
11. REFERENCES ....................................................................................................... 86 


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LIST OF TABLES 
PAGE 
Table 1 
Potential Risk and Mitigation Strategy .................................................... 24 
Table 2 
Objectives and Endpoints ....................................................................... 29 
Table 3 
Study Intervention .................................................................................. 42 
Table 4 
Parameters of Early Clinical Response .................................................. 48 
Table 5 
Parameters of Primary Clinical Response .............................................. 49 
Table 6 
Parameters of Secondary Clinical Response ......................................... 49 
Table 7 
Prevalence for Division of Sample Size .................................................. 56 
Table 8 
Sample Size Sensitivity for Precision ..................................................... 57 
Table 9 
Analysis Population ................................................................................ 57 
Table 10 
Protocol-Required Safety Laboratory Assessments ............................... 66 
 
 
 


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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: A Multicentre, Open-label, Non-comparative Phase IV Clinical Study to 
Evaluate the Safety and Clinical Efficacy of Augmentin Extra Strength (ES)-600 
(amoxicillin/potassium clavulanate 14:1 combination) in Children with Acute Respiratory 
Tract Infections (ARTIs) in India. 
Short Title: A Phase IV Study to Evaluate the Safety and Efficacy of Augmentin Extra 
Strength (ES)-600 (amoxicillin/potassium clavulanate 14:1 combination) in Children with 
Acute Respiratory Tract Infections (ARTIs) in India. 
Rationale: Augmentin (ES)-600 is a high-dose amoxicillin/clavulanic acid (AMC/CVA) 
14:1 formulation that allows administration at 90/6.4 mg/kg/day in two divided doses, ie, 
double the previously recommended standard amoxicillin dosage (45 mg/kg/day) without 
doubling the unit dose of potassium clavulanate in a fixed dose combination formulation, 
inhibitory activity of CVA against bacterial beta-lactamases is maintained. Optimizing 
the PK/PD (ie, T>MIC values) of Augmentin (ES)-600 maximizes bacterial eradication 
such as Streptococcus pneumoniae (including penicillin-resistant S. pneumoniae (PRSP); 
MIC 2-4 ug/mL), Haemophilus influenzae (H. influenzae) and Moraxella catarrhalis (M. 
catarrhalis); principal respiratory pathogens implicated in acute respiratory tract 
infections (ARTIs) in children. This assures the highest probability of clinical cure and 
reduce the spread and development of resistance.  
The safety profile of AMC/CVA is also well understood. Clinical and post marketing 
surveillance data has also shown favourable results across all AMC/CVA paediatric and 
adult formulations. Most adverse events are mild and transient. The most commonly 
occurring events reported in children are mild transient gastrointestinal effects.  
Due to non-availability of Augmentin (ES)-600 in India, most physicians can only use 
available standard Augmentin 7:1 (45/6.4 mg/kg/day) formulation and double the dose to 
achieve the guideline recommended higher dose of amoxicillin at 90 mg/kg/day in ARTIs 
like AOM. However, doubling the dosage using 7:1 formulation causes unnecessary 
exposure to higher proportionate dose of CVA (12.8 mg/kg/day) as a unit dose of 
6.4 mg/kg/day of CVA is only required for efficacy against beta-lactamase producing 
respiratory pathogens like H. influenzae and M. catarrhalis. Hence, there is an unmet 
need for availability of Augmentin (ES)-600 in India. 
In this regard, the Indian Regulatory Agency (CDSCO) has granted a marketing 
authorization on 08 June 2020 for import/marketing of Augmentin (ES)-600 in India to 
the Sponsor (GlaxoSmithKline), with a post marketing commitment to conduct a 


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Phase IV study in India, whose purpose is to generate safety data on Augmentin (ES)-600 
in paediatric population in India. 
To this effect, the current study is designed to assess the safety and clinical efficacy of 
Augmentin (ES)-600, AMC/CVA (14:1) at 90/6.4 mg/kg/day in two divided doses every 
12 hours in children (age between 6 months and 12 years) with ARTIs, including acute 
otitis media (AOM), acute bacterial rhinosinusitis (ABRS) and community acquired 
bacterial pneumonia (CABP). 
The purpose of this study is to confirm the safety and clinical efficacy profile of 
Augmentin (ES)-600 in paediatric population in India. 
Objectives and Endpoints: 
The following are the objectives and endpoints of the study: 
Objectives 
Endpoints 
Primary 
Primary 
• The primary objective of the study 
is to assess treatment-emergent 
adverse events (TEAEs) in children 
receiving Augmentin (ES)-600 
(AMC/CVA 14:1) at 
90/6.4 mg/kg/day in two divided 
doses, administered for 10 days in 
ARTIs (AOM, ABRS or CABP). 
• Safety will be evaluated by assessing the 
incidences of treatment emergent adverse 
events (TEAE).$ 
Secondary 
Secondary 
• The secondary objective of the 
study is to assess clinical efficacy 
and incidence of protocol defined 
diarrhoea (PDD)** in children 
receiving Augmentin (ES)-600 
(AMC/CVA 14:1) at 90/6.4 
mg/kg/day in two divided doses 
administered for 10 days in ARTIs 
(AOM, ABRS or CABP). 
• Efficacy assessment* will be based on: 
1. Early clinical response at on-therapy 
visit (Day 3 to 5), defined in terms of 
‘success’ or ‘failure’ to study 
intervention 
2. Primary clinical response at the 
end-of-therapy visit (Day 12 to 14), 
defined in terms of ‘success’ or 
‘failure’ to study intervention  
3. Secondary clinical response at follow-
up (Day 22 to 28) ie, ‘success’ or 
‘failure’. 


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Objectives 
Endpoints 
• Incidence of protocol-defined diarrhoea 
(PDD)** in children receiving 
Augmentin (ES)-600 (AMC/CVA 14:1) 
at 90/6.4 mg/kg/day in two divided doses 
administered for 10 days in ARTIs 
(AOM, ABRS or CABP). 
$A treatment-emergent adverse effect (TEAE) is defined as an AE which has its onset date on or 
after treatment start date and on or before treatment stop date + 1 day. All adverse events (AEs) 
experienced during the same period will be monitored. The detail is described in Section 8.3: 
“Adverse Events and Serious Adverse Events”. 
**Protocol-defined diarrhoea is: 
• 
3 or more watery stools in one day OR 
• 
4 or more loose/watery stools in one day OR 
• 
2 watery stools per day for two consecutive days OR 
• 
3 loose/watery stools per day for two consecutive days. 
*Efficacy assessment will be made using following criteria: 
• Early or Primary Clinical Response 
Success Clinical cure 
Sufficient resolution or improvement of the signs and 
symptoms. No additional antibiotic therapy is indicated. 
Improvement  
Improvement in at least 1 presenting sign/symptoms. No 
additional antibiotic indicated. 
Failure 
Clinical failure  
Non-improvement or deterioration in any 
sign/symptoms after 2 or more days of therapy. 
Additional antibiotic therapy is indicated. 
Unable to 
determine  
A valid assessment of clinical outcome could not be 
made (eg, participant did not attend or consent to 
clinical examination or lost to follow-up). 
• Secondary Clinical Response 
Success Persistent clinical 
cure* 
Sufficient resolution of signs/symptoms for those 
participants who were clinically cured or improved at 
the end of therapy. No additional antibiotic indicated. 
Failure 
Clinical 
recurrence  
Reappearance of signs/symptoms for those participants 
who were clinically cured or improved at the end of 
therapy. Additional antibiotic therapy is indicated. 


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Unable to 
determine  
A valid assessment of clinical outcome could not be 
made (eg, participant did not attend end of therapy visit, 
or extenuating circumstances or lost to follow-up). 
* Participants who showed ‘improvement’ at EOT (ie, clinical ‘success’) and remained same at FU without 
requiring additional intervention, will be categorized as ‘persistent clinical cure’. 
Overall Design:  
This study is an open label, multicentre, non-comparative study. Participants will be 
children aged between 6 months to 12 years, presenting with ARTIs, including AOM, 
ABRS or CABP. 
At Preliminary Visit (Day 0) after signing the informed consent form by the 
parent/guardian and assent form by children between 7 to 12 years of age, a series of 
screening evaluations will be performed including laboratory and radiographic 
evaluations, in order to determine whether prospective study participant meets the 
inclusion criteria. Enrolled participants will receive supervised first dose of study 
intervention from participant pack, after demonstration of medication reconstitution 
procedure. In case first dose can be given on Day 0 (after availability of laboratory test 
result and radiological evaluation [Only if needed by investigator’s discretion]), the same 
will be considered as Day 1. All participants will receive Augmentin (ES)-600 at 90/6.4 
mg/kg/day administered in two divided doses, every 12 hours with food for 10 days. 
The incidence of protocol-defined diarrhoea will be determined from information 
collected from the Patient Diary cards, which will be appropriately translated for all 
languages required based on sites participating in the trial. Protocol-defined diarrhoea is: 
• 
3 or more watery stools in one day OR 
• 
4 or more loose/watery stools in one day OR 
• 
2 watery stools per day for two consecutive days OR 
• 
3 loose/watery stools per day for two consecutive days. 
After a minimum of two treatment days (four doses) of study intervention has been taken, 
an ‘on-therapy’ (OT) visit will be scheduled between Day 3 and 5. 
During this visit, the Investigator/study coordinator shall assess safety (primary endpoint) 
and ‘early clinical response’ (secondary endpoint).  Safety parameter includes treatment-
emergent adverse events (TEAEs) for primary study objective. Additionally, clinical 
status, study intervention compliance, completion of Patient Diary cards, and use of 
concomitant medications will also be assessed. The Investigator will assess safety 
parameters and clinical status whereas study coordinator will check other parameters with 
coordinated effort. 


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Participants with worsening of signs and symptoms, severe AE, SAE, or having PDD at 
OT visit (Day 3 to 5) will be assessed by investigators and withdrawn from study as per 
investigator’s discretion and treated appropriately. In such case, the OT visit will be 
considered as End of Therapy (EOT), and all evaluations that are planned at scheduled 
EOT (Day 12 to 14) will be completed at this visit. However, these participants will 
return at Follow-Up (FU) visit (Day 22 to 28) for safety assessment. 
Participants with worsening of signs and symptoms, severe AE, SAE, or having PDD 
after OT visit (Day 3 to 5) but prior to EOT visit will be assessed by investigators and 
withdrawn from study as per investigator’s discretion and treated appropriately. In such 
case, the interim visit will be considered as EOT visit, and all evaluations that are 
planned at scheduled EOT (Day 12 to 14) will be completed in this visit. However, these 
participants will return at FU visit (Day 22 to 28) for safety assessment. 
The participants continuing in the study will return for the scheduled EOT evaluation 
between Day 12 and 14. The Investigator will enquire the participant or parent/legal 
guardian about development of AEs and use of concomitant medication(s). The 
Investigator will perform safety (primary endpoint) and primary clinical response 
(secondary endpoint) evaluation. Patient Diary cards and unused medication will be 
returned at this visit. 
Participants who experience recurrence of signs/symptoms or any new AEs after  EOT 
visit (Day 12 to 14), but prior to scheduled FU visit (Day 22 to 28) will be required to 
visit the study site twice post EOT - once for the interim visit at the time of any 
recurrence (Day 15 to 21) and for the scheduled FU visit (Day 22 to 28). At the interim 
visit, all the evaluations which are to be performed at scheduled FU visit will be 
conducted. However, in such cases, all evaluations except secondary clinical response 
evaluation will be repeated at scheduled FU visit (Day 22 to 28). All participants 
experiencing recurrence post EOT will be treated according to the Investigator’s 
discretion. 
All participants, including withdrawals or clinical “failures” at EOT or had disease 
recurrence after EOT, will return for scheduled FU visit on Day 22 to 28. This visit is 
required for safety assessment and administration of additional medication, if warranted. 
The participants continuing in the study will return for the scheduled FU visit between 
Day 22 and 28. The visit be considered as ‘end of study’ visit, where the Investigator will 
perform final safety (primary endpoint) and secondary clinical response (secondary 
endpoint) evaluation (except for recurrence) during the visit. 
In general, FU visit at Day 22 to 28 includes both safety and efficacy assessment for 
participants who were clinical “success” at EOT, but only safety assessment for the 


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participants who were clinical “failures” at EOT or had disease recurrence after EOT. 
These participants are, by definition, clinical failures at follow-up visit. 
Disclosure Statement: This is a single group open-label treatment study in ARTI in 
children (age 6 months to 12 years).  
Number of Participants: A total of 310 subjects will be enrolled and dosed. 
Note: "Enrolled" means a participant's, or their legally acceptable representative’s, 
agreement to participate in a clinical study following completion of the informed consent 
process.  
Intervention Groups and Duration: The current study is a single arm, open label, 
non-comparative study. Eligible participants will receive Augmentin (ES)-600 
[AMC/CVA 14:1] at 90/6.4 mg/kg/day administered in two divided doses, every 12 hours 
with food for 10 days. 
Data Monitoring or Other Committee: Not Applicable. 
1.2. 
Schema 
 
a. 
Abbreviations: AE=Adverse event; ECR=Early Clinical Response; PCR=Primary Clinical Response; SAE = 
Serious Adverse Event, SCR=Secondary Clinical Response. 
b. 
Safety parameter is TEAE (All visits). Efficacy parameter includes ECR (OT visit), PCR (EOT visit), SCR (FU visit) 
categorized as clinical ‘success’ or ‘failure’ as defined in Section 8.1 
c. 
Visit 1 can be completed on the same day as the preliminary Day 0 visit if the laboratory test results and 
radiological assessment (Only if needed by investigator’s discretion) are available on the same day. 
d. 
Participants with clinical ‘failure’ or having PDD or severe AE or SAE at OT visit (Day 3 to 5), will be withdrawn 
from the study intervention and treated appropriately (as per Investigator discretion). In such case, the OT visit will 
be considered as EOT, and all evaluations that are planned at scheduled EOT (Day 12 to 14) will be completed in 
this visit. However, these participants will return at FU visit (Day 22 to 28) for safety assessment. 
e. 
Participants with clinical ‘failure’ or having PDD or severe AE or SAE after OT visit (Day 3 to 5) but prior to EOT, 
will be scheduled to return to the site for an interim evaluation, within 24 hours of notification to the Investigator. 
Subjects will then be withdrawn from the study intervention and treated appropriately (as per Investigator 
discretion). In such case, the interim visit will be considered as EOT visit, and all evaluations that are planned at 


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scheduled EOT (Day 12 to 14) will be completed in this visit. However, these participants will return at FU visit 
(Day 22 to 28) for safety assessment. 
f. 
Participants who experience recurrence of signs/symptoms after EOT visit (Day 12 to 14), but prior to scheduled 
FU visit (Day 22 to 28) will be required to visit the study site twice post EOT - once during interim visit at the time 
of any recurrence (Day 15 to 21) and at scheduled FU visit (Day 22 to 28). At this interim visit, all the evaluations 
which are to be performed at scheduled FU visit will be conducted. However, in such cases, all evaluations except 
secondary clinical response will be repeated at scheduled FU visit (Day 22 to 28). All participants experiencing 
recurrence post EOT will be treated according to the Investigator’s discretion. 


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1.3. 
Schedule of Activities (SoA) 
Assessments   
 
Preliminary 
Visit 
Visit 1* 
On-therapy Visita 
(OT) 
Interim Visitb 
(‘Failure’ or AE) 
End of 
Therapy Visitc 
(EOT) 
Interim Visitd 
(Recurrence) 
Follow up Visite 
(FU) 
Days** 
Day 0* 
Day 1 
Days 3 to 5 
Within 24 hours 
Day 12 to 14 
Day 15 to 21*** 
Day 22 to 28 
Written dated informed consent 
X**** 
Inclusion/exclusion 
X 
Medical history 
X 
Demographics 
X 
 
 
 
Vital signsf 
X 
X 
X 
X 
X 
X 
Physical examinationg 
X 
X 
X 
X 
X 
X 
Laboratory evaluationsh 
X 
 
 
 
Radiographic evaluationsi 
X 
 
 
 
Prior/concomitant medication 
X 
X 
X 
X 
X 
X 
Bowel movements 
X 
X 
X 
X 
X 
X 
Local examinationj 
X 
X 
X 
X 
X 
X 
Clinical assessmentk 
X 
X 
X 
X 
X 
X 


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Assessments   
 
Preliminary 
Visit 
Visit 1* 
On-therapy Visita 
(OT) 
Interim Visitb 
(‘Failure’ or AE) 
End of 
Therapy Visitc 
(EOT) 
Interim Visitd 
(Recurrence) 
Follow up Visite 
(FU) 
Baseline signs and symptomsl 
X 
Dispensing of study intervention 
 
X 
 
 
 
Dispensing of Patient Diary cardm 
 
X 
 
 
 
Adverse eventsn 
X 
X 
X 
X 
X 
X 
Early clinical response 
 
X 
 
 
Primary clinical response 
X 
X 
Secondary clinical response 
 
 
 
X 
Xo 
Protocol-defined Diarrhoeap 
 
X 
X 
X 
X 
X 
Return of remaining study 
intervention 
 
 
X 
X 
 
Collection of Patient Diary card 
 
 
X 
X 
 
Review of Patient Diary card 
X 
X 
X 
Assessment of compliance 
Xq 
Xq 
Study conclusion 
X 
a Scheduled OT (Safety and early clinical response). If clinical ‘failure’ or PDD or severe AE/SAE at OT, participant will be withdrawn and treated appropriately. In 
such case, OT visit will be considered as EOT visit. 


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b Interim visit (< 24 hrs of notification). Only if clinical ‘failure’ or having PDD or severe AE or SAE occurring after OT visit (Day 3 to 5) but prior to EOT.  
c Primary clinical response at EOT. 
d Required only if ‘recurrence’ occurs between EOT and FU. 
e Safety and clinical response at follow up. 
f Vital signs include body temperature, pulse rate, and respiratory rate. 
g Physical examination will include, measurement of height and weight, assessments of the skin, cardiovascular, respiratory, gastrointestinal and neurological 
systems. 
h Laboratory evaluations include hematology, plasma creatinine, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and bilirubin. 
i Radiographic evaluation will include Chest X ray and X ray of nasal/paranasal sinus (performed for patients presumed to have CABP and ABRS) as per 
investigators discretion. 
j Local examination refers to ear, nose/paranasal sinus or chest examination depending upon the primary diagnosis ie, AOM, ABRS or CABP  
k Includes assessment of disease at baseline and evaluation of clinical improvement or deterioration at other visits during study, as per Investigator’s discretion. 
l Includes baseline signs and symptoms (other than disease under study). 
m The parent/legal guardian should record the AEs, dosing information, diarrhoea related information in the Dairy Card through the treatment period and until EOT. 
Patient Diary cards will be appropriately translated for all languages required based on sites participating in the trial. 
n All AEs will be collected from the signing of the ICF until the follow-up visit at the time points specified. 
 
o The secondary clinical response evaluation will be performed at scheduled FU visit only for participants who were treatment successes at the EOT. This is unlike 
participants with disease recurrence post EOT, whose secondary clinical response evaluation would have already taken place at interim visit, at the time of recurrence. 
p Incidence of protocol-defined diarrhoea will be assessed (as a secondary endpoint) at EOT (Day 12 to 14), scheduled FU visit (Days 22 to 28) and interim visit, if 
any. 
q Not required for the participants who were withdrawn from the study intervention due to worsening, or no improvement, or requirement of additional antibiotics 
during OT visit (Day 3 to 5). 
*In case first dose can be given on Day 0 (after laboratory test result availability), the same will be considered as Day 1. 
**Rationale for range: Days 3 to 5; 12 to 14; 15 to 21, and 22 to 28: Basis previous GSK studies. Day 15 to 21 is to cover interim period between EOT and FU to 
factor any disease recurrence. Refer to Section 5.4 for the details of the evaluation to be performed at each visit. 
*** Participants with disease recurrence following the EOT visit (Day 12 to 14), but prior to the scheduled FU visit (Day 22 to 28) will be required to visit the study 
site twice - once during interim visit at time of recurrence (Day 15 to 21) and again at scheduled FU visit (Day 22 to 28). At interim visit all the evaluations which are 
to be performed at scheduled FU visit, including primary and secondary endpoint assessments will be performed. However, at scheduled FU visit (Day 22 to 28), all 
evaluations conducted at interim visit will be repeated, except secondary clinical response. 
**** Informed consent to be taken from by the parent/guardian and assent from children between 7 to 12 years.


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2. 
INTRODUCTION 
Augmentin is an oral antibacterial combination of the semisynthetic beta-lactam 
antibiotic, amoxicillin, and the beta-lactamase inhibitor clavulanate potassium. The 
presence of clavulanate potassium in Augmentin protects amoxicillin from degradation 
by beta-lactamase enzymes and effectively extends the antimicrobial spectrum of 
amoxicillin to include many gram-negative aerobic and anaerobic bacteria. It is indicated 
for use when amoxicillin-resistant pathogens, such as those expressing beta lactamases, 
are suspected as a cause of respiratory tract and other infections.  
 
Augmentin (ES)-600 is a high-dose amoxicillin/clavulanic acid (AMC/CVA) (14:1) 
formulation that allows administration at 90/6.4 mg/kg/day in two divided doses, double 
the previously recommended standard amoxicillin dosage without doubling the unit dose 
of potassium clavulanate in a fixed dose combination formulation, inhibitory activity of 
CVA against bacterial beta-lactamases is maintained.[AUGMENTIN ES-600 Prescribing 
Information, 2019] 
Optimizing the PK/PD (ie, T>MIC values) of Augmentin (ES)-600 (14:1) maximizes 
bacterial eradication such as Streptococcus pneumoniae (including penicillin-resistant 
S. pneumoniae (PRSP); MIC 2-4 ug/mL), Haemophilus influenzae (H. influenzae) and 
Moraxella catarrhalis (M. catarrhalis); principal respiratory pathogens implicated in 
Acute Respiratory Tract Infections (ARTIs) in children. This assures highest probability 
of clinical cure, thus reducing the spread and development of resistance. Augmentin 
(ES)-600 therefore plays an important role in the management of ARTIs in children.  
2.1. 
Study Rationale 
Due to non-availability of Augmentin (ES)-600 in India, most physicians can only use 
available standard Augmentin 7:1 (45/6.4 mg/kg/day) formulation and double the dose to 
achieve the guideline recommended higher dose of amoxicillin at 90 mg/kg/day in ARTIs 
in children. However, using the 7:1 formulation causes unnecessary exposure to higher 
proportionate dose of CVA (12.8 mg/kg/day) as a unit dose of 6.4 mg/kg/day of CVA is 
only required for efficacy against beta-lactamase producing respiratory pathogens. 
Hence, there is an unmet need for availability of Augmentin (ES)-600 in India. 
The safety profile of AMC/CVA is also well understood. Most adverse events are mild 
and transient. Main adverse effects (in adults and children) include gastrointestinal (GI) 
disturbances, including diarrhoea, nausea, vomiting and indigestion (each <5% 
incidence). [Todd PA et al, 1990] [Huttner A et al, 2020] [Easton J et al, 2003] 
[Bottenfield GW et al, 1998] [Dietz H et al, 1999] 
In this regard, the Indian Regulatory Agency (CDSCO) has granted a marketing 
authorization on 08 June 2020 for import/marketing of Augmentin (ES)-600 in India to 
the Sponsor (GlaxoSmithKline), with a post marketing commitment to conduct a 


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Phase IV study in India, whose purpose is to generate safety data on Augmentin (ES)-600 
in paediatric population in India. 
To this effect, the current study is designed to assess the safety and clinical efficacy of 
Augmentin (ES)-600, AMC/CVA (14:1) at 90/6.4 mg/kg/day in two divided doses every 
12 hours in children (age between 6 months and 12 years) with ARTIs, including Acute 
otitis media (AOM), Acute bacterial rhinosinusitis (ABRS) and Community acquired 
bacterial pneumonia (CABP). 
The purpose of this study is to confirm the safety and efficacy profile of Augmentin 
(ES)-600 in paediatric population in India. 
2.2. 
Background 
 Acute respiratory tract infections (ARTIs) like acute otitis media, sinusitis and 
community-acquired pneumonia are a leading cause of infectious disease–related 
morbidity, hospitalization, and mortality among children worldwide, particularly in low-
income countries.[Williams BG et al, 2002] [World Health Organization. World health 
statistics, 2017b] [World Health Organization. Acute respiratory infections in children, 
2017a] Although, in children under 5 years, primary infections with viral pathogens can 
also predispose to secondary bacterial infections.[Fan J et al, 1998] [Bellau-Pujol S et al, 
2005] 
The most frequently isolated bacteria in ARTIs include Streptococcus pneumoniae, non-
typeable Haemophilus influenzae and Moraxella catarrhalis.[Marom T et al, 2014] These 
bacteria were increasingly resistant to commonly used antibiotics for ARTI treatment, 
leading to increase in mortality rates, hospital durations, and health care–associated 
costs.[Mauldin PD et al, 2010] For instance, the increase in S. pneumoniae of 
intermediate susceptibility to penicillin-(PISP; penicillin MICs 0.12 to 1.0 μg/mL), and 
many, but not all, highly resistant serotypes of PRSP (penicillin MICs, ≥2 μg/mL) strains 
pose serious clinical problems.[Camara M et al, 2017] [Yamanaka N et al, 2008] [Kim 
SH et al, 2012] 
Based on such trends, an increase in the daily dose of amoxicillin from 45 mg/kg to 
90 mg/kg was introduced in late 2000 to respond to increasing presence of PRSP. This is 
because, amoxicillin, with or without clavulanate potassium, has one of the lowest MICs 
for S. pneumoniae among the available oral beta-lactam agents.[Jacobs MR et al, 1999] 
[Geng Q et al, 2014] [Pan F et al, 2015] [Li QH et al, 2013] [Fu J et al, 2019] Currently, 
most treatment guidelines on ARTIs recommend the use of higher doses of amoxicillin 
with or without clavulanic acid in ARTIs, mostly where PISP/PRSP is suspected.[Dagan 
R et al, 2001] [Piglansky L et al, 2003] [Arrieta A et al, 2003] [Casellas JM Jr et al, 2005] 
[Block SL et al, 2006] [Chu CH et al, 2014] [Casey JR et al, 2012] [Hoberman A et al, 
2017] [Lieberthal AS et al, 2013] 


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For instance, in 2013 (reaffirmed in 2019), American Academy of Pediatrics 
recommended high-dose amoxicillin (80 to 90 mg/kg/day in 2 divided doses) for 5 to 
10 days as preferred therapy in AOM.[Lieberthal AS et al, 2013] An alternative 
recommended first-line treatment is AMC/CVA  at 90/6.4 mg per kg/day in 2 divided 
doses who have received AMC in the previous 30 days or having recurrent/persistent 
otitis media or who have the otitis-conjunctivitis syndrome.[Lieberthal AS et al, 2013] 
In 2012 IDSA recommended “high-dose” AMC/CVA (90 mg/kg/day orally twice daily) 
for children with ABRS from geographic regions with high endemic rates (≥10%) of 
invasive PRSP, those with severe infection (eg, evidence of systemic toxicity with fever 
of 39°C [102°F] or higher, and threat of suppurative complications), attendance at 
day-care, age <2 years, recent hospitalization, antibiotic use within the past month, or 
who are immunocompromised.[Anthony W et al, 2012] 
High dose amoxicillin (90 mg/kg/day) with or without clavulanic acid has also been 
recommended in CABP in children age >3 months by American Academy of Pediatrics, 
British Thoracic Society, especially where higher rates of PRSP exist. Amoxicillin 
clavulanic acid is the preferred agent when empirical coverage of H influenzae and 
M catarrhalis is warranted (30% of H influenzae and 100% of M catarrhalis produce 
beta-lactamase).[Messinger AI et al, 2017] [Ostapchuk M et al, 2004] 
Overall, the selection of high-dose AMC/CVA (90 mg/kg/day) in ARTIs has been made 
based on long-term safety of the drug; its efficacy against the key respiratory pathogens 
and a first choice-to-treat PRSP and beta-lactamase producing strains that have potential 
to cause disease recurrence or therapy failure.  
Safety profile of AMC/CVA is also well understood. The most frequently reported 
adverse events are GI disturbances, including diarrhoea, nausea, vomiting and indigestion 
that can be reduced by taking AMC/CVA with food.[Stein GE et al, 1984] [Easton J et al, 
2003] High-dose AMC/CVA (90/6.4 mg/kg/day ) has shown similar tolerability profile to 
a conventional twice-daily regimen (45/6.4 mg/kg/day).[Bottenfield GW et al, 1998] 
Adverse events (AEs) were reported in a total of 50.2% and 47.3% of patients, with 
protocol-defined diarrhoea in 11% and 8.8% patients. The most frequently reported 
adverse events in 521 children treated with the high-dose formulation in another study 
were diaper rash (4.0%), diarrhoea (3.6%), vomiting (2.3%) and other rash (1.3%). 
Events probably or possibly related to the medication were documented in 14% of 
patients. 
In summary, Augmentin ES-600 (AMC/CVA 14:1) has been developed based on a 
combination of PK/PD considerations, in vitro, in vivo animal, and clinical data, and 
primarily intended to treat ARTIs in cases where PRSP is suspected and beta-lactamase 
producing organism cannot be ruled out. Its safety profile is well understood and is 
comparable to conventional Augmentin dosing regimens. 


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2.3. 
Benefit/Risk Assessment 
2.3.1. 
Risk Assessment 
The risk/benefit considerations for therapy in ARTIs must also be extended to consider 
the environmental consequences of using sub-optimally effective antibiotics which may 
be drivers of the development and spread of antibiotic resistance. There has been clearly 
a need for alternative dosage regimens and to use measures to control and reduce the 
emergence of resistant organisms, particularly PRSP.  
In this regard, time above MIC (T>MIC) data suggest that doses of AMC at 
90 mg/kg/day administered in divided doses every 12 hours may provide concentrations 
of antibiotic sufficient to kill PRSP with MICs 2-4 μg/mL. This regimen was calculated 
to provide a T>MIC of 38% for an MIC of 4 μg/mL, in contrast to 23% of T>MIC 
provided by the current dose of 45/6.4 mg/kg/day given in divided doses every 12 hours. 
The low toxicity of amoxicillin and experience already gained with higher doses 
worldwide suggest that the increase in the daily dose of amoxicillin will be unlikely to 
adversely affect tolerability. In addition, presence of clavulanic acid in Augmentin (ES)-
600 would provide coverage against beta-lactamase producing pathogens like as H. 
influenzae and M. catarrhalis, that are inherently resistant to amoxicillin. The rationale 
for dosage and administration is described in Section 4.3. 
Overall, the broad spectrum of activity against aerobic and anaerobic Gram-positive and 
Gram-negative bacteria, together with a good PK/PD profile and well understood safety 
profile, makes Augmentin (ES)-600 a useful antimicrobial in limiting ARTIs and 
development of resistance. 
The following section outlines the potential risk assessment and mitigation strategy for 
this protocol (Table 1).


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Table 1 
Potential Risk and Mitigation Strategy 
Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Investigational Medicinal Product (IP)  
Hypersensitivity reactions to 
study treatment and/or beta-
lactams 
Global data sheet (GDS), , Prescribing 
Information/potential risk of fatal hypersensitivity 
(anaphylactoid) reactions have been reported in 
patients on penicillin therapy. These reactions are 
more likely to occur in individuals with a history 
of penicillin hypersensitivity. 
Exclusion of subjects with a known 
hypersensitivity to any component of amoxicillin 
or clavulanic or beta-lactams, e.g. penicillins and 
cephalosporins acid and its excipients or history of 
a serious adverse reaction possibly related to any 
of these agents. (See exclusion criteria in Section 
5.2). 
In case of anaphylaxis or unanticipated 
hypersensitivity reaction, participant will be 
withdrawn and managed as per Investigator’s 
discretion. However, such participants will have to 
return for safety assessment at scheduled FU visit. 
Infectious mononucleosis 
GDS, Prescribing Information/ a morbilliform rash 
has been associated with this condition following 
the use of amoxicillin. 
Exclusion of patients with an infectious 
mononucleosis. (See exclusion criteria in 
Section 5.2). 
Pseudomembranous colitis 
and antibiotic associated 
diarrhoea   
GDS/ pseudomembranous colitis has been 
reported with the use of antibiotics and may range 
in severity from mild to life-threatening. It is 
important to consider its diagnosis in patients who 
develop diarrhoea during or after antibiotic use. 
If prolonged or significant diarrhoea occurs or the 
participant experiences abdominal cramps, 
treatment should be discontinued immediately, 
and the participant should be investigated further 
as per Investigator’s discretion. 


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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Hepatic Dysfunction 
GDS/ - amoxicillin-clavulanate-associated 
jaundice/hepatic dysfunction has been rarely 
reported. 
GDS/A moderate rise in ALT and AST has been 
associated with use of - amoxicillin-clavulanate. 
Exclusion of patients with current hepatic 
impairment, or history of jaundice or hepatic 
impairment due to any component of 
Amoxicillin/Clavulanic acid. (See exclusion 
criteria in Section 5.2). 
Renal Impairment 
GDS/dose needs to be adjusted in patients with 
creatinine clearance less than 30 mL/min. 
Exclusion of patients with known renal 
insufficiency e.g. plasma creatinine > 1.5 times 
upper limit of normal range for age. (See 
exclusion criteria in Section 5.2). 
Phenylketonuria 
GDS/ amoxicillin-clavulanate suspensions contain 
aspartame, which is a source of phenylalanine and 
so should be used with caution in patients with 
phenylketonuria. 
Exclusion of patients with phenylketonuria. 
Drug-Drug Interaction 
Potential 
GDS/ In common with other antibiotics, 
amoxicillin-clavulanate may affect the gut flora, 
leading to lower oestrogen re-absorption and 
reduced efficacy of combined oral contraceptives. 
GDS/ Concomitant use of probenecid is not 
recommended. Probenecid decreases the renal 
tubular secretion of amoxicillin. Concomitant use 
with amoxicillin-clavulanate may result in 
This subject population is unlikely to be on OCP. 
 
 
 
The use of Probenecid is to be prohibited during 
the study. Patients should be excluded who are on 
Probenecid. 


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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
increased and prolonged blood levels of 
amoxicillin, but not of clavulanic acid. 
GDS/ In the literature there are rare cases of 
increased international normalised ratio in patients 
maintained on acenocoumarol or warfarin and 
prescribed a course of amoxicillin. If 
co-administration is necessary, the prothrombin 
time or international normalised ratio should be 
carefully monitored with the addition or 
withdrawal of amoxicillin. 
This population is unlikely to be on warfarin. If 
participants are on Warfarin, they should be 
excluded from study. 
Pregnancy/Lactation 
GDS/Reproduction studies in animals (mice and 
rats at doses up to 10 times the human dose) with 
orally and parenterally administered amoxicillin-
clavulanate have shown no teratogenic effects. In 
a single study in women with pre-term, premature 
rupture of the fetal membrane (pPROM), it was 
reported that prophylactic treatment with 
amoxicillin-clavulanate may be associated with an 
increased risk of necrotizing enterocolitis in 
neonates. 
Augmentin is not contraindicated in pregnancy. 
Details of all pregnancies in female participants 
will be collected at Day 0. 
Participants will be instructed to notify the 
Investigator if they become pregnant during study 
period. Such participants will be immediately 
withdrawn from the study. 
Any reported pregnancy must be informed to 
Sponsor by Investigator within 24 hours of receipt 
of information and should follow the procedures 
outlined in Appendix 4.  


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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Any abnormal pregnancy outcomes (eg, 
spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are 
considered SAE. 
Exposure to ionizing 
radiation from X ray 
- 
Since children demonstrate signs and 
symptoms of CAP differently than adults and 
may deteriorate more rapidly than adults, 
keeping an option of chest X ray in inclusion 
criteria is critical for investigators to rule out 
need for hospitalization.  
- 
Even if an X ray is only one radiological assay 
is required. (Only basis for the reference in 
addition of clinical judgement if needed)  
- 
There will be no follow up assay needed. The 
dose from a single chest X ray should not 
exceed 20 microsieverts and this corresponds 
to a lifetime risk of a fatal malignancy of about 
1 in 1 million (ICRP 103), which falls into the 
‘trivial’ risk category as defined by ICRP 62. 
malignancy of approximately 1 in 300,000). 
- 
The study will minimize exposure by using 
X rays acquired as part of clinical care 
whenever possible.  
- 
Robust study design and CRF will factor in 
detailed history, lab screening and clinical 
examination parameters which should reduce 
the need of radiation exposure in the pediatric 
age group patients. (It will be considered only 
if clinicians would like to have additional 
confirmation in addition of clinical decision) 
- 
All procedures will be performed by a 
qualified technician. 
 
More detailed information about the known and expected benefits and risks and reasonably expected AEs of Augmentin (ES)-600 (14:1) 
may be found in the Prescribing Information.[AUGMENTIN ES-600 Prescribing Information, 2019] 


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2.3.2. 
Benefit Assessment 
Amoxicillin-clavulanic acid continues to be a reliable antibiotic for the treatment of 
ARTIs in children caused by amoxicillin-clavulanate susceptible organisms. Worldwide 
amoxicillin clavulanic acid has shown to be highly effective clinically in Phase III 
clinical trials in children including infections caused by PRSP and beta lactamase 
producing pathogens such as H. influenzae and M. catarrhalis. 
The safety profile is well-defined and supported by over 40-years of post-marketing 
experience. The most commonly occurring events reported in children are mild transient 
gastrointestinal effects. Clinical and post marketing surveillance data has also shown a 
good safety profile that is similar across all AMC/CVA pediatric formulations. 
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of Augmentin (ES)-600 may be found in the 
Prescribing Information. 
2.3.3. 
Overall Benefit: Risk Conclusion 
Optimizing the PK/PD (ie, T>MIC values) of Augmentin (ES)-600 maximizes bacterial 
eradication Streptococcus pneumoniae (including penicillin-resistant S. pneumoniae 
(PRSP); MIC 2-4 ug/mL), Haemophilus influenzae (H. influenzae) and Moraxella 
catarrhalis (M. catarrhalis); principal respiratory pathogens implicated in ARTIs in 
children. This assures highest probability of clinical cure, thus reducing the spread and 
development of resistance. 
Thus, it can be considered that the investigation of the safety and clinical efficacy of 
Augmentin (ES)-600 justified in children having ARTIs with a positive benefit/risk ratio. 
Considering the measures taken to minimize the risk to participants in this study, the 
potential risks identified in association with Augmentin (ES)-600 are justified by the 
anticipated benefits that may be afforded to patients with ARTIs. 
3. 
OBJECTIVES AND ENDPOINTS 
The objectives and endpoints of the study are provided in Table 2 below: 


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Table 2 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
Primary 
• The primary objective of the study is 
to assess treatment-emergent adverse 
events (TEAEs) in children receiving 
Augmentin (ES)-600 (AMC/CVA 
14:1) at 90/6.4 mg/kg/day in two 
divided doses, administered for 10 
days in ARTIs(AOM, ABRS or 
CABP). 
• Safety will be evaluated by 
assessing the incidences of 
treatment emergent adverse 
events (TEAE).$ 
Secondary 
Secondary 
• The secondary objective of the study 
is to assess clinical efficacy and 
incidence of protocol defined 
diarrhoea (PDD)* in children 
receiving Augmentin (ES)-600 
AMC/CVA 14:1 at 90/6.4 mg/kg/day 
in two divided doses administered for 
10 days in ARTIs (AOM, ABRS or 
CABP). 
• Efficacy assessment* will be based on: 
1. Early clinical response at the 
on-therapy visit (Day 3 to 5), 
defined in terms of ‘success’ or 
‘failure’ to study intervention. 
2. Primary clinical response at the 
end-of-therapy visit (Day 12 to 
14), defined in terms of 
‘success’ or ‘failure’ to study 
intervention  
3. Secondary clinical response at 
follow-up (day 22 to 28) ie, 
‘success’ or ‘failure’. 
• Incidence of protocol-defined diarrhea 
(PDD)** in children receiving 
Augmentin (ES)-600 (AMC/CVA 
14:1) at 90/6.4 mg/kg/day in two 
divided doses administered for 10 days 
in ARTIs (AOM, ABRS or CABP). 
$A treatment-emergent adverse effect (TEAE) is defined as an AE which has its onset date on or after 
treatment start date and on or before treatment stop date + 1 day. All adverse events (AEs) experienced 
during the same period will be monitored. The detail is described in Section 8.3 “Adverse Events and 
Serious Adverse Events”. 
**Protocol-defined diarrhoea is: 
• 
3 or more watery stools in one day OR 
• 
4 or more loose/watery stools in one day OR 


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• 
2 watery stools per day for two consecutive days OR 
• 
3 loose/watery stools per day for two consecutive days. 
* Efficacy assessment will be made using following criteria: 
• Early or Primary Clinical Response 
Success 
Clinical cure 
Sufficient resolution or improvement of the signs and symptoms 
such that no additional antibiotic therapy is indicated. 
Improvement  
Improvement in at least 1 presenting sign/symptoms. No additional 
antibiotic indicated. 
Failure 
Clinical failure  
Non-improvement or deterioration in any sign/symptoms after 2 or 
more days of therapy. Additional antibiotic therapy is indicated. 
Unable to determine  
A valid assessment of clinical outcome could not be made (eg, 
participant did not attend or consent to clinical examination or lost 
to follow-up). 
• Secondary Clinical Response 
Success 
Persistent clinical 
cure* 
Sufficient resolution of signs/symptoms for those participants who 
were clinically cured or improved at the end of therapy. No 
additional antibiotic indicated. 
Failure 
Clinical recurrence  
Reappearance of signs/symptoms for those participants who were 
clinically cured or improved at the end of therapy. Additional 
antibiotic therapy is indicated. 
Unable to determine  
A valid assessment of clinical outcome could not be made (eg, 
participant did not attend end of therapy visit, or extenuating 
circumstances or lost to follow-up). 
* Participants who showed ‘improvement’ at EOT (ie, clinical ‘success’) and remained same at FU without 
requiring additional intervention, will be categorized as ‘persistent clinical cure’. 
4. 
STUDY DESIGN 
4.1. 
Overall Design 
This study is an open label, multicentre, non-comparative study. Participants will be 
children aged between 6 months to 12 years, presenting with ARTIs including AOM, 
ABRS and CABP. 
At Preliminary Visit (Day 0) after signing the inform consent form by the parent/guardian 
and assent form by children between 7 to 12 years of age, a series of screening 
evaluations will be performed (Section 5.4.2) including laboratory and radiographic 
evaluations, in order to determine whether prospective study participant meets the 
inclusion criteria. Enrolled participants will receive supervised first dose of study 
intervention from the participant pack. Dosing will be accompanied by 
demonstration/instruction on reconstitution procedure, product handling, storage, and 


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accountability (Section 6.2). Additional information on the same will be included in 
Study reference manual. 
Visit 1 can be completed on the same day as the preliminary visit (Day 0) if the 
laboratory test results and radiological evaluation [Only if needed by investigator’s 
discretion] are available on the same day. All participants will receive Augmentin 
(ES)-600 at 90/6.4 mg/kg/day administered in two divided doses, every 12 hours with 
food for 10 days. 
The incidence of protocol-defined diarrhoea will be determined from information 
collected from the Patient Diary cards, which will be appropriately translated for all 
languages required based on sites participating in the trial. Protocol-defined diarrhoea is: 
• 3 or more watery stools in one day OR 
• 4 or more loose/watery stools in one day OR 
• 2 watery stools per day for two consecutive days OR 
• 3 loose/watery stools per day for two consecutive days. 
After a minimum of two treatment days (four doses) of study intervention has been taken, 
an ‘on-therapy’ (OT) visit will be scheduled between Day 3 and 5. 
During this visit, the investigator/study coordinator shall assess safety (primary endpoint) 
and ‘early clinical response’ (secondary endpoint). Safety parameter includes treatment-
emergent adverse events (TEAEs) for primary study objective. Additionally, clinical 
status, study intervention compliance, completion of Patient Diary cards, and 
concomitant medications use will also be assessed. The Investigator will assess safety 
parameters and clinical status whereas study coordinator will check other parameters with 
coordinated effort. 
Participants with clinical ‘failure’ or having PDD or severe AE or SAE at OT visit (Day 3 
to 5), will be withdrawn from the study intervention (as per Investigator discretion) and 
treated appropriately. In such case, the OT visit will be considered as End of Therapy 
(EOT), and all evaluations that are planned at scheduled EOT (Day 12 to 14) will be 
completed in this visit. However, these participants will return at FU visit (Day 22 to 28) 
for safety assessment. 
Participants with clinical ‘failure’ or having PDD or severe AE or SAE after OT visit 
(Day 3 to 5) but prior to EOT, will be scheduled to return to the site for an interim 
evaluation, within 24 hours of notification to the Investigator. Subjects will then be 
withdrawn from the study intervention (as per Investigator discretion) and treated 
appropriately. In such case, the interim visit will be considered as EOT visit, and all 
evaluations that are planned at scheduled EOT (Day 12 to 14) will be completed in this 


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visit. However, these participants will return at FU visit (Day 22 to 28) for safety 
assessment. 
The participants continuing in the study will return for the scheduled ‘end of therapy’ 
(EOT) evaluation between Day 12 and 14. The Investigator will enquire the participant or 
parent/legal guardian about development of AEs and use of concomitant medication(s). 
The Investigator will perform safety (primary endpoint) and primary clinical response 
(secondary endpoint) evaluation. Patient Diary cards and unused medication will be 
returned at this visit. 
Participants who experience recurrence of signs/symptoms after EOT visit (Day 12 to 
14), but prior to scheduled FU visit (Day 22 to 28) will be required to visit the study site 
twice post EOT - once for the interim visit at the time of any recurrence (Day 15 to 21) 
and for the scheduled FU visit (Day 22 to 28). At the interim visit, all the evaluations 
which are to be performed at scheduled FU visit will be conducted. However, in such 
cases, all evaluations except secondary clinical response will be repeated at scheduled FU 
visit (Day 22 to 28). All participants experiencing recurrence post EOT will be treated 
according to the Investigator’s discretion. 
All participants, including withdrawals or clinical ‘failures’ at EOT or had disease 
recurrence after EOT, will return for scheduled FU visit on Day 22 to 28. This visit is 
required for safety assessment and administration of additional medication, if warranted.  
The participants continuing in the study will return for the scheduled ‘follow-up’ (FU) 
visit between Day 22 and 28. The visit be considered as ‘end of study’ visit, where the 
Investigator will perform final safety (primary endpoint) and secondary clinical response 
(secondary endpoint) evaluation (except for recurrence) during the visit. 
In general, FU visit at Day 22 to 28 includes both safety and efficacy assessment for 
participants who were clinical ‘success’ at EOT, but only safety assessment for the 
participants who were clinical ‘failures’ at EOT or had disease recurrence after EOT. 
These participants are, by definition, clinical failures at follow-up visit. 
4.2. 
Scientific Rationale for Study Design 
As a commitment of receiving Augmentin (ES)-600 marketing authorization from Indian 
regulators on 08 June 2020, GSK India will have to conduct a Phase IV clinical study in 
the Indian population. Being a phase IV study, assessment of adverse event profile of 
Augmentin (ES)-600 would be considered as primary objective. Assessment of clinical 
efficacy would be considered as secondary objective in this study. 


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The purpose of this study is to confirm the safety and efficacy profile of Augmentin 
(ES)-600 in the paediatric population in India, administered at 90/6.4 mg/kg/day in two 
divided doses for 10 days in ARTIs. 
The current study design is a single arm, open-label, non-comparative study, and is based 
on several GSK-sponsored studies conducted in the past.[SB Report No. HH-1017/BRL-
025000/2/CPMS-382] [SB Report No. BRL-025000/RSD-1006FN/3/CPMS-446] [SB 
Report No. BRL-25000/RSD-1009XZ/3/CPMS-447] [SB Report No BRL-025000/RSD-
1016FL/2/CPMS-536] [SEIKEL K et al, 1997] 
4.2.1. 
Participant Input into Design 
There was no input from participants/participant organisations into the design of this 
study. 
4.3. 
Justification for Dose 
Augmentin (ES)-600, (AMC/CVA 14:1) was chosen to provide an increased dose of 
amoxicillin that would be enough to treat ARTIs (AOM, ABRS and CABP) not only due 
to PSSP/PISP, but also due to PRSP (MIC 2-4 µg/mL). This formulation is also effective 
against respiratory pathogens like beta-lactamase-positive or negative H. influenzae and 
M. catarrhalis.[AUGMENTIN ES-600 Prescribing Information, 2019] 
High dose amoxicillin with or without clavulanic acid has been recommended as 
preferred therapy in ARTIs, including AOM (AAP 2013/2019), ABRS (IDSA 2012) and 
CABP (AAP 2004, BTS etc). The selection of high-dose AMC/CVA has been made 
based on long-term safety of the drug; its efficacy against the key respiratory pathogens 
in children and a first intention-to-treat PRSP strains and where beta-lactamase producing 
organism cannot be ruled out. 
The Indian National Treatment Guideline 2016 also mentions use of high-dose 
AMC/CVA (14:1) at 90/6.4 mg/kg/day in (AOM).[National Treatment Guidelines for 
Antimicrobial Use in Infectious Diseases, 2019] 
Augmentin (ES)-600 is recommended for dosing at 90/6.4 mg/kg/day in two divided 
doses every 12 hours for 10 days, in children aged 3 months and older. There is no 
experience in paediatric patients weighing > 40 kg or in adults. There are no clinical data 
in children under 3 months of age.[AUGMENTIN ES-600 Prescribing Information, 
2019]  
4.4. 
End of Study Definition 
A participant is considered to have completed the study if he/she has completed all 
phases of the study including scheduled FU visit (Day 22 to 28) and excludes those who 
are early treatment failures and do not complete all visits. 


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The end of the study is defined as the date of the last visit of the last participant in the 
study or last scheduled procedure shown in the Schedule of Activities (SoA) for the last 
participant in the study. 
5. 
STUDY POPULATION 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if they meet all the below 
inclusion criteria: 
1. Age: 6 months to 12 years of either gender. 
2. Diagnosis of AOM on basis of otoscopic findings as defined below:  
• Purulent otorrhea of less than 24 hours duration 
OR 
• 
Middle ear effusion (MEE) 
o Middle ear effusion is evidenced by at least two of the following: 
o Decreased or absent tympanic mobility measured by pneumatic 
otoscopy, 
o Yellow or white discoloration of the tympanic membrane, or  
o Opacification of the tympanic membrane. 
PLUS 
At least one of the following indicators of acute inflammation: 
• Ear pain within 24 hours, including unaccustomed tugging or 
rubbing of ear, 
• Marked redness of the tympanic membrane, or 
• Distinct fullness or bulging of the tympanic membrane. 
OR 
Child with ABRS with inflammation as bacterial infection who has the 
following symptoms/signs on the day of or the day before the first dose of the 
investigational product: 
• Redness of the nasal mucosa  
• Nasal or postnasal discharge is purulent or mucopurulent  
• Pathological shadow in the paranasal sinus on a radiogram (only 
for reference-based on investigator discretion). Patient with 
surgical history should be excluded but patient with a pervious 
surgery more than 365 days before and apparently preserved 
maxillary sinus mucosa or patient with a previous surgery of nasal 
polypectomy more than 90 days before may be enrolled in the 
study. 


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• Child with ABRS whose severity is classified as moderate or 
severe (total score ≥4) based on the nasal cavity findings and 
symptoms as shown below. 
 
 
 
None 
Mild/small 
amount 
Moderate or 
severe 
Symptom 
Rhinorrhoea 
0 
1 
2 
Bad mood/ 
productive cough 
0 
1 
2 
Nasal cavity 
finding 
Nasal/postnasal 
discharge 
0 
(Serous) 
2 
(Mucopurulent, 
small amount) 
4 
(Moderate or 
larger amount) 
The severity of condition will be determined by the total score of the above symptoms/findings: 
1 to 3 = mild, 4 to 6 = moderate, 7 to 8 = severe. 
OR 
Child diagnosed with CABP based on following criteria: (At least three of the 
four criteria should be met to include in the study) 
i. 
History of documented fever (rectal, ear, or oral temperature ≥38°C or 
axillary temperature ≥37.5°C) or hypothermia (rectal, ear, or oral 
temperature <35°C or axillary temperature <34.5°C)  
ii. 
Acute onset or worsening within the previous 5 days of at least two of the 
following nine clinical signs and symptoms: 
• cough,  
• tachycardia, defined as follows: 
▪ 6 months to <24 months: ≥160 beats/min  
▪ 24 months to <10 years: ≥140 beats/min 
▪ ≥10 years: ≥100 beats/min 
• tachypnea, defined as follows: 
▪ 6 months to <12 months: ≥50 breaths/min  
▪ 12 months to <5 years: ≥40 breaths/min 
▪ ≥5 years: ≥20 breaths/min 
• dyspnea, 
• grunting,  
• sputum production,  
• chest pain,  
• cyanosis, 
• increased work of breathing 
iii. 
At least one of the five following laboratory findings: 
• leukocytosis (>15,000 white blood cells/mm3),  
• >15% immature neutrophils (bands) regardless of total peripheral 
white blood cell (WBC),  


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• leukopenia (4,500 WBC/mm3) and  
iv. 
Presence with new infiltrates consistent with bacterial pneumonia 
including new alveolar or lobal infiltrate or consolidation (based on 
imaging result) - based on investigator’s discretion only 
3. The participant and parent(s)/legal guardian(s) are willing and able to comply 
with the study protocol. 
4. In accordance with regional/local laws and regulations, the parent(s)/legal 
guardian(s) has given signed informed, dated consent; and the participant has 
given written assent, if applicable, to participate in the study. 
5.2. 
Exclusion Criteria 
Participants will be excluded from the study if they meet any of the following exclusion 
criteria: 
1. Weight ≥ 40 kg 
2. Pre-existing renal insufficiency (eg, plasma creatinine >1.5 times upper limit of 
normal range for age) 
3. Pre-existing liver disease(s) and/or hepatic dysfunction 
4. A serious underlying disease as per clinician’s judgment. 
5. Currently having diarrhea at the time of screening 
6. Concomitant infection which would preclude evaluation of the response to study 
intervention. 
7. Concomitant condition precluding evaluation of clinical response (such as acute 
mastoiditis, facial palsy, bacterial meningitis, and brain tumor) that would 
preclude evaluation of the response to study intervention. 
8. Congenital disorders such as maxillofacial dysplasia. 
9. Spontaneous perforation of the tympanic membrane and drainage for longer than 
24 hours. 
10. Tympanoplastic tube(s) in place, or has anatomic abnormalities associated with 
recurrent AOM, prolonged middle ear effusion, including cleft palate or repair, 
high-arched palate, or Down’s syndrome. 
11. Severe cases of CABP including Hypoxemic, Septic, Ventilator-associated or 
hospital-acquired pneumonia 
12. Need corticosteroid for systemic (inhalational steroids as controller therapy in 
asthma is allowed) 
13. Infectious mononucleosis 
14. Evidence of leukopenia and/or thrombocytopenia. 
15. History of previous hypersensitivity reaction to penicillins, cephalosporins or 
other Beta-lactam antibiotics. 
16. History of AMC/CVA-associated cholestatic jaundice/hepatic dysfunction. 
17. History of phenylketonuria or a known hypersensitivity to aspartame. 


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18. Received, within 48 hours of study entry, or is scheduled to receive during the 
study period, any medication which may alter bowel function. 
19. Currently receiving or has received more than one dose of systemic antibiotic 
therapy within one week prior to the initiation of the study. 
20. Receipt of an investigational compound (non-FDA and non-DCGI approved) or 
device within the previous 30 days or five half-lives, whichever is longer, 
preceding the first dose of study intervention or during the study.  
21. Participants with symptoms suggestive of active COVID-19 infection (ie, fever, 
cough, etc). 
22. Participants with known COVID-19 positive contacts within the past 14 days. 
5.3. 
Lifestyle modifications 
Lifestyle modifications are not mandated in this study. Advise related to diet and activity 
will be based on physician’s discretion. 
5.4. 
Study Procedure 
5.4.1. 
Schedule of Assessments 
Schedule of assessment is presented in Section 1.3. 
5.4.2. 
Screening, Enrolment and Baseline Assessments 
Preliminary Visit (Day 0): 
A series of screening evaluations will be performed at Preliminary Visit in order to 
determine whether prospective study participant meet the selection criteria for the study. 
The following assessments will take place at the Preliminary visit: 
• The Investigator or designated study personnel will inform each participant’s 
parent/ guardian of the nature of the study, explain the potential risks, and obtain 
written informed consent prior to performing any study-related procedures.  
• Participant is 6 months to 12 years of age at the time of signing of informed 
consent by parent(s)/legal guardian(s), as applicable.  
• Children between 7 to 12 years to assent prior to performing any study-related 
procedures. 
• The participant and parent(s)/legal guardian(s) are willing and able to comply 
with the study protocol. 
• In accordance with regional/local laws and regulations, the parent(s)/legal 
guardian(s) has given written informed, dated consent; and the participant (age 7 
to 12 years) has given written assent, if applicable, to participate in the study. 
• Assessment for eligibility against the inclusion and exclusion criteria. 
• Medical history documentation. 
• Demographic data (race, age, sex). 


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• Vital signs (body temperature, pulse rate, and respiratory rate). 
• Physical examination (assessments of the skin, cardiovascular, respiratory, 
gastrointestinal, and neurological systems, height, and weight). 
• Laboratory evaluations (hematology, plasma creatinine, aspartate 
aminotransferase [AST], alanine aminotransferase [ALT] and bilirubin). 
• Chest X ray and X ray of nasal/paranasal sinus to be performed for patients 
presumed to have CABP and ABRS (only for reference, as per investigators 
discretion). 
• Prior/concomitant medications. 
• Baseline bowel movements. 
• Documentation of the baseline signs and symptoms (other than disease under 
study). 
5.4.3. 
On Therapy 
5.4.3.1. 
Day 1  
• On Day 1 of the treatment period, the parent/guardian of the participant will be 
provided with the following: 
o Study intervention 
o Patient Diary card 
• The parent(s)/legal guardian(s) of the participant will be instructed about study 
intervention reconstitution, dosing, storage and entering the details in the Patient 
Dairy card. The first dose will be from the participant pack. 
• 
Any adverse events after signing the inform consent form will be collected. 
Note: Visit 1 can be completed on the same day as the preliminary day 0 visit if the 
laboratory test results are available on the same day. 
5.4.3.2. 
On-therapy Visit (Days 3 to 5) 
After a minimum of two treatment days (four doses) of study intervention has been taken, 
an ‘on-therapy’ (OT) visit will be scheduled between Day 3 and 5. 
During this visit, the investigator / study coordinator shall assess safety (primary 
endpoint) and ‘early clinical response’(secondary endpoint). Safety parameter includes 
treatment-emergent adverse events for primary study objective. Additionally, clinical 
status, study intervention compliance, completion of Patient Diary cards, and 
concomitant medications use will also be assessed. The Investigator will assess safety 
parameters and clinical status whereas study coordinator will check other parameters with 
coordinated effort. 
Hence, the following will be evaluated at the OT Visit: 
• TEAE (primary endpoint) 
• Early Clinical Response (secondary endpoint) 


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• Incidence of Protocol-defined diarrhea (secondary endpoint) 
• Vital signs 
• Local examination 
• Concomitant medication 
• Bowel movements 
• Physical examination (assessments of the skin, cardiovascular, respiratory, 
gastrointestinal, and neurological systems, height and weight) 
• Clinical assessment 
5.4.3.3. 
Interim Visit (Within 24 Hours of Notification) 
Participants will be called for interim visit within 24 hours of notification to the site for 
the interim evaluation after OT visit (Day 3 to 5) but prior to EOT, if there is worsening 
of signs and symptoms, severe AE or SAE, or occurrence of PDD. Failure shall be 
assessed by the investigator. If the clinical failure or PDD or SAE is diagnosed/confirmed 
by the Investigator, then the subjects will be withdrawn from the study intervention (as 
per Investigator) and treated appropriately. In such case, the interim visit will be 
considered as EOT visit, and all evaluations that are planned at scheduled EOT (Day 12 
to 14) will be completed in this visit. However, these participants will return at FU visit 
(Day 22 to 28) for safety assessment. 
The following will be evaluated at the Interim Visit: 
• TEAE (primary endpoint) 
• Primary Clinical Response (secondary endpoint) 
• Incidence of Protocol-defined diarrhea (secondary endpoint) 
• Vital signs 
• Local examination 
• Concomitant medication 
• Bowel movements 
• Physical examination (assessments of the skin, cardiovascular, respiratory, 
gastrointestinal, and neurological systems, height and weight) 
• Clinical assessment 
• Review of Patient Diary card 
5.4.4. 
End of Therapy Visit (Day 12 to 14) 
At the EOT visit the following evaluations will be performed: 
• TEAE (primary endpoint) 
• Primary clinical response (secondary endpoint) 
• Incidence of Protocol-defined diarrhea (secondary endpoint) 
• Vital signs 
• Concomitant medication 


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• Bowel movements 
• Local examination 
• Physical examination (assessments of the skin, cardiovascular, respiratory, 
gastrointestinal, and neurological systems, height and weight) 
• Clinical assessment 
• Review of Patient Diary card 
• Collection of Patient Diary card 
• Assessment of compliance 
• Return of study intervention (used and unused) 
All participants, including participants who had treatment ‘failure’ at EOT will be 
managed as per Investigator’s discretion, and their next visit (FU) will be scheduled on 
Day 22 to 28 (unless there is a recurrence). 
5.4.5. 
Post Therapy 
5.4.5.1. 
Interim Visit (Day 15 to 21) 
This visit shall occur between the EOT and Follow up Visit (Days 22 to 28) for 
participants with recurrence of sign/symptoms after EOT visit. Participants will be 
required to return to the site at the time of recurrence. At post therapy interim visit, the 
following evaluations will be performed: 
• Follow up of ongoing TEAEs (primary endpoint) 
• Recording new AEs 
• Secondary clinical response (secondary endpoint)  
• Incidence of Protocol-defined diarrhea (secondary endpoint) 
• Vital signs 
• Concomitant medication 
• Bowel movements 
• Local examination 
• Physical examination (assessments of the skin, cardiovascular, respiratory, 
gastrointestinal, and neurological systems, height and weight) 
• Clinical assessment 
The participants evaluated at post therapy interim visit, are required to return at scheduled 
FU visit (Days 22 to 28) for additional safety (not efficacy) assessment. 
5.4.5.2. 
Follow up Visit (Day 22-28) 
All participants including withdrawals will return for a scheduled FU visit. This will 
occur on Days 22 to 28. 
At scheduled FU visit, the following evaluations will be performed: 
• TEAE (primary endpoint) 


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• Secondary clinical response* (secondary endpoint)  
• Incidence of Protocol-defined diarrhea (secondary endpoint) 
• Vital signs 
• Concomitant medication 
• Bowel movements 
• Local examination 
• Physical examination (assessments of the skin, cardiovascular, respiratory, 
gastrointestinal, and neurological systems, height and weight) 
• Clinical assessment 
*Except for participants with disease recurrence post EOT, as their secondary clinical 
response evaluation will be completed at the interim visit (Day 15-21) ie, at the time of 
recurrence. 
At both scheduled EOT and FU visits, the parent or legal guardian will be asked about 
any AE(s) or concomitant medications. All unused study intervention, empty medication 
bottles and Patient Diary cards should be returned at any EOT visit, or the FU visit if not 
returned at the EOT visit. At the time of return, Patient Diary cards will be reviewed by 
the study coordinator for completeness. 
Overall compliance with the study intervention schedule will be monitored using Patient 
Diary cards. Compliance of between 80% and 120% (and intake of at least four doses on 
Days 1 and 2) is required for the participant to be considered as evaluable. 
5.4.6. 
Reason of Concluding Study 
In this study, a completed participant is one who satisfy all study entry criteria, complete 
the 10-day treatment phase, and complete scheduled visits ie, OT, EOT, and FU visits. 
The Investigator has the option of removing a participant from the study prematurely for 
a variety of reasons, including AE(s), insufficient therapeutic effect, deviation from 
protocol (including noncompliance to study intervention schedule, dosing regimen or 
visit schedule), lost to follow-up, or other reason as specified by the Investigator. 
5.5. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently entered in the study. A minimal set of screen failure information 
is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, any protocol deviations, and any 
serious adverse events (SAEs). Individuals who do not meet the criteria for participation 
in this study (screen failure) will not be rescreened. 


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6. 
STUDY INTERVENTION 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol. 
6.1. 
Study Intervention(s) Administered 
Table 3 below provides the details of study intervention administered. 
Table 3 
Study Intervention 
ARM Name 
Single arm interventional trial 
Intervention Name 
Augmentin (ES)-600 
Type  
Drug 
Dose Formulation  
Suspension 
Unit Dose Strength(s)  
Each 5 mL of the reconstituted suspension contains: 
Amoxicillin Trihydrate IP equivalent to Amoxicillin 600 
mg Potassium Clavulanate Diluted IP equivalent to 
Clavulanic Acid 42.9 mg 
Dosage Level(s) 
90/6.4 mg/kg/day, 12 hourly 
Route of Administration 
Oral 
Use 
Experimental 
IMP and NIMP 
Amoxycillin and Potassium Clavulanate Oral 
Suspension IP 600 mg/42.9 mg per 5 ml 
Sourcing 
Provided centrally by the Sponsor 
Packaging and Labeling 
 
Study Intervention will be provided in container. Each 
container will be labelled as required per country 
requirements. 
Current/Former Name(s) or 
Alias(es) 
Augmentin (ES)-600 


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6.1.1. 
Medical Devices 
• 
There are no GSK manufactured medical devices (or devices manufactured for GSK 
by a third party) provided for use in this study. 
• 
Other medical devices (not manufactured by or for GSK) provided for use in this 
study are: adapta-caps and labelled oral dosing syringes (5 mL). 
• 
Instructions for medical device use are provided in Study Reference Manual. 
• 
All device deficiencies, (including malfunction, use error and inadequate labelling) 
shall be documented, and reported by the Investigator throughout the study (see 
Section 8.3.9) and appropriately managed by the sponsor. 
6.2. 
Preparation/Handling/Storage/Accountability 
1. The Investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study intervention received and any 
discrepancies are reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 
interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with 
access limited to the Investigator and authorized site staff. 
3. The Investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records). 
4. Further guidance and information for the final disposition of unused study 
intervention are provided in the Study Reference Manual. 
Participants will be dosed at 90/6.4 mg/kg/day in two equally divided doses every 
12 hours. The supervised first-dose will be from participant pack. Parents/legal guardians 
will be demonstrated reconstitution, handling, and storage procedures on Day 0/1. They 
will then administer the daily dose over the course of the study as per the instruction 
provided by the Investigator/designee. The amount to be dosed for the participant as per 
the weight should be according to recommended dosing chart provided in the Study 
Reference Manual.  
The volume of the dose to be administered will be recorded in the Patient Diary card. The 
two daily doses should be given approximately 12 hours apart immediately at the start of 
meal in morning and evening. Parents/legal guardians will be instructed on proper dose 
measurement, dosing techniques, method of reconstitution, and handling and storage of 
reconstituted study intervention as per the details provided in Study reference manual. 
Graduated cylinders will be provided to assist the study co-ordinator with the 
reconstitution of the study intervention. Adapta-caps and labelled oral dosing syringes 


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(5 mL) will be provided to assist with dispensing of the reconstituted study intervention. 
A separate syringe will be used on the study day (Day 1). 
Participant will be supplied one unit (prepared) of study intervention after supervised first 
dose intake on Day 1. For subsequent dosing, participants will reconstitute medication at 
home as per instructions given on Day 1. Reconstituted suspension should be stored 
refrigerated at 2°C to 8°C and should not be frozen. The non-reconstituted study 
intervention should be stored in a dry place in the original package to protect from 
moisture. Each participant will receive enough study intervention for 10 days of dosing, 
as appropriate to the treatment regimen and body weight. Each package will be labelled 
as required per regulatory requirement. 
Drug Accountability 
The sites will maintain drug accountability and retain all used, partially used, and unused 
study drug materials until the end of the study. Completed Patient Diary cards will be 
used by the Investigator to assess compliance. 
Missed Doses 
The parent/legal guardian should be instructed to administer the study drug on time. If the 
parent/legal guardian forgets to administer a dose, it should be administered immediately 
and no later than 3 hours from the scheduled timing of the dose. The next daily dose 
should be administered on the same time. If more than 3 hours is lapsed beyond 
scheduled time, that particular dose should be skipped, and the next daily dose should be 
administered as scheduled. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
This is a non-comparative open-label study. Therefore, randomization and blinding are 
not applicable for this study. 
6.4. 
Study Intervention Compliance 
Unused clinical supplies and empty medication bottles should be returned from the site 
for shipment to GlaxoSmithKline Pharmaceuticals. 
Participant compliance with the dosing schedule will be monitored using Patient Diary 
cards that will be completed by the parent/guardian and will be reviewed by the study 
coordinator on return to the site at EOT visit (Day 12 to 14). Compliance is required to be 
80 to 120% through EOT. Noncompliance with the study intervention schedule prior to 
withdrawal from or completion of the study will be considered a protocol violation. 
Overall percentage of the study intervention compliance will be calculated as follows: 
Compliance = number of doses taken/(number of days on therapy x 2) x 100% 


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6.5. 
Concomitant Therapy 
During the trial, concomitant medication(s) necessary for the health of the participant will 
be permitted (as per physician/Investigator assessment); however, no additional 
antimicrobial therapy will be allowed. Participants who receive alternate antibiotics 
because of no improvement, worsening, or recurrence of signs/symptoms will be 
considered, by definition, clinical “failures". 
Medications with the potential to alter bowel habit are to be avoided during the study 
period. Concomitant use of oral or nasal antihistamines, decongestants, antifungals and/or 
inhaled steroids (controller therapy for asthma) are permitted during the study. Tubular 
secretion inhibitors of Augmentin (eg, probenecid) is prohibited. All concomitant 
medications taken during the study (up to and including the post-therapy FU visit) will be 
recorded on the eCRF. 
6.5.1. 
Rescue Medicine 
Not applicable.  
6.6. 
Dose Modification 
Dose-modification or re-treatment is not allowed in the study. 
6.7. 
Intervention after the End of the Study 
The participants will not be provided with any intervention after the end of the study. 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Intervention 
In rare instances, it may be necessary for a participant to permanently discontinue 
(definitive discontinuation) study intervention. If study intervention is definitively 
discontinued, the participant will remain in the study to be evaluated for safety and 
efficacy. See the SoA (Section 1.3) for data to be collected at the time of discontinuation 
of study intervention and follow-up and for any further evaluations that need to be 
completed. 
7.2. 
Participant Discontinuation/Withdrawal from the Study 
• 
A participant may withdraw from the study at any time at his/her own request or 
may be withdrawn at any time at the discretion of the Investigator for safety, 
behavioral, compliance or administrative reasons. This is expected to be 
uncommon. 


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• 
After a minimum of two treatment days (four doses) of study intervention has 
been taken, an ‘on-therapy’ (OT) visit will be scheduled between Day 3 and 5. 
• 
Participants with worsening of signs and symptoms, severe AE, SAE, or having 
PDD at OT visit (Day 3 to 5) will be assessed by investigators and withdrawn 
from study as per investigator’s discretion and treated appropriately. In such 
case, the OT visit will be considered as EOT visit, and all evaluations that are 
planned at scheduled EOT (Day 12 to 14) will be completed in this visit. 
However, these participants will return at FU visit (Day 22 to 28) for safety 
assessment. 
• 
Participants with worsening of signs and symptoms, severe AE, SAE, or having 
PDD after OT visit (Day 3 to 5) but prior to EOT visit will be assessed by 
investigators and withdrawn from study as per investigator’s discretion and 
treated appropriately. In such case, the interim visit will be considered as EOT 
visit, and all evaluations that are planned at scheduled EOT (Day 12 to 14) will 
be completed in this visit. However, these participants will return at FU visit 
(Day 22 to 28) for safety assessment. 
• 
See SoA for data to be collected at the time of study discontinuation and follow-
up and for any further evaluations that need to be completed. 
• 
If the participant withdraws consent for disclosure of future information, the 
Sponsor may retain and continue to use any data collected before such a 
withdrawal of consent. 
If a participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the Investigator must document this in the site 
study records. 
7.3. 
Lost to Follow Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit: 
• 
The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible and counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain whether the participant wishes to 
and/or should continue in the study. 
• 
Before a participant is deemed lost to follow up, the Investigator or designee 
must make every effort to regain contact with the participant (where possible, 
3 telephone calls on 3 consecutive days and, if necessary, a certified letter to the 


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participant’s last known mailing address or local equivalent methods). These 
contact attempts should be documented in the participant’s medical record. 
• 
Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study.  
Discontinuation of specific sites or of the study are handled as part of Appendix 1. 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
• 
Study procedures and their timing are summarized in the SoA.  
• 
Protocol waivers or exemptions are not allowed. 
• 
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study intervention. 
• 
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening 
log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.  
• 
Procedures conducted as part of the participant’s routine clinical management (eg, 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and was 
performed within the time frame defined in the SoA. 
8.1. 
Efficacy Assessments 
The efficacy is secondary endpoint in this study and assessed by clinical response. 
The early clinical response is categorized as treatment “success" or treatment “failure" at 
OT (Day 3 to 5). A treatment “success” at OT is defined as either "clinical cure" or 
"improvement". A treatment “failure” is defined as a participant whose clinical outcome 
is "clinical failure" (due to worsening or non-improvement in symptoms or requirement 
of additional antibiotic) or "unable to determine" at OT (Day 3 to 5). 
The primary clinical response is categorized as treatment “success" or treatment “failure" 
at EOT. A treatment “success” at EOT is defined as either "clinical cure" or 
"improvement" at scheduled EOT (Day 12-14). A treatment “failure” is defined as a 
participant whose clinical outcome is "clinical failure" (due to worsening or non-
improvement in symptoms) or "unable to determine" at scheduled EOT (Day 12 to 14) or 
interim visit as EOT. 


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The secondary clinical response is categorized as treatment “success” or treatment 
“failure” at FU visit. A treatment “success” at FU is defined as “persistent clinical cure” 
and treatment “failure” (clinical recurrence or unable to determine). 
Participants experiencing clinical ‘failure’ or having PDD or severe AE or SAE after OT 
visit (Day 3 to 5) but prior to EOT, the primary clinical response is categorized as 
treatment “success" (clinical cure or improvement) or “failure” (worsening or non-
improvement in symptoms or "unable to determine") at interim visit (pre EOT). 
For participants experiencing disease recurrence post EOT (Day 12 to 14), secondary 
clinical response is categorized as treatment “failure” (clinical recurrence) at post EOT 
interim visit. 
Evaluation of Early Clinical Response at OT visit (Day 3 to 5) 
Early clinical response will be evaluated by comparing baseline (pre-treatment) 
signs/symptoms with those observed at OT visit (ie, Day 3 to 5). The Investigator will 
evaluate each participant’s clinical outcome as follows (Table 4): 
Table 4 
Parameters of Early Clinical Response  
Success 
Clinical cure 
Sufficient resolution or improvement of the signs and 
symptoms. No additional antibiotic therapy is indicated. 
Improvement  Improvement in at least 1 presenting sign/symptoms. No 
additional antibiotic indicated. 
Failure 
Clinical 
failure  
Non-improvement or deterioration in any sign/symptoms 
after 2 or more days of therapy. Additional antibiotic 
therapy is indicated. 
Unable to 
determine  
A valid assessment of clinical outcome could not be 
made (eg, participant did not attend or consent to clinical 
examination or lost to follow-up). 
 
Evaluation of Primary Clinical Response at EOT visit (Day 12 to 14) or Interim visit 
after OT but prior to EOT (within 24hrs of notification, in case of clinical ‘failure’ 
or ‘AE’) 
Primary clinical response will be evaluated by comparing baseline signs/symptoms with 
those observed at the scheduled EOT visit (ie, Day 12 to 14) or at the time of withdrawal 
(visit), the Investigator will evaluate each participant’s clinical outcome as shown in 
Table 5. 


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Table 5 
Parameters of Primary Clinical Response 
Success 
Clinical cure 
Sufficient resolution or improvement of the signs and 
symptoms. No additional antibiotic therapy is indicated. 
 
Improvement  Improvement, but incomplete resolution of presenting 
sign/symptoms. No additional antibiotic indicated. 
 
Failure 
Clinical 
failure  
Non-improvement or deterioration in any sign/symptoms 
after 2 or more days of therapy. Additional antibiotic 
therapy is indicated. 
 
Unable to 
determine  
A valid assessment of clinical outcome could not be 
made (eg, participant did not attend or consent to clinical 
examination or lost to follow-up). 
Note: Participants with clinical ‘failure’ or having PDD or severe AE or SAE after OT 
visit (Day 3 to 5) but prior to EOT, will be scheduled to return to the site for an interim 
evaluation, within 24 hours of notification to the Investigator. Subjects will then be 
withdrawn from the study intervention and treated appropriately (as per Investigator). In 
such case, the interim visit will be considered as EOT visit, and all evaluations that are 
planned at scheduled EOT (Day 12 to 14) will be completed in this visit. However, these 
participants will return at FU visit (Day 22 to 28) for safety assessment. 
Evaluation of Secondary Clinical Response at Follow-Up (Day 22 to 28) or Post 
therapy interim visit (in case of recurrence) 
Clinical assessments will be performed at follow-up visit only for participants who were 
treatment successes at the EOT. By reviewing the clinical information obtained at the 
follow-up evaluation (Day 22 to 28), the Investigator will determine whether a 
satisfactory response is maintained, or a relapse has occurred (Table 6). 
Table 6 
Parameters of Secondary Clinical Response 
Success 
Persistent 
clinical 
cure*  
Sufficient resolution of signs/symptoms for those 
participants who were clinically cured or improved at the 
end of therapy. No additional antibiotic indicated. 
Failure 
Clinical 
recurrence  
Reappearance of signs/symptoms for those participants who 
were clinically cured or improved at the end of therapy. 
Additional antibiotic therapy is indicated. 


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Unable to 
determine  
A valid assessment of clinical outcome could not be made 
(eg, participant did not attend end of therapy visit, or 
extenuating circumstances or lost to follow-up). 
* Participants who showed ‘improvement’ at EOT (ie, clinical ‘success’) and remained same at FU without 
requiring additional intervention, will be categorized as ‘persistent clinical cure’. 
8.2. 
Safety Assessments 
Safety is the primary objective of the study. 
The primary endpoint of the study is to assess treatment-emergent adverse events (TEAE) 
in children with AOM receiving Augmentin (ES)-600 at a dose of 90/6.4 mg/kg/day in 
two divided doses, administered for 10 days. 
Incidence of PDD will be evaluated as secondary endpoint, along with efficacy 
parameters. protocol-defined diarrhea (PDD) is defined as: 
• 3 or more watery stools in one day OR 
• 4 or more loose/watery stools in one day OR 
• 2 watery stools per day for two consecutive days OR 
• 3 loose/watery stools per day for two consecutive days. 
Participants who withdraw due to diarrhea or has a documented SAE of diarrhea will be 
considered to have fulfilled the criteria for PDD and will be analyzed as such, even in the 
absence of Patient Diary card data. 
8.2.1. 
Physical Examinations 
• 
Physical examination will include, at a minimum, assessments of the skin, 
cardiovascular, respiratory, gastrointestinal, and neurological systems. Height 
and weight will also be measured and recorded. 
• 
Investigators should pay special attention to clinical signs related to previous 
serious illnesses. 
8.2.2. 
Vital Signs 
• 
Body temperature, pulse rate, and respiratory rate will be assessed. 
• 
Pulse measurements will be assessed with a completely automated device. 
Manual techniques will be used only if an automated device is not available. 
• 
Pulse measurements should be preceded by at least 5 minutes of rest for the 
participant in a quiet setting without distractions. 


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8.2.3. 
Clinical Safety Laboratory Assessments 
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the 
SoA for the timing and frequency. The evaluations will be performed at local laboratory 
at each site. 
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the SoA. 
8.2.4. 
Radiographic Evaluations (X Ray) 
An X ray will be performed only at preliminary visit at the study site. Chest X ray and 
X ray of nasal/paranasal sinus to be performed for patients presumed to have CABP and 
ABRS. The X ray is not mandatory and performed only for reference, as per investigators 
discretion. The purpose of radiographic evaluation is only to confirm the diagnosis when 
CABP or ABRS clinically, reasonably suspected but can’t be confirmed with clinical 
criteria. Since children demonstrates signs and symptoms of CABP differently than adults 
and may deteriorate more rapidly than adults, keeping an option of chest X ray in the 
inclusion criteria is critical for investigators to rule out any need for hospitalization. 
8.3. 
Adverse Events and Serious Adverse Events 
The definitions of an AE or SAE can be found in Appendix 3. 
The definitions of device-related safety events, (adverse device effects [ADEs]) and 
serious adverse device effects (SADEs), can be found in Appendix 5. Device deficiencies 
are covered in Section 8.3.9. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant's legally authorized representative). 
The Investigator and any qualified designees are responsible for detecting, documenting, 
and reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study intervention or the 
study, or that caused the participant to discontinue the study intervention or study (see 
Section 7). 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE 
Information 
• 
All SAEs will be collected from the signing of the informed consent form until 
the follow-up visit at the time points specified in the SoA (Section 1.3). 
• 
All AEs will be collected from the start of study intervention until the follow-up 
visit at the time points specified in the SoA (Section 1.3). 


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• 
Medical occurrences that begin before the start of study intervention but after 
obtaining informed consent will be recorded on the Medical History/Current 
Medical Conditions section of the case report form (eCRF) not the AE section. 
• 
All SAEs will be recorded and reported to the Sponsor or designee immediately 
and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 3. The Investigator will submit any updated SAE data to the Sponsor 
within 24 hours of it being available. 
• 
Investigators are not obligated to actively seek AEs or SAEs after the conclusion 
of the study participation. However, if the Investigator learns of any SAE, 
including a death, at any time after a participant has been discharged from the 
study, and he/she considers the event to be reasonably related to the study 
intervention or study participation, the Investigator must promptly notify the 
Sponsor. 
8.3.2. 
Method of Detecting AEs and SAEs 
• 
The method of recording, evaluating, and assessing causality of AEs and SAEs 
and the procedures for completing and transmitting SAE reports are provided in 
Appendix 3. 
• 
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-
ended and non-leading verbal questioning of the participant is the preferred 
method to inquire about AE occurrence. 
• 
Physical examination may reveal certain AEs not reported by the participant. 
8.3.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, will be followed until the event is 
resolved, stabilized, otherwise explained, or the participant is lost to follow-up (as 
defined in Section 7.3). Further information on follow-up procedures is given in 
Appendix 3. 
8.3.4. 
Regulatory Reporting Requirements for SAEs 
• 
Prompt notification by the Investigator to the Sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities toward the safety of 
participants and the safety of a study intervention under clinical investigation are 
met.  
• 
The Sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies (if applicable) about the safety of a study 
intervention under clinical investigation. The Sponsor will comply with country-


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specific regulatory requirements relating to safety reporting to the regulatory 
authority, Institutional Review Boards (IRB)/Independent Ethics Committees 
(IEC), and Investigators. 
• 
For all studies except those utilizing medical devices Investigator safety reports 
must be prepared for suspected unexpected serious adverse reactions (SUSAR) 
according to local regulatory requirements and Sponsor policy and forwarded to 
Investigators as necessary. 
• 
An Investigator who receives an Investigator safety report describing a SAE or 
other specific safety information (eg, summary or listing of SAEs) from the 
Sponsor will review and then file it and will notify the IRB/IEC, if appropriate 
according to local requirements. 
8.3.5. 
Pregnancy 
• 
Details of all pregnancies in female participants will be collected at Day 0. 
• 
Participants will be instructed to notify the Investigator if they become pregnant 
during study period. Such participants will be immediately withdrawn from the 
study. 
• 
Any reported pregnancy must be informed to Sponsor by Investigator within 
24 hours of receipt of information and should follow the procedures outlined in 
Appendix 4. 
• 
Any abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE. 
8.3.6. 
Cardiovascular and Death Events 
For any cardiovascular events detailed in Appendix 3 and all deaths, whether they are 
considered SAEs, specific Cardiovascular (CV) and Death sections of the eCRF will be 
required to be completed. These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death.  
The CV eCRFs are presented as queries in response to reporting of certain CV MedDRA 
terms. The CV information should be recorded in the specific cardiovascular section of 
the eCRF within one week of receipt of a CV event data query prompting its completion. 
The Death eCRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within 1 week 
of when the death is reported. 


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8.3.7. 
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs 
There are no disease related events (DREs) commonly seen in participants with AOM 
which can be serious/life-threatening. 
8.3.8. 
Adverse Events of Special Interest 
There are no adverse events of special interest planned to be monitored. 
8.3.9. 
Medical Device Deficiencies 
Medical devices are being provided for use in this study to measure and administer the 
study intervention. In order to fulfil regulatory reporting obligations worldwide, the 
Investigator is responsible for the detection and documentation of events meeting the 
definitions of device deficiency that occur during the study with such devices. 
The definition of a Medical Device Deficiency can be found in Appendix 5. 
NOTE: Incidents fulfilling the definition of an AE/SAE will also follow the processes 
outlined in Section 8.3.3 and Appendix 3 of the protocol. 
8.3.9.1. 
Time Period for Detecting Medical Device Deficiencies 
• 
Medical device deficiencies will be detected, documented, and reported during 
all periods of the study in which the medical device is used. 
• 
If the Investigator learns of any device deficiency at any time after a participant 
has been discharged from the study, and such device deficiency is considered 
reasonably related to a medical device provided for the study, the Investigator 
will promptly notify the Sponsor. 
The method of documenting Medical Device Incidents is provided in Appendix 5. 
8.3.9.2. 
Follow-up of Medical Device Deficiencies 
• 
Follow-up applies to all participants, including those who discontinue study 
intervention or the study. 
• 
The Investigator is responsible for ensuring that follow-up includes any 
supplemental investigations as indicated to elucidate the nature and/or causality 
of the deficiency. 
• 
New or updated information will be recorded on the originally completed form 
with all changes signed and dated by the Investigator. 


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8.3.9.3. 
Prompt Reporting of Medical Device Deficiencies to Sponsor 
• 
Device deficiencies will be reported to the Sponsor within 24 hours after the 
Investigator determines that the event meets the protocol definition of a device 
deficiency. 
• 
The Medical Device Deficiency Report Form will be sent to the Sponsor by fax. 
If fax is unavailable, then email should be utilized. 
• 
The Sponsor will be the contact for the receipt of device deficiency reports. 
8.3.9.4. 
Regulatory Reporting Requirements for Medical Device Incidents 
• 
The Investigator will promptly report all deficiencies occurring with any 
medical device provided for use in the study for the Sponsor to fulfill the legal 
responsibility to notify appropriate regulatory authorities and other entities about 
certain safety information relating to medical devices being used in clinical 
studies. 
The Investigator, or responsible person according to local requirements (eg, the head of 
the medical institution), will comply with the applicable local regulatory requirements 
relating to the reporting of device deficiencies to the IRB/IEC. 
8.4. 
Treatment of Overdose 
For this study, any dose of Augmentin (ES)-600 greater than 90/6.4 mg/kg/day within a 
24-hour time period will be considered an overdose. 
Sponsor does not recommend any specific treatment for an overdose. 
In the event of an overdose, the Investigator should: 
5. Contact the Medical Monitor immediately. 
6. Document the quantity of the excess dose as well as the duration of the overdosing in 
the eCRF. 
Further decision regarding dose interruptions or modifications will be made by the 
Investigator in consultation with the Medical Monitor based on the clinical evaluation of 
the participant. 
8.5. 
Pharmacokinetics 
Pharmacokinetic parameters are not evaluated in this study. 
8.6. 
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 


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8.7. 
Genetics 
Genetics are not evaluated in this study. 
8.8. 
Biomarkers 
Biomarkers are not evaluated in this study. 
8.9. 
Immunogenicity Assessments 
Immunogenicity assessments are not evaluated in this study. 
8.10. 
Health Economics OR Medical Resource Utilization and 
Health Economics. 
Health Economics/Medical Resource Utilization and Health Economics parameters are 
not evaluated in this study. 
9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypotheses 
No formal hypothesis is considered. 
9.2. 
Sample Size Determination 
A total of 310 subjects will be enrolled and dosed. These 310 participants will be enrolled 
for each indication based on the respective prevalence as mentioned in Table 7 below. 
These prevalence values are based on all ARTIs in India. 
Table 7 
Prevalence for Division of Sample Size 
Study 
Indication 
Prevalence % 
Kumari et al (2016) 
AOM 
17.6 
Acharya et al (2003) 
CAP 
8.6 (0.5% severe) 
Shahid et al (2012) 
ABRS 
14 
The approximate ratio of samples in each indication will be 18:9:14 (AOM: CABP: 
ABRS). Based on this ratio, at least 136 subjects with AOM, 68 with CABP and 106 with 
ABRS will be enrolled for the study.  
If the proportion of participants reporting at least one TEAE is 37.9% (as observed in 
Young et al, 2003), and assuming a sample size of 310 participants, it is estimated that 
the width of the 95% confidence interval would be within +/- 5.43% of the sample 


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proportion (ie, [32.5%, 43.3%]), which equates to the lower and upper bounds of the 95% 
confidence interval lying within approximately 14% of the estimated proportion. 
9.2.1. 
Sample Size Sensitivity 
The sensitivity of the precision is calculated with respect to 5 different proportions 
estimated as presented below in Table 8. 
Table 8 
Sample Size Sensitivity for Precision 
Proportion estimate 
Sample size 
Precision 
95% CI 
30% 
310 
5.10% 
(24.9%, 35.1%) 
35% 
310 
5.31% 
(29.7%, 40.3%) 
37.9% 
310 
5.43% 
(32.5%, 43.3%) 
40% 
310 
5.45% 
(34.5%, 45.5%) 
45% 
310 
5.54% 
(39.5%, 50.5%) 
50% 
310 
5.57% 
(44.4%, 55.6%) 
9.3. 
Populations for Analyses 
The following populations are defined (Table 9): 
Table 9 
Analysis Population 
Population 
Description 
Enrolled 
All participants who sign the ICF 
Intent-to-Treat 
All participants who are enrolled and receive at least 1 
administration of the investigational product (Augmentin [ES]-600) 
will be included in the analysis. 
 
9.4. 
Statistical Analyses 
The statistical analysis plan will include a more technical and detailed description of the 
statistical analyses described in this section. This section is a summary of the planned 
statistical analyses of the most important endpoints including primary and key secondary 
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9.4.1. 
General Considerations 
Descriptive statistics will be provided for baseline characteristics, efficacy, and safety 
data. Descriptive statistics on continuous measurements will include means, medians, 
standard deviations, and ranges, while categorical data will be summarized using counts 
and percentages. Graphical summaries of the data may also be presented. No subgroup 
analysis will be conducted. 
9.4.2. 
Primary Endpoint(s) 
Statistical analyses on safety endpoints will be conducted using participants from the 
Intent-to-Treat (ITT) population. 
Adverse Events 
The primary safety endpoint is the incidence of participants reporting at least one TEAE 
combined across all the indications. 
The primary estimand is the percentage of participants reporting at least one TEAE 
regardless of withdrawal from the study resulting in loss to follow-up. The while-on-
treatment strategy will be used, which will count and analyse adverse event occurred 
during treatment effect (During treatment Period + lag time of 1day). 
Apart from the TEAE, overall adverse events would be reported as collected (Treatment 
Policy). 
The primary safety endpoint will be summarized using number and percentage of 
participants reporting any TEAEs and participants with at least one TEAE with 
corresponding exact 95% CI. 
Participant incidence of all TEAEs will be tabulated by system organ class (SOC) and 
preferred term (PT). The number and percentage of participants reporting adverse events 
will be evaluated and will also be tabulated by relationship to study drug. 
All summaries will be reported as overall summaries and also stratified by indication. 
Further details will be provided in the Statistical Analysis Plan (SAP). 
9.4.3. 
Secondary Endpoint(s) 
Statistical analyses on efficacy endpoints will be conducted using participants from the 
Intent to treat population. All the displays will be created as overall summaries and as 
stratified by indication. 


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Early Clinical Response 
The estimand is the proportion of successful clinical responses. The intercurrent events 
expected for this endpoint are: 
• Discontinuation of study treatment due to AE 
• Discontinuation of study treatment due to lack of efficacy 
• Use of rescue medication 
• Discontinuation of study treatment due to any other reason 
The estimand strategies for the above intercurrent events are 
• A composite strategy would be used if intercurrent event ‘Discontinuation of 
study treatment due to AE’ Discontinuation of study treatment due to lack of 
efficacy’ and ‘Use of rescue medication’occur. That is, if a subject discontinues 
the study treatment due to AE or due to lack of efficacy or uses rescue 
medication, the subject will be imputed as a failure. 
• A treatment policy would be used if intercurrent event ‘Discontinuation of study 
treatment due to any other reason’ occurs. That is, if a subject discontinues the 
study treatment due to any other reason (other than AE, lack of efficacy or use of 
rescue medication), the data for that subject will be analysed as collected 
The proportion of clinical response OT (Days 3 to 5)  (defined as: A treatment success is 
defined as either “clinical cure” or “improvement” at end of therapy and treatment failure 
is defined as a participant whose clinical outcome was “clinical failure” or “unable to 
determine”) with corresponding 95% CI will be calculated. A full description of 
statistical analysis methods will be mentioned in SAP of study. 
Primary Clinical Response 
The estimand is the proportion of successful clinical responses. The intercurrent events 
expected for this endpoint are: 
• Lack of compliance (<80%) 
• Discontinuation of study treatment due to lack of efficacy 
• Discontinuation of study treatment due to AE 
• Use of rescue medication 
• Discontinuation of study treatment due to any other reason 
The estimand strategies for the above intercurrent events are 
• A principal stratum strategy will be used in case of ‘Lack of compliance 
(<80%)’. That is, only those subjects who have more than 80% compliance 
would be considered in the calculation of proportion. 
• A composite strategy would be used if intercurrent events ‘Discontinuation of 
study treatment due to lack of efficacy’ and ‘Discontinuation of study 
treatment due to AE’ and ‘Use of rescue medication’  occur. That is, if a 


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subject discontinues the study treatment due to lack of efficacy or due to AE or 
uses rescue medication, the subject will be imputed as a failure. 
• A treatment policy would be used if intercurrent event ‘Discontinuation of study 
treatment due to any other reason’ occurs. That is, if a subject discontinues the 
study treatment due to any other reason (other than AE, lack of efficacy or use of 
rescue medication), the data for that subject will be analysed as collected. 
The proportion of clinical response at EOT (defined as: A treatment success is defined as 
either “clinical cure” or “improvement” at end of therapy and treatment failure is defined 
as a participant whose clinical outcome was “clinical failure” or “unable to determine”) 
with corresponding exact 95% CI will be calculated. A full description of statistical 
analysis methods will be mentioned in SAP of study. 
Secondary Clinical Response 
No intercurrent event is defined for this endpoint as no events are expected to occur 
during the follow-up period. The data will be analyzed as collected.  
The proportion of clinical response (defined as any of the following: treatment success is 
defined as a “persistent clinical cure” and Treatment failure is defined as a participant 
whose clinical outcome was “clinical recurrence” or “unable to determine”) with 
corresponding exact 95% CI will be calculated.  
Protocol-defined diarrhoea (PDD) 
No intercurrent event is defined for this endpoint. The data will be analyzed as collected. 
The number and percentage of participants reporting incidence of PDD with 
corresponding exact 95% CI will be calculated and tabulated. 
9.4.4. 
Other Safety Analyse(s) 
Safety data including clinical assessments, physical examination findings will be 
presented in tabular and/or graphical format and summarized descriptively according to 
GSK’s Integrated Data Standards Library (IDSL) standards. Complete details will be 
documented in the SAP. 
9.5. 
Interim Analyses 
No interim analysis is planned for the study. 
9.6. 
Data Monitoring Committee (DMC) or Other Review Board 
Not applicable. 


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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
• 
This study will be conducted in accordance with the protocol and with: 
• Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines 
• Applicable ICH Good Clinical Practice (GCP) Guidelines 
• Applicable laws and regulations 
• 
The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (eg, advertisements) must be submitted to an IRB/IEC by 
the Investigator and reviewed and approved by the IRB/IEC before the study is 
initiated. 
• 
Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants.  
• 
The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/EC 
• Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures 
• Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations 
10.1.2. 
Financial Disclosure 
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate 
financial information as requested to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 


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Investigators are responsible for providing information on financial interests during the 
study and for 1 year after completion of the study. 
10.1.3. 
Informed Consent Process 
• 
The Investigator or his/her representative will explain the nature of the study to 
the participant or his/her legally authorized representative (defined in ICH-GCP 
as an individual, juridical or other body authorized under applicable law to 
consent, on behalf of a prospective individual, to the individual's participation in 
the clinical trial) and answer all questions regarding the study. 
• 
Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center. 
• 
The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF. 
• 
Participants between age 7 to 12 years will sign the most current version assent 
form during participation in the study. Procedure of obtaining assent will 
conform to ICH-GCP regulations, details of which will be mentioned in the 
assent form. 
• 
Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study. 
• 
A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative.  
GSK (alone or working with others) may use participant’s coded study data and samples 
and other information to carry out this study; understand the results of this study; learn 
more about the study intervention or about the study disease; publish the results of these 
research efforts; work with government agencies or insurers to have the the study 
intervention approved for medical use or approved for payment coverage. 
10.1.4. 
Data Protection 
• 
Participants will be assigned a unique identifier by the Sponsor. Any participant 
records or datasets that are transferred to the Sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred.  


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• 
The participant must be informed that his/her personal study-related data will be 
used by the Sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant who will be required to give 
consent for their data to be used as described in the informed consent.  
• 
The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed 
by the Sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities. 
10.1.5. 
Committees Structure 
Not applicable. 
10.1.6. 
Dissemination of Clinical Study Data 
• 
Where required by applicable regulatory requirements, an Investigator signatory 
will be identified for the approval of the clinical study report. The Investigator 
will be provided reasonable access to statistical tables, figures, and relevant 
reports and will have the opportunity to review the complete study results at a 
GSK site or other mutually agreeable location. 
• 
GSK will also provide the Investigator with the full summary of the study 
results. The Investigator is encouraged to share the summary results with the 
study participants, as appropriate. 
• 
The procedures and timing for public disclosure of the protocol and results 
summary and for development of a manuscript for publication for this study will 
be in accordance with GSK Policy. 
• 
GSK intends to make anonymized patient-level data from this trial available to 
external researchers for scientific analyses or to conduct further research that 
can help advance medical science or improve patient care. This helps ensure the 
data provided by trial participants are used to maximum effect in the creation of 
knowledge and understanding 
• 
A manuscript will be progressed for publication in the scientific literature if the 
results provide important scientific or medical knowledge. 
10.1.7. 
Data Quality Assurance 
• 
All participant data relating to the study will be recorded on printed or electronic 
eCRF unless transmitted to the Sponsor or designee electronically (eg, 
laboratory data). The Investigator is responsible for verifying that data entries 
are accurate and correct by physically or electronically signing the eCRF.  
• 
The Investigator must maintain accurate documentation (source data) that 
supports the information entered in the eCRF. 


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• 
The Investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 
• 
Monitoring details describing strategy (eg, risk-based initiatives in operations 
and quality such as Risk Management and Mitigation Strategies and Analytical 
Risk-Based Monitoring), methods, responsibilities and requirements, including 
handling of noncompliance issues and monitoring techniques (central, remote, 
or on-site monitoring) are provided in the Monitoring Plan. 
• 
The Sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 
• 
The Sponsor assumes accountability for actions delegated to other individuals 
(eg, Contract Research Organizations). 
• 
Study monitors will perform ongoing source data verification to confirm that 
data entered into the eCRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants 
are being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 
• 
Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the Investigator for 25 years from the issue of the final 
Clinical Study Report (CSR)/ equivalent summary unless local regulations or 
institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without 
written notification to the Sponsor. 
10.1.8. 
Source Documents 
• 
Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
Investigator’s site. 
• 
Data reported on the eCRF or entered in the eCRF that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained. The Investigator may need to request previous 
medical records or transfer records, depending on the study. Also, current 
medical records must be available. 
• 
Definition of what constitutes source data can be found in Study Reference 
Manual. 


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10.1.9. 
Study and Site Start and Closure 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the first participant in and will be the study start date. 
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include 
but are not limited to: 
• 
Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor's procedures, or GCP guidelines 
• 
Inadequate recruitment of participants by the Investigator 
• 
Discontinuation of further study intervention development 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform 
the Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified 
by the applicable regulatory requirements. The Investigator shall promptly inform the 
participant and should assure appropriate therapy and/or follow-up of the participant. 
10.1.10. 
Publication Policy 
• 
The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the Investigator agrees to submit all manuscripts or abstracts to 
the Sponsor before submission. This allows the Sponsor to protect proprietary 
information and to provide comments.  
• 
The Sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the Sponsor will 
generally support publication of multicenter studies only in their entirety and not 
as individual site data. In this case, a coordinating Investigator will be 
designated by mutual agreement. 
• 
Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements. 


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10.2. 
Appendix 2: Clinical Laboratory and Radiographic Tests 
• 
The tests detailed in Table 10 will be performed at the local laboratory.  
• 
Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 5 of the protocol. 
• 
Additional tests may be performed at any time during the study as determined 
necessary by the Investigator or required by local regulations. 
Table 10 
Protocol-Required Safety Laboratory Assessments 
Assessments 
Parameters 
Hematology 
Platelet 
Count  
RBC Indices: 
MCV 
MCH 
%Reticulocytes 
WBC count with 
Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
RBC Count 
Hemoglobin 
Hematocrit 
Clinical 
Chemistry 
Plasma 
creatinine 
Aspartate Aminotransferase 
(AST) 
Alanine Aminotransferase (ALT) 
Total and direct bilirubin 
Radiography 
Chest X ray to be performed for patients presumed to a diagnosis of CABP. 
X ray of nasal/paranasal sinus to be performed for patients presumed to have 
ABRS (both only for reference, as per investigators discretion) 
 


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10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
10.3.1. 
Definition of AE 
AE Definition 
• 
An AE is any untoward medical occurrence in a clinical study participant, 
temporally associated with the use of a study intervention, whether or not 
considered related to the study intervention. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a study intervention. 
 
Events Meeting the AE Definition 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or 
urinalysis) or other safety assessments (eg, ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the Investigator (ie, not 
related to progression of underlying disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae. 
• 
The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will 
be reported as AE or SAE if they fulfill the definition of an AE or SAE. Also, 
"lack of efficacy" or "failure of expected pharmacological action" constitutes an 
AE or SAE. 
 


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Events NOT Meeting the AE Definition  
• 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by 
the Investigator to be more severe than expected for the participant’s condition. 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition. 
• 
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. 
10.3.2. 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
o Results in death 
o Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• In general, hospitalization signifies that the participant has been detained 
(usually involving at least an overnight stay) at the hospital or emergency ward 
for observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AE. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered 
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• Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
Results in persistent or significant disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
Is a congenital anomaly/birth defect 
Other situations: 
• 
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but 
may jeopardize the participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events 
should usually be considered serious. 
• 
Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse. 
10.3.3. 
Definition of Cardiovascular Events 
Cardiovascular Events (CV) Definition: 
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs: 
• 
Myocardial infarction/unstable angina 
• 
Congestive heart failure 
• 
Arrhythmias 
• 
Valvulopathy 
• 
Pulmonary hypertension 
• 
Cerebrovascular events/stroke and transient ischemic attack 
• 
Peripheral arterial thromboembolism 


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• 
Deep venous thrombosis/pulmonary embolism 
• 
Revascularization 
10.3.4. 
Recording and Follow-Up of AE and SAE 
AE and SAE Recording 
• 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event. 
• 
The Investigator will then record all relevant AE/SAE information in the eCRF. 
• 
It is not acceptable for the Investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK /AE/SAE eCRF page. 
• 
There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK. 
• 
The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories:  
• 
Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort, and not interfering with everyday activities. 
• 
Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities. 
• 
Severe: An event that prevents normal everyday activities. An AE that is assessed 
as severe should not be confused with an SAE. Severe is a category utilized for 
rating the intensity of an event; and both AE and SAE can be assessed as severe. 
An event is defined as ‘serious’ when it meets at least 1 of the predefined 
outcomes as described in the definition of an SAE, NOT when it is rated as severe. 
 


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Assessment of Causality 
• 
The Investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE. 
• 
A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out. 
• 
The Investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• 
The Investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment. 
• 
For each AE/SAE, the Investigator must document in the medical notes that 
he/she has reviewed the AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred, and the Investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the Investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to GSK. 
• 
The Investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-up of AE and SAE 
• 
The Investigator is obligated to perform or arrange for the conduct of 
supplemental measurements and/or evaluations as medically indicated or as 
requested by GSK to elucidate the nature and/or causality of the AE or SAE as 
fully as possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care 
professionals. 
• 
If a participant dies during participation in the study or during a recognized 
follow-up period, the Investigator will provide GSK with a copy of any post-
mortem findings including histopathology. 
• 
New or updated information will be recorded in the originally completed eCRF. 


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• 
The Investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information. 
10.3.5. 
Reporting of SAE to GSK 
SAE Reporting to GSK via Electronic Data Collection Tool 
• 
The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool. 
• 
If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours. 
• 
The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• 
The Investigator or medically-qualified sub-Investigator must show evidence 
within the eCRF (eg, check review box, signature, etc.) of review and verification 
of the relationship of each SAE to IP/study participation (causality) within 72 
hours of SAE entry into the eCRF. 
• 
After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data. 
• 
If a site receives a report of a new SAE from a study participant or receives 
updated data on a previously reported SAE after the electronic data collection tool 
has been taken off-line, then the site can report this information on a paper SAE 
form (see next section) or to the medical monitor by telephone. 
• 
Contacts for SAE reporting can be found in Study Reference Manual. 
 
SAE Reporting to GSK via Paper CRF 
• 
Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the medical monitor. 
• 
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by 
overnight mail or courier service. 
• 
Initial notification via telephone does not replace the need for the Investigator to 
complete and sign the SAE CRF pages within the designated reporting time 
frames. 
• 
Contacts for SAE reporting can be found in Study Reference Manual. 
 


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10.4. 
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information 
10.4.1. 
Definitions: 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below). 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle 
cannot be confirmed before first dose of study intervention, additional evaluation should 
be considered. 
Women in the following categories are not considered WOCBP 
7. Premenarchal 
8. Premenopausal female with 1 of the following: 
• 
Documented hysterectomy 
• 
Documented bilateral salpingectomy 
• 
Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other 
than the above, (eg, mullerian agenesis, androgen insensitivity), Investigator 
discretion should be applied to determining study entry. 
Note: Documentation can come from the site personnel’s: review of the 
participant’s medical records, medical examination, or medical history interview. 
9. Postmenopausal female 
• 
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  
• 
A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not 
using hormonal contraception or hormonal replacement therapy (HRT). 
However, in the absence of 12 months of amenorrhea, confirmation with 
more than one FSH measurement is required.  
• 
Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-estrogen hormonal highly effective contraception methods 
if they wish to continue their HRT during the study. Otherwise, they must 


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discontinue HRT to allow confirmation of postmenopausal status before 
study enrolment. 
10.4.2. 
Contraception Guidance 
• 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
• 
Highly Effective Methodsb That Have Low User Dependency Failure rate of <1% per 
year when used consistently and correctly. 
• 
Implantable progestogen-only hormone contraception associated with inhibition of 
ovulationb 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) b 
• 
Bilateral tubal occlusion 
• 
Vasectomized partner 
Note: Vasectomized partner is a highly effective contraceptive method provided that 
the partner is the sole sexual partner of the woman of childbearing potential and the 
absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. Spermatogenesis cycle is approximately 90 days. 
• 
Highly Effective Methodsb That Are User Dependent Failure rate of <1% per year when 
used consistently and correctly. 
• 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationc 
• 
oral 
• 
intravaginal 
• 
transdermal 
• 
injectable 
• 
Progestogen-only hormone contraception associated with inhibition of ovulationc 
• 
oral 
• 
injectable 
• 
Sexual abstinence 
• 
Note: Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with 
the study intervention. The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the study and the preferred and usual lifestyle of the 
participant. 


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• 
ACCEPTABLE METHODSd 
• 
Progestogen-only oral hormonal contraception where inhibition of ovulation is not the 
primary mode of action 
• 
Male or female condom with or without spermicidee 
• 
Cervical cap, diaphragm, or sponge with spermicide 
• 
A combination of male condom with either cervical cap, diaphragm, or sponge with 
spermicide (double-barrier methods)c 
a. 
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies. 
b. 
Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those 
when used consistently and correctly. 
c. 
If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable 
contraceptive methods are limited to those which inhibit ovulation as the primary mode of action. 
d. 
Considered effective, but not highly effective - failure rate of ≥1% per year. Periodic abstinence (calendar, 
sympto-thermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational 
amenorrhoea method (LAM) are not acceptable methods of contraception.  
e. 
Male condom and female condom should not be used together (due to risk of failure with friction). 
10.4.3. 
Collection of Pregnancy Information: 
Female Participants who become pregnant 
• 
The Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study.  
• 
The initial information will be recorded on the appropriate form and submitted to 
GSK within 24 hours of learning of a participant's pregnancy.  
• 
Participant will be followed to determine the outcome of the pregnancy. The 
Investigator will collect follow up information on participant and neonate, which will 
be forwarded to GSK Generally, follow-up will not be required for longer than 6 to 
8 weeks beyond the estimated delivery date. 
• 
Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.  
• 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE.  
• 
A spontaneous abortion (occurring at < 22 weeks gestational age) or still birth 
(occurring at > 22 weeks gestational age) is always considered to be an SAE and will 
be reported as such. 
• 
Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study intervention by the Investigator, will be reported to 


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GSK as described in Appendix 3. While the Investigator is not obligated to actively 
seek this information in former study participants, he or she may learn of an SAE 
through spontaneous reporting.  
Any female participant who becomes pregnant while participating will discontinue study 
intervention or be withdrawn from the study. 


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10.5. 
Appendix 5: Medical Device Adverse Events (AEs), Adverse 
Device Effects (ADEs), Serious Adverse Events (SAEs) and 
Device Deficiencies: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
• 
The definitions and procedures detailed in this appendix are in accordance with 
ISO 14155.  
• 
Both the Investigator and the Sponsor will comply with all local medical device 
reporting requirements. 
• 
The detection and documentation procedures described in this protocol apply to all 
GSK medical devices provided for use in the study (see Section 6.1.1 for the list of 
GSK medical devices). 
10.5.1. 
Definition of AE and ADE 
AE and ADE Definition  
• 
An AE is defined as any untoward medical occurrence, unintended disease or 
injury, or untoward clinical signs (including abnormal laboratory finding) in study 
participants, users, or other persons, whether or not related to the investigational 
medical device. This definition includes events related to the investigational 
medical device or comparator and events related to the procedures involved except 
for events in users or other persons, which only include events related to 
investigational devices. 
• 
An adverse device effect (ADE) is defined as an adverse event related to the use of 
an investigational medical device. This definition includes any adverse events 
resulting from insufficient or inadequate instructions for use, deployment, 
implantation, installation, or operation, or any malfunction of the investigational 
medical device as well as any event resulting from use error or from intentional 
misuse of the investigational medical device. 
• 
A treatment emergent adverse effect (TEAE) is defined as, an AE with its onset 
date on or after treatment start date and on or before treatment stop date + 1 day. 
10.5.2. 
Definition of SAE, SADE and USADE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease). 
An SAE is an AE that: 
a. 
Led to death  
b. Led to serious deterioration in the health of the participant, that either resulted in: 
1. A life-threatening illness or injury. The term ‘life-threatening' in the definition 
of serious' refers to an event in which the participant was at risk of death at the 


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time of the event. It does not refer to an event, which hypothetically might have 
caused death, if it were more severe 
2. A permanent impairment of a body structure or a body function, 
3. Inpatient or prolonged hospitalization, planned hospitalization for a pre-existing 
condition, or a procedure required by the protocol, without serious deterioration 
in health, is not considered an SAE 
4. Medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function 
c. 
Led to fetal distress, fetal death or a congenital abnormality or birth defect 
SADE definition 
• 
A SADE is defined as an adverse device effect that has resulted in any of the 
consequences characteristic of a serious adverse event. 
USADE definition 
• 
A USADE is a serious adverse device effect which by its nature, incidence, 
severity or outcome has not been identified in the current version of the risk 
analysis report (see Section 2.3). 
 
10.5.3. 
Definition of Device Deficiency 
Device Deficiency definition 
• 
A device deficiency is an inadequacy of a medical device with respect to its 
identity, quality, durability, reliability, safety, or performance. Device deficiencies 
include malfunctions, use errors, and inadequate labeling. 
10.5.4. 
Recording and Follow-Up of AE and/or SAE and Device 
Deficiencies 
AE, SAE, and Device Deficiency Recording 
• 
When an AE/SAE/device deficiency occurs, it is the responsibility of the 
Investigator to review all documentation (eg, hospital progress notes, laboratory 
reports, and diagnostics reports) related to the event. 
• 
The Investigator will then record all relevant AE/SAE/device deficiency 
information in the participant’s medical records, in accordance with the 
Investigator’s normal clinical practice, and on the appropriate form of the CRF. 
• 
It is not acceptable for the Investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the AE/SAE/device deficiency 
CRF page. 


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• 
There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK. 
• 
The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE/SAE. 
• 
For device deficiencies, it is very important that the Investigator describes any 
corrective or remedial actions taken to prevent recurrence of the incident. 
• 
A remedial action is any action other than routine maintenance or servicing of a 
medical device where such action is necessary to prevent recurrence of a device 
deficiency. This includes any amendment to the device design to prevent 
recurrence. 
Assessment of Intensity 
• 
The Investigator will make an assessment of intensity for each AE/SAE/device 
deficiency reported during the study and assign it to one of the following 
categories:  
• 
Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities. 
• 
Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities. 
• 
Severe: An event that prevents normal everyday activities. An AE that is assessed 
as severe should not be confused with a SAE. Severe is a category utilized for 
rating the intensity of an event; and both AEs and SAEs can be assessed as severe. 
• 
An event is defined as ‘serious’ when it meets at least 1 of the predefined 
outcomes as described in the definition of an SAE, NOT when it is rated as severe. 
• 
Other measures to evaluate AEs and SAEs may be utilized (eg, National Cancer 
Institute Common Terminology Criteria for Adverse Events [NCI-CTCAE]). 
 
Assessment of Causality 
• 
The Investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE/device deficiency 
• 
A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out. 
• 
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• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• 
The Investigator will also consult the Product Information, in his/her assessment. 
• 
For each AE/SAE/device deficiency, the Investigator must document in the 
medical notes that he/she has reviewed the AE/SAE/device deficiency and has 
provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred and the Investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the Investigator always make an assessment of causality for every 
event before the initial transmission of the SAE data to GSK. 
• 
The Investigator may change his/her opinion of causality in light of follow-up 
information and send a SAE follow-up report with the updated causality 
assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-up of AE/SAE/device deficiency 
• 
The Investigator is obligated to perform or arrange for the conduct of 
supplemental measurements and/or evaluations as medically indicated or as 
requested by GSK to elucidate the nature and/or causality of the AE/SAE/device 
deficiency as fully as possible. This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health 
care professionals. 
• 
New or updated information will be recorded in the originally completed CRF. 
• 
The Investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information. 
10.5.5. 
Reporting of SAEs 
SAE Reporting to GSK via an Electronic Data Collection Tool 
• 
The primary mechanism for reporting an SAE to GSK will be the electronic data 
collection tool. 
• 
If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours. 
• 
The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• 
After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data. 


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• 
If a site receives a report of a new SAE from a study participant or receives 
updated data on a previously reported SAE after the electronic data collection tool 
has been taken off-line, then the site can report this information on a paper SAE 
form (see next section) or to the GSK medical monitor by telephone. 
• 
Contacts for SAE reporting can be found in Study Reference Manual. 
 
SAE Reporting to GSK via Paper CRF 
• 
Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the GSK medical monitor. 
• 
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by 
overnight mail or courier service. 
• 
Initial notification via telephone does not replace the need for the Investigator to 
complete and sign the SAE CRF pages within the designated reporting time 
frames. 
• 
Contacts for SAE reporting can be found in Study Reference Manual. 
10.5.6. 
Reporting of SADEs 
SADE Reporting to GSK  
NOTE: There are additional reporting obligations for medical device incidents that are 
potentially related to SAEs that must fulfil the legal responsibility to notify 
appropriate regulatory authorities and other entities about certain safety 
information relating to medical devices being used in clinical studies.  
• 
Any device deficiency that is associated with an SAE must be reported to GSK 
within 24 hours after the Investigator determines that the event meets the 
definition of a device deficiency. 
• 
GSK shall review all device deficiencies and determine and document in writing 
whether they could have led to an SAE. These shall be reported to the regulatory 
authorities and IRBs/IECs as required by national regulations. 
• 
Contacts for SAE reporting can be found in Study Reference Manual. 
 


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10.6. 
Appendix 6: COVID-19 Considerations 
10.6.1. 
Overall Rationale for This Appendix  
COVID-19 pandemic may impact the conduct of clinical studies. Challenges may arise 
from quarantines, site closures, travel limitations, interruptions to the supply chain for the 
investigational product or other considerations if site personnel or study participants 
become infected with COVID-19. These challenges may lead to difficulties in meeting 
protocol-specified procedures, including administering or using the investigational 
product or adhering to protocol-mandated visits and laboratory/diagnostic testing. 
This protocol appendix outlines measures that may be applicable for any site impacted by 
the COVID-19 pandemic. The purpose of the appendix is to provide information on the 
measures to be taken to protect participants’ safety, welfare and rights, and promote data 
integrity. 
These measures will remain in place until study completion. 
10.6.2. 
Study Procedures During Covid-19 Pandemic 
During the special circumstances caused by the current COVID-19 pandemic, you should 
consider specific public health guidance, the impact of any travel restrictions 
implemented by local/regional health authorities and local institutions, and individual 
benefit /risk when making enrolment and treatment decisions for trial participants. 
As outlined in Section 8, Protocol waivers or exemptions are not allowed and every effort 
should be made to adhere to protocol-specified assessments for participants on study 
intervention, including follow up however when not possible, for the duration of these 
special circumstances, the following measures may be implemented for enrolled 
participants. 
• 
Clinical investigators should document in site files and in participant notes as 
appropriate how restrictions related to COVID-19 led to the changes in study 
conduct and duration of those changes and indicate which trial participants are 
impacted and how those trial participants are impacted (as per the current local 
COVID-19 related regulatory guidance). 
• 
Missing protocol required data/visits due to COVID-19 should be noted in 
participant notes and recorded as a COVID-19 protocol deviation. 
Protocol Defined Procedures/Visits: 
• 
The protocol defined interval for the collection of samples during the follow-up visit 
(see Section 1.3: Schedule of Activities), may be extended up to a maximum length 
of 14 days.  
Data Management/Monitoring: 
• 
If a situation arises where on-site monitoring is no longer permitted, GSK will 
consider remote Source Data Verification/Source Document Review (SDV/SDR) 


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where permitted by the clinical site/institution. Remote SDV/SDR will be proposed 
to study sites to meet a participant and/or critical quality need, eg, to assess 
participant safety or to ensure data integrity. In case of remote SDV/SDR, GSK will 
work with the site to ensure participant privacy. 
• 
eCRF/CRF Final or Interim Sign off Process: The Principal Investigator (PI) is 
responsible for ensuring that the data within the eCRF casebook and any other data 
sources utilized during the study for each study participant is complete and 
consistent with source documents throughout the study (ICH GCP 4.9.1 and 4.9.2). 
The PI may sign/re-sign the eCRF from any computer/location by accessing InForm 
(or other eDC platform) using his/her unique eCRF log-in credentials. The PI may 
delegate this activity to another medically qualified and trained sub-investigator and 
this must be documented on the Delegation of Responsibilities (DoR) Log. It is 
recommended that the PI identifies a sub-investigator as a back-up for eCRF 
signatures. The sub-investigator must be appropriately trained on the protocol and 
eCRF requirements (with training documented), and the DoR log updated 
accordingly. 
• 
Essential Document Sign Off Process: If an Investigator is unable to print and sign 
essential documents such as Protocol /Amendment signature page, then Email 
approval can be accepted by replying to the relevant email that is sent by GSK. 


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10.7. 
Appendix 7: Abbreviations and Trademarks 
Abbreviation 
Definition 
ABRS 
Acute bacterial rhinosinusitis 
ADE 
Adverse Device Effects 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AMC 
Amoxicillin 
AOM 
Acute otitis media 
ARTI 
Acute respiratory tract infection 
AST 
Aspartate aminotransferase 
CABP 
Community acquired bacterial pneumonia 
CARTI 
Community acquired respiratory tract infections 
CIOMS 
Council for International Organizations of Medical Sciences 
CV 
Cardiovascular 
CVA 
Clavulanic acid 
eCRF 
Electronic case report form 
EOT 
End of Therapy 
ES 
Extra strength 
FU 
Follow up 
GCP 
Good Clinical Practice 
HCP 
Healthcare professional 
HRT 
Hormonal replacement therapy 
ICF 
Informed consent form 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 


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Abbreviation 
Definition 
MEE 
Middle ear effusion 
MIC 
Minimum inhibitory concentration 
OT 
On-therapy 
PD 
Pharmacodynamics 
PDD 
Protocol-defined diarrhea 
PI 
Principal Investigator 
PISP 
Penicillin‐intermediate resistant S. pneumoniae 
PK 
Pharmacokinetics 
PRSP 
Penicillin resistance S. pneumoniae 
SADE 
Serious adverse device effects 
SAE 
Serious adverse events 
SoA 
Schedule of Activities 
SUSAR 
Suspected unexpected serious adverse reactions 
TEAE 
Treatment-emergent adverse events 
TM 
Tympanic membrane 
Trademark Information 
Trademarks of the GlaxoSmithKline 
group of companies 
 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
None 
 
Chiron RIBA 
 
 
SAS 
 
 
WinNonlin 
 


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Piglansky L, Leibovitz E, Raiz S, et al. Bacteriologic and clinical efficacy of high dose 
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concentrations in plasma and middle ear fluid following administration of Augmentin 
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1997. 
SB Report No. BRL-25000/RSD-1009XZ/3/CPMS-447. A comparison of the safety and 
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Bevivino M. 9 October 1997 [Ref.NDA 50-755, vol. 6, pg. 000002, submitted October 
31, 1997. 
SB Report No. HH-1017/BRL-025000/2/CPMS-382. A parallel group study to estimate 
the steady-state pharmacokinetics of amoxicillin and clavulanic acid in pediatric patients 
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CONFIDENTIAL 
 
 
 
213514 
 
89 
 
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SAP_001.pdf: 
Statistical Analysis Plan 
Study ID: 213514 
Official Title of Study: A Multicentre, Open-label, Non-comparative Phase IV Clinical Study to 
Evaluate the Safety andClinical Efficacy of Augmentin Extra Strength (ES)-600 
(amoxicillin/potassium clavulanate 14:1 combination) in Children with Acute Respiratory Tract 
Infections (ARTIs) in India 
NCT Number-NCT04600752
Approval Date of Document: 18 Jul 2022 


 
Gla x o S mit h Kli ne
P har mace utic als Lt d.  
2 1 3 5 1 4  
St ati sti c al A n al y si s Pl a n  
P a g e 1 of 4 3  
 
D o c u m e nt:  
\\i e e d c- v n a s c 0 1\ BI O S d at a\ G S K\ B R L 2 5 0 0 0\ 
\ Bi o st ati sti c s\ D o c u m e nt ati o n\ S A P 
A ut h or: 
V er si o n N u m b er: 
V 1. 0  
 
V er si o n D at e:  
1 8 J U L 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6 
R ef er e n c e:  C S _ WI _ B S 0 0 5 
Eff e cti v e D at e: 0 2 D e c 2 0 1 9 
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
S T A TI S TI C A L A N A L Y SI S P L A N  
 
 
 
 
 
2 1 3 5 1 4 
A M ultice ntre, O pe n-la b el, N o n-c o m parati ve P hase I V Cli nical St u d y t o E v al uate t he S afet y a n d 
Cli nical Efficac y of A u g me nti n E xtra Stre n gt h ( E S)- 6 0 0 (a m o xicilli n/ p otassi u m cla v ula nate 1 4: 1 
c o m bi nati o n) i n C hil dre n wit h Ac ute Res pirat or y Tract I nfecti o ns ( A R TIs) i n I n dia 
 
 
 
A U T H O R :
V E R SI O N N U M B E R A N D D A T E : V 1. 0, 1 8 J U L 2 0 2 2  
 
 
 
P P D
P P D
P P D


 
Gla x o S mit h Kli ne
P har mace utic als Lt d.  
2 1 3 5 1 4  
St ati sti c al A n al y si s Pl a n  
P a g e 2 of 4 3  
 
D o c u m e nt:  
\\i e e d c- v n a s c 0 1\ BI O S d at a\ G S K\ B R L 2 5 0 0 0\ 
Bi o st ati sti c s\ D o c u m e nt ati o n\ S A P 
A ut h or: 
V er si o n N u m b er: 
V 1. 0  
 
V er si o n D at e:  
1 8 J U L 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6 
R ef er e n c e:  C S _ WI _ B S 0 0 5 
Eff e cti v e D at e: 0 2 D e c 2 0 1 9 
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
S T A TI S TI C A L A N A L Y SI S P L A N S I G N A T U R E P A G E  
Statistical A nal ysis Pla n v 1. 0 ( Date d 1 8J ul 2 0 2 2) f or Pr ot oc ol 2 1 3 5 1 4/ A me n d me nt 0 1.  
 
 
N a me 
Si g n at ure  
D ate ( D D M M Y Y Y Y) 
A ut h or: 
Refer t o e Si g nat ur e  
  
P ositi o n: 
Statistical Scie ntist 
  
C o m p a n y: 
I Q VI A, I n dia 
A ut h or: 
Refer t o e Si g n at ur e 
  
P ositi o n: 
Bi ostatisti cia n 1 
  
C o m p a n y: 
I Q VI A, I n dia 
A ut h or: 
Refer t o e Si g nat ur e 
  
P ositi o n: 
Bi ostatisti cia n 1 
  
C o m p a n y: 
I Q VI A, I n dia 
 
U p o n re vie w of t his d oc u me nt, t he u n dersi g ne d a p pr o ves t his versi o n of t he Statistical A nal ysis 
Pla n, a ut h orizi n g t hat t he c o nte nt is acce pta ble f or t he re p orti n g of t his st u d y. 
 
N a me 
Si g n at ure  
D ate ( D D M M Y Y Y Y) 
A p pr o ve d B y: 
 
  
P ositi o n: 
Ma na ger 
 Statistics 
  
C o m p a n y: 
Gla x o S mit h Kli ne P har mace utic als Lt d
 
A p pr o ve d B y: 
 
  
P ositi o n: 
Se ni or Ma na ger  Statistics 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


 
Gla x o S mit h Kli ne
P har mace utic als Lt d.  
2 1 3 5 1 4  
St ati sti c al A n al y si s Pl a n  
P a g e 3 of 4 3  
 
D o c u m e nt:  
\\i e e d c- v n a s c 0 1\ BI O S d at a\ G S K\ B R L 2 5 0 0 0\ 
\ Bi o st ati sti c s\ D o c u m e nt ati o n\ S A P 
A ut h or: 
V er si o n N u m b er: 
V 1. 0  
 
V er si o n D at e:  
1 8 J U L 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6 
R ef er e n c e:  C S _ WI _ B S 0 0 5 
Eff e cti v e D at e: 0 2 D e c 2 0 1 9 
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
  
C o m p a n y: 
Gla x o S mit h Kli ne P har mace uti cals Lt d 
P P D
P P D


 
Gla x o S mit h Kli ne
P har mace utic als Lt d.  
2 1 3 5 1 4  
St ati sti c al A n al y si s Pl a n  
P a g e 4 of 4 3  
 
D o c u m e nt:  
\\i e e d c- v n a s c 0 1\ BI O S d at a\ G S K\ B R L 2 5 0 0 0\ 
Bi o st ati sti c s\ D o c u m e nt ati o n\ S A P 
A ut h or: 
V er si o n N u m b er: 
V 1. 0  
 
V er si o n D at e:  
1 8 J U L 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6 
R ef er e n c e:  C S _ WI _ B S 0 0 5 
Eff e cti v e D at e: 0 2 D e c 2 0 1 9 
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
 M O DI FI C A TI O N H I S T O R Y 
 
U ni q u e 
I de ntifier 
f or t his 
Versi o n  
D ate of t he 
D oc u me nt 
Versi o n  
A ut h or  
Si g nific a nt C h a n g es fr o m  
Pre vi o us A ut h o rize d V ersi o n  
1. 0  
1 8J U L 2 0 2 2 
N ot A p plica ble 
 First V ersi o n
  
 
 
P P D
P P D
P P D


 
Gla x o S mit h Kli ne
P har mace utic als Lt d.  
2 1 3 5 1 4  
St ati sti c al A n al y si s Pl a n  
P a g e 5 of 4 3  
 
D o c u m e nt:  
\\i e e d c- v n a s c 0 1\ BI O S d at a\ G S K\ B R L 2 5 0 0 0\ 
Bi o st ati sti c s\ D o c u m e nt ati o n\ S A P 
A ut h or: 
V er si o n N u m b er: 
V 1. 0  
 
V er si o n D at e:  
1 8 J U L 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6 
R ef er e n c e:  C S _ WI _ B S 0 0 5 
Eff e cti v e D at e: 0 2 D e c 2 0 1 9 
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
A B B R E VI A TI O N S  
 
A E 
A d verse E v e nt 
A B R S 
Ac ute bacterial r hi n osi n usitis 
A L T 
Ala ni ne a mi n otra nsferase 
A M C 
A m o xicilli n 
A O M 
Ac ute otitis me dia 
A R TI 
Ac ute Res pirat or y Tract I nfecti o ns 
A S T 
As p artate a mi n otra nsferase 
A T C 
A nat o mi cal T hera pe utic Class 
C A B P 
C o m m u nit y- A c q uire d Bacterial P ne u m o nia 
CI 
C o nfi de nce I nter val 
C T M S 
Cli nical Trial Ma na ge me nt S yst e m 
C V A 
Cla v ula ni c aci d 
D M C 
Data M o nit ori n g C o m mittee  
E C G 
Electr ocar di o gra m 
E O T 
E n d of Treat me nt 
E N R 
E nr oll e d P o p ulati o n 
F U 
F oll o w U p 
E S 
E xtra Stre n gt h 
I T T 
I nte nt- T o- Treat 
M E d D R A 
Me dical Dicti o nar y f or R e g ul at or y A cti vities 
P P D
P P D


 
Gla x o S mit h Kli ne
P har mace utic als Lt d.  
2 1 3 5 1 4  
St ati sti c al A n al y si s Pl a n  
P a g e 6 of 4 3  
 
D o c u m e nt:  
\\i e e d c- v n a s c 0 1\ BI O S d at a\ G S K\ B R L 2 5 0 0 0\ 
Bi o st ati sti c s\ D o c u m e nt ati o n\ S A P 
A ut h or: 
V er si o n N u m b er: 
V 1. 0  
 
V er si o n D at e:  
1 8 J U L 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6 
R ef er e n c e:  C S _ WI _ B S 0 0 5 
Eff e cti v e D at e: 0 2 D e c 2 0 1 9 
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
O T 
O n T hera p y 
P T 
Preferre d ter m 
P D D 
Pr ot oc ol Defi n e d Diarr hea 
S A E 
Seri o us A d vers e E v e nt 
S A P 
St atistical A nal ysis Pla n 
S O C 
S yste m Or ga n Cl ass 
T E A E 
Treat m e nt E mer ge nt A d v erse E ve nt 
W H O 
W orl d Healt h Or ga niz ati o n 
W H O- D D 
W H O Dr u g Dicti o nar y 
 
 
 
P P D
P P D


 
Gla x o S mit h Kli ne
P har mace utic als Lt d.  
2 1 3 5 1 4  
St ati sti c al A n al y si s Pl a n  
P a g e 7 of 4 3  
 
D o c u m e nt:  
\\i e e d c- v n a s c 0 1\ BI O S d at a\ G S K\ B R L 2 5 0 0 0\ 
Bi o st ati sti c s\ D o c u m e nt ati o n\ S A P 
A ut h or: 
V er si o n N u m b er: 
V 1. 0  
 
V er si o n D at e:  
1 8 J U L 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6 
R ef er e n c e:  C S _ WI _ B S 0 0 5 
Eff e cti v e D at e: 0 2 D e c 2 0 1 9 
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
T A B L E O F C O N T E N T S  
1.  
I N T R O D U C TI O N............................................................................................................. 1 0  
2.  
S T U D Y O B J E C TI V E S, E N D P OI N T S A N D E S TI M A N D S ......................................... 1 0  
2. 1.  
P ri m ar y a n d Sec o n d a r y O bjecti v e ................................................................................................................ 1 0  
2. 2.  
Esti m a n ds ....................................................................................................................................................... 1 1  
3.  
S T U D Y D E SI G N ............................................................................................................... 1 4  
3. 1.  
Ge ner al Descri pti o n ....................................................................................................................................... 1 4  
3. 2.  
Sc he d ule of E ve nts ......................................................................................................................................... 1 6  
3. 3.  
C h a n g es t o A n al ysis fr o m Pr ot o c ol .............................................................................................................. 1 6  
4.  
P L A N N E D A N A L Y S E S ................................................................................................... 1 7  
4. 1.  
D at a M o nit o ri n g C o m mittee ( D M C) ............................................................................................................ 1 7  
4. 2.  
I nteri m A n al ysis ............................................................................................................................................. 1 7 
4. 3.  
Fi n al A n al ysis ................................................................................................................................................. 1 7  
5.  
A N A L Y SI S P O P U L A TI O N S .......................................................................................... 1 7  
5. 1.  
E nr olle d P o p ul ati o n [ E N R] ........................................................................................................................... 1 7  
5. 2.  
I nte nt T o Tre at P o p ul ati o n (I T T) ................................................................................................................. 1 7 
6.  
G E N E R A L C O N SI D E R A TI O N S ................................................................................... 1 8  
6. 1.  
Refere nce St a rt D ate a n d St u d y D a y ........................................................................................................... 1 8  
6. 2.  
B aseli ne ........................................................................................................................................................... 1 8  
6. 3.  
C o m p ut ati o n of A g e ....................................................................................................................................... 1 8  
6. 4.  
A n al ysis P eri o d .............................................................................................................................................. 1 9  
P P D
P P D


 
Gla x o S mit h Kli ne
P har mace utic als Lt d.  
2 1 3 5 1 4  
St ati sti c al A n al y si s Pl a n  
P a g e 8 of 4 3  
 
D o c u m e nt:  
\\i e e d c- v n a s c 0 1\ BI O S d at a\ G S K\ B R L 2 5 0 0 0\ 
\ Bi o st ati sti c s\ D o c u m e nt ati o n\ S A P 
A ut h or: 
V er si o n N u m b er: 
V 1. 0  
 
V er si o n D at e:  
1 8 J U L 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6 
R ef er e n c e:  C S _ WI _ B S 0 0 5 
Eff e cti v e D at e: 0 2 D e c 2 0 1 9 
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
6. 5.  
Retests, U nsc he d ule d Visits a n d E arl y Ter mi n ati o n D at a ......................................................................... 2 1  
6. 6.  
Wi n d o wi n g C o n ve nti o ns ............................................................................................................................... 2 1  
6. 7.  
St atistic al Tests .............................................................................................................................................. 2 2  
6. 8.  
S a m ple Size Esti m ati o n ................................................................................................................................. 2 2  
6. 9.  
S oft w a re Versi o n ............................................................................................................................................ 2 3  
7.  
S T A TI S TI C A L C O N SI D E R A TI O N S ............................................................................ 2 3  
7. 1.  
A dj ust me nts f or C o v a ri ates a n d F a ct o rs t o be I ncl u de d i n A n al yses ....................................................... 2 3  
7. 2.  
M ultice nter St u dies ........................................................................................................................................ 2 3  
7. 3.  
Missi n g d at a ................................................................................................................................................... 2 3  
7. 4.  
M ulti ple C o m p a ris o ns/ M ulti plicit y ............................................................................................................. 2 3  
8.  
O U T P U T P R E S E N T A TI O N S ......................................................................................... 2 4  
9.  
DI S P O SI TI O N A N D WI T H D R A W A L S ........................................................................ 2 4  
9. 1.  
Dis p ositi o n ...................................................................................................................................................... 2 4  
9. 2.  
P r ot o c ol De vi ati o ns ........................................................................................................................................ 2 5  
1 0.  
D E M O G R A P HI C A N D O T H E R B A S E LI N E C H A R A C T E RI S TI C S ....................... 2 5  
1 1.  
S U R GI C A L A N D M E DI C A L HI S T O R Y ...................................................................... 2 6  
1 2.  
C O N C O MI T A N T M E DI C A TI O N S ............................................................................... 2 7  
1 3.  
S T U D Y M E DI C A TI O N E X P O S U R E ............................................................................ 2 7  
1 3. 1.  
Deri v ati o ns ................................................................................................................................................. 2 8  
1 4.  
S T U D Y M E DI C A TI O N C O M P LI A N C E ...................................................................... 2 8  
1 4. 1.  
Deri v ati o ns ................................................................................................................................................. 2 8  
1 5.  
E F FI C A C Y E N D P OI N T S................................................................................................ 2 8  
1 5. 1.  
Sec o n d a r y Effic ac y E n d p oi nt S ................................................................................................................. 2 8  
P P D
P P D


 
Gla x o S mit h Kli ne
P har mace utic als Lt d.  
2 1 3 5 1 4  
St ati sti c al A n al y si s Pl a n  
P a g e 9 of 4 3  
 
D o c u m e nt:  
\\i e e d c- v n a s c 0 1\ BI O S d at a\ G S K\ B R L 2 5 0 0 0\ 
\ Bi o st ati sti c s\ D o c u m e nt ati o n\ S A P 
A ut h or: 
V er si o n N u m b er: 
V 1. 0  
 
V er si o n D at e:  
1 8 J U L 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6 
R ef er e n c e:  C S _ WI _ B S 0 0 5 
Eff e cti v e D at e: 0 2 D e c 2 0 1 9 
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
1 5. 1. 1.  
A nal ysis of Sec o n dar y E n d p oi nt .............................................................................................................. 3 1  
1 5. 1. 1. 1.  
Cli nical Res p o nse ............................................................................................................................ 3 1  
1 5. 1. 1. 2.  
I nci d e nce of  pr ot oc ol- defi ne d diarr h oea  ( P D D)............................................................................ 3 1 
1 5. 1. 1. 3.  
P atie nt diar y e n d p oi nts ..................................................................................................................... 3 2  
1 6.  
S A F E T Y E N D P OI N T S .................................................................................................... 3 2  
1 6. 1.  
A d v erse E v e nts ........................................................................................................................................... 3 2  
1 6. 1. 1.  
T E A Es: Pri mar y Safet y E n d p oi nt ............................................................................................................ 3 3  
1 6. 1. 1. 1.  
Se verit y ............................................................................................................................................ 3 4  
1 6. 1. 1. 2.  
Relati o ns hi p t o St u d y M e dicati o n .................................................................................................... 3 4  
1 6. 1. 2.  
T E A Es Lea di n g t o P er ma ne nt Disc o nti n uati o n of St u d y Me dicati o n or Wit h dra wal St u d y .................... 3 4  
1 6. 1. 3.  
Seri o us A d verse E ve nts ........................................................................................................................... 3 5  
1 6. 1. 4.  
A d verse E ve nts Lea di n g t o De at h............................................................................................................ 3 5  
1 6. 1. 5.  
. Car di o vasc ular E ve nts ........................................................................................................................... 3 5 
1 6. 2.  
De at hs ......................................................................................................................................................... 3 6  
1 6. 3.  
L a b o r at o r y E v al u ati o ns ............................................................................................................................ 3 6  
1 6. 4.  
E C G E v al u ati o ns ....................................................................................................................................... 3 7  
1 6. 5.  
Vit al Si g ns ................................................................................................................................................... 3 7  
1 6. 6.  
Ot her S afet y Assess me nts ......................................................................................................................... 3 7  
1 7.  
D A T A N O T S U M M A RI Z E D O R P R E S E N T E D .......................................................... 3 8  
1 8.  
R E F E R E N C E S .................................................................................................................. 3 8  
A P P E N DI X 1.  P R O G R A M MI N G C O N V E N TI O N S F O R O U T P U T S .............................. 3 9  
I Q VI A O ut p ut C o n v e nti o ns...................................................................................................................................... 3 9 
D ates & Ti mes ............................................................................................................................................................ 3 9  
S pelli n g F or m at.......................................................................................................................................................... 3 9  
P rese nt ati o n of Tre at me nt Gr o u ps .......................................................................................................................... 3 9  
A P P E N DI X 2.  P A R TI A L D A T E C O N V E N TI O N S ............................................................. 4 1  
A P P E N DI X 3.  S A S C O D E F O R A N A L Y S E S....................................................................... 4 2  
A P P E N DI X 4.  M A XI M U M R E C O M M E N D E D D O S E B Y B O D Y W EI G H T ................. 4 3  
 
 
P P D
P P D


 
Gla x o S mit h Kli ne
P har mace utic als Lt d.  
2 1 3 5 1 4  
St ati sti c al A n al y si s Pl a n  
P a g e 1 0 of 4 3  
 
D o c u m e nt:  
\\i e e d c- v n a s c 0 1\ BI O S d at a\ G S K\ B R L 2 5 0 0 0 
\ Bi o st ati sti c s\ D o c u m e nt ati o n\ S A P 
A ut h or: 
V er si o n N u m b er: 
V 1. 0  
 
V er si o n D at e:  
1 8 J U L 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6 
R ef er e n c e:  C S _ WI _ B S 0 0 5 
Eff e cti v e D at e: 0 2 D e c 2 0 1 9 
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
1.  IN T R O D U C TI O N  
T his d oc u me nt descri b es t h e r ules a n d c o n v e nti o ns t o be use d i n t he prese ntati o n a n d a nal ysis of 
safet y a n d cli nical effi cac y d ata f or Pr ot o c ol 2 1 3 5 1 4. It des cri bes t he data t o be s u m m ariz e d a n d 
a nal yze d, i n cl u di n g s pecifics of t he statisti cal a nal ys es t o be p erf or me d.  
T his statistical a nal ysis pla n ( S A P) is bas e d o n pr ot oc ol versi o n 1. 0 a me n d me nt 0 1 date d 
1 9 Ma y 2 0 2 1. 
2.  S T U D Y O B J E C TI V E S , E N D P OI N T S A N D E S TI M A N D S  
2. 1.  P RI M A R Y A N D S E C O N D A R Y O B J E C TI V E  
Ta ble 1 
O bjecti v es 
E n d p oi nts 
Pri mar y 
Pri mar y 
 T he pri mar y o bjecti ve of t h e st u d y is 
t o assess treat m e nt-e mer ge nt a d vers e 
e ve nts ( T E A Es) i n c hil dre n recei vi n g 
A u g me nti n ( E S)- 6 0 0 ( A M C/ C V A 
1 4: 1) at 9 0/ 6. 4 m g/ k g/ da y i n t w o 
di vi d e d d oses, a d mi nistere d f or 1 0 
da ys i n A R TIs( A O M, A B R S or 
C A B P). 
 Safet y will be e val uate d b y ass essi n g 
t he i nci de nces of treat me nt e mer ge nt 
a d verse e ve nts ( T E A E). 
Sec o n dar y  
Sec o n d ar y 
 T he sec o n d ar y o bjecti ve of t he st u d y 
is t o assess cli nical efficac y a n d 
i nci de nce of pr ot oc ol defi ne d 
diarr h oea ( P D D) i n c hil dre n recei vi n g 
A u g me nti n ( E S)- 6 0 0 A M C/ C V A 1 4: 1 
at 9 0/ 6. 4 m g/ k g/ da y i n t w o di vi de d 
d oses a d mi nistere d f or 1 0 da ys i n 
A R TIs ( A O M, A B R S or C A B P). 
 Efficac y assess me nt will be base d o n:  
1.  Earl y cli nical res p o nse at t he o n-
t hera p y visit ( Da y 3 t o 5), defi ne d i n 
i nter ve nti o n.  
2.  Pri mar y cli nical res p o nse at t he e n d-
of-t h era p y visit ( Da y 1 2 t o 1 4), 
P P D
P P D


 
Gla x o S mit h Kli ne
P har mace utic als Lt d.  
2 1 3 5 1 4  
St ati sti c al A n al y si s Pl a n  
P a g e 1 1 of 4 3  
 
D o c u m e nt:  
\\i e e d c- v n a s c 0 1\ BI O S d at a\ G S K\ B R L 2 5 0 0 0 
\ Bi o st ati sti c s\ D o c u m e nt ati o n\ S A P 
A ut h or: 
V er si o n N u m b er: 
V 1. 0  
 
V er si o n D at e:  
1 8 J U L 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6 
R ef er e n c e:  C S _ WI _ B S 0 0 5 
Eff e cti v e D at e: 0 2 D e c 2 0 1 9 
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
 
3.  Sec o n dar y cli nic al res p o nse at f oll o w-
u p ( da y 2 2 t o 2 8) i.e.
 
 I n ci de nce of pr ot oc ol- defi ne d diarr hea 
( P D D) i n c hil dre n recei vi n g 
A u g me nti n ( E S)- 6 0 0 ( A M C/ C V A 
1 4: 1) at 9 0/ 6. 4 m g/ k g/ da y i n t w o 
di vi d e d d oses a d mi nistere d f or 1 0 
da ys i n A R TIs ( A O M, A B R S or 
C A B P). 
2. 2.  E S TI M A N D S  
T he pri mar y, a n d s ec o n d ar y esti ma n ds t o s u p p ort re g ulat or y decisi o ns are descri be d i n  
f oll o wi n g ta ble: 
Pri mar y Esti ma n d: - 
T he pri mar y cli nical q uesti o n of i nterest is: 
T o assess treat me nt-e mer ge nt a d vers e e ve nts ( T E A Es) i n c hil dre n recei vi n g A u g me nti n ( E S)-
6 0 0 ( A M C/ C V A 1 4: 1) at 9 0/ 6. 4 m g/ k g/ d a y i n t w o di vi de d d oses, a d mi nist ere d f or 1 0 da ys i n 
A R TIs ( A O M, A B R S or C A B P). 
T he pri mar y esti ma n d is descri b e d b y t he f oll o wi n g attri b utes: 
 P o p ulati o n: 
C hil dre n wit h ac ute res pirat or y tract i nfecti o ns ( A R TIs) i n I n di a bet w ee n 6 m o nt hs t o 
1 2 years of eit her ge n d er 
 Treat m e nt c o n diti o ns:  
A u g me nti n ( E S)- 6 0 0 wit h d ose le vel 9 0/ 6. 4 m g/ k g/ d a y t wice dail y ( 1 2 h o url y) f or 1 0 
da ys. 
 Vari a bles/ E n d p oi nts:  
Treat m e nt e mer ge nt a d v erse e ve nts ( T E A Es), Seri o us treat me nt e mer ge nt a d verse 
e ve nts ( T E S A Es). 
 S u m mar y meas ure:  
P P D
P P D


 
Gla x o S mit h Kli ne
P har mace utic als Lt d.  
2 1 3 5 1 4  
St ati sti c al A n al y si s Pl a n  
P a g e 1 2 of 4 3  
 
D o c u m e nt:  
\\i e e d c- v n a s c 0 1\ BI O S d at a\ G S K\ B R L 2 5 0 0 0\ 
\ Bi o st ati sti c s\ D o c u m e nt ati o n\ S A P 
A ut h or: 
V er si o n N u m b er: 
V 1. 0  
 
V er si o n D at e:  
1 8 J U L 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6 
R ef er e n c e:  C S _ WI _ B S 0 0 5 
Eff e cti v e D at e: 0 2 D e c 2 0 1 9 
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
      C o u nts a n d perce nta ges f or i nci de nce of T E A Es a n d T E S A Es, 9 5 % CI f or s u bjects 
w h o ha ve at le ast o ne or A n y T E A E.   
 I nterc urre nt e v e nts (I C Es): 
Disc o nti n uati o n of st u d y treat m e nt d ue t o a n y reas o n 
 W hile- o n-treat me nt strate g y 
f or T E A Es a n d T E S A Es.  
Rati o nale f or Esti ma n d: 
T he rati o nale of t he w hile- o n-treat m e nt strate g y is t o esti mate t h e occ urre nce of T E A Es a n d 
T E S A Es  w he n s u bjects ha ve ta ke n t h e d ose/treat m e nt c o n diti o n. 
Treat m e nt P olic y will be use d f or p ost-treat m e nt A Es, Pre- a n d P ost- treat m e nt S A Es. 
T he reas o ni n g of treat me nt p oli c y (as c oll ecte d) is t o esti mate t he o cc urre nce of p ost-treat me nt 
A Es, a n d pre- a n d p ost-treat me nt S A Es u ntil s u bjects are o n st u d y will be c oll ecte d a n d re p orte d. 
N o i nterc urre nt e ve nt is defi n e d f or ot h er s afet y e n d p oi nts. T he data will be a nal yze d as c oll ecte d.  
Sec o n dar y Esti ma n ds :- 
T he sec o n d ar y cli nical q uesti o ns of i nterest are: 
T o assess E arl y a n d Pri mar y res p o nses i n c hil dre n recei vi n g A u g m e nti n ( E S)- 6 0 0 ( A M C/ C V A 
1 4: 1) at 9 0/ 6. 4 m g/ k g/ da y i n t w o di vi de d d oses a d mi nistere d f or 1 0 d a ys i n A R TIs ( A O M, A B R S 
or C A B P). 
T he sec o n d ar y esti ma n ds are des cri b e d b y t he f oll o wi n g attri b utes: 
1.  Earl y cli nical res p o nse at o n-t hera p y [( O T) ( Da y 3 t o 5)] 
 
 P o p ulati o n: 
C hil dre n wit h ac ute res pirat or y tract i nfecti o ns ( A R TIs) i n I n di a bet w ee n 6 m o nt hs t o 
1 2 years of eit her ge n d er. 
 Treat m e nt c o n diti o ns:  
A u g me nti n ( E S)- 6 0 0 wit h d ose le vel 9 0/ 6. 4 m g/ k g/ d a y t wice dail y ( 1 2 h o url y) f or 1 0 
da ys. 
 Vari a ble/ E n d p oi nt:  
Pr o p orti o n of s uccessf ul earl y cli nical res p o nse at o n-t hera p y ( O T) visit. 
 S u m mar y meas ure:  
C o u nts a n d perce nta ges f or earl y cli nical res p o nse at o n-t hera p y ( O T) visit wit h 
c orres p o n di n g 9 5 % CI.  
 I nterc urre nt e v e nts (I C Es): 
P P D
P P D


 
Gla x o S mit h Kli ne
P har mace utic als Lt d.  
2 1 3 5 1 4  
St ati sti c al A n al y si s Pl a n  
P a g e 1 3 of 4 3  
 
D o c u m e nt:  
\\i e e d c- v n a s c 0 1\ BI O S d at a\ G S K\ B R L 2 5 0 0 0\ 
\ Bi o st ati sti c s\ D o c u m e nt ati o n\ S A P 
A ut h or: 
V er si o n N u m b er: 
V 1. 0  
 
V er si o n D at e:  
1 8 J U L 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6 
R ef er e n c e:  C S _ WI _ B S 0 0 5 
Eff e cti v e D at e: 0 2 D e c 2 0 1 9 
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
- Disc o nti n uati o n of st u d y treat me nt d ue t o A E, disc o nti n uati o n of st u d y treat me nt d ue t o 
lac k of efficac y a n d us e of resc u e me dicati o n - C o m p osite strate g y  
 
If s u bject disc o nti n ue d u e t o a b o ve me nti o ne d I C Es, t he n earl y res p o nse f or t hat s u bj ect 
will b e i m p ute d as a fail ure.   
 
- Disc o nti n uati o n of st u d y treat me nt d ue t o a n y ot her reas o n  Treat m e nt P oli c y  
 
Rati o nale f or esti ma n d: 
Disc o nti n uati o n of st u d y tr eat me nt d ue t o A E, disc o nti n uati o n of st u d y treat m e nt d ue t o lac k of  
effic ac y a n d use of res c u e me dicati o n will affect t he earl y cli nic al res p o ns e t h us t he earl y cli nical 
res p o nse will be c o u nte d as fail ure u n d er c o m p osit e strate g y. 
T he reas o ni n g of tr eat me nt p olic y is t o esti mate t he earl y cli nical res p o ns e u ntil s u bjects are o n 
st u d y will be c ollect e d a n d re p orte d (re gar dless of t h e i nterc urre nt e ve nt o cc urri n g). 
2.  Pri mar y cli nical res p o nse at e n d of t hera p y [ E O T ( Da y 1 2 t o 1 4)]  
 
 P o p ulati o n: 
C hil dre n wit h ac ute res pirat or y tract i nfecti o ns ( A R TIs) i n I n di a bet wee n 6 m o nt hs t o 
1 2 years of eit her ge n d er. 
 Treat m e nt c o n diti o ns:  
A u g me nti n ( E S)- 6 0 0 wit h d ose le vel 9 0/ 6. 4 m g/ k g/ d a y t wice dail y ( 1 2 h o url y) f or 1 0 
da ys. 
 Vari a ble/ E n d p oi nt:  
Pr o p orti o n of s uccessf ul pri mar y cli nical res p o nse at e n d of t h era p y ( E O T) visit. 
 S u m mar y meas ure:  
C o u nts a n d perce nta ges f or pri mar y cli nical res p o nse at e n d of t h era p y ( E O T) visit 
wit h c orres p o n di n g 9 5 % CI.  
 I nterc urre nt e v e nts (I C Es): 
- Lac k of c o m plia nce ( < 8 0 %) - Pri nci p al strat u m  
O nl y t h ose s u bjects w h o ha ve at le ast 
 8 0 % c o m pli a nce w o ul d be c o nsi dere d i n t he 
calc ulati o n f or pr o p orti o n of pri mar y cli nical res p o nse  
- Disc o nti n uati o n of st u d y treat me nt d ue t o A E, disc o nti n uati o n of st u d y treat me nt d ue t o 
lac k of efficac y a n d us e of resc u e m e dicati o n - C o m p osite strate g y  
 
P P D
P P D


 
Gla x o S mit h Kli ne
P har mace utic als Lt d.  
2 1 3 5 1 4  
St ati sti c al A n al y si s Pl a n  
P a g e 1 4 of 4 3  
 
D o c u m e nt:  
\\i e e d c- v n a s c 0 1\ BI O S d at a\ G S K\ B R L 2 5 0 0 0 
\ Bi o st ati sti c s\ D o c u m e nt ati o n\ S A P 
A ut h or: 
V er si o n N u m b er: 
V 1. 0  
 
V er si o n D at e:  
1 8 J U L 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6 
R ef er e n c e:  C S _ WI _ B S 0 0 5 
Eff e cti v e D at e: 0 2 D e c 2 0 1 9 
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
If s u bject disc o nti n ue d u e t o a b o ve me nti o ne d t hree I C Es, t he n pri m ar y cli nical res p o nse 
f or t h at s u bject will be i m p ute d as a f ail ure.   
 
- Disc o nti n uati o n of st u d y treat m e nt d ue t o a n y ot her reas o n  Treat m e nt P oli c y  
 
Rati o nale f or esti ma n d: 
Lac k of c o m plia n ce ( < 8 0 %) will i m pact o n pri mar y cli nical res p o nse t h eref ore s u bjects w h o h a ve 
at least ( ) 8 0 % w o ul d be c o nsi d ere d f or pri mar y cli nical res p o ns e u n der pri nci p al strat u m 
strate g y.  
Disc o nti n uati o n of st u d y tr eat me nt d ue t o A E, disc o nti n uati o n of st u d y treat m e nt d ue t o lac k of  
effic ac y a n d use of resc u e m e dicati o n will affect t h e pri m ar y cli nical res p o nse t h us t he pri mar y 
cli nical res p o nse will be c o u nte d as fail ure u n der c o m p osite strate g y. 
T he reas o ni n g of treat m e nt p olic y is t o esti mate t he pri mar y cli nical res p o nse u ntil s u bjects are o n 
st u d y will be c ollect e d a n d re p orte d (re gar dless of t h e i nterc urre nt e ve nt o cc urri n g). 
N o i nterc urre nt e v e nt is d efi n e d f or sec o n d ar y cli nical res p o ns e e n d p oi nt as n o e ve nts are e x pecte d 
t o occ ur d uri n g t h e f oll o w- u p peri o d. T h e data will be a nal yze d as c ollect e d. 
N o i nterc urre nt e ve nt is defi n e d f or Pr ot oc ol- d efi ne d diarr h oea ( P D D) e n d p oi nt. T he data will be 
a nal yze d as c ollect e d.  
3.  S T U D Y D E SI G N  
3. 1.  G E N E R A L D E S C RI P TI O N  
T his st u d y is a n o pe n la bel, m ulti-ce ntre, n o n-c o m parati v e st u d y. S u bjects will be c hil dre n a ge d 
bet wee n 6 m o nt hs t o 1 2 years, prese nti n g wit h A R TIs i ncl u di n g A O M, A B R S a n d C A B P. 
 
At Preli mi nar y Visit ( Da y 0) after si g ni n g t he i nf or m c o nse nt f or m b y t h e pare nt/ g uar dia n a n d 
asse nt f or m b y c hil dre n bet wee n 7 t o 1 2 years of a ge, a s eries of scree ni n g e val u ati o ns will be 
perf or me d i n or der t o deter mi ne w het her pr os p ecti ve st u d y p artici pa nt me ets t he i ncl usi o n criteria. 
E nr olle d a n d s cree n p ass e d s u bjects will recei ve A u g me nti n ( E S)- 6 0 0 at 9 0/ 6. 4 m g/ k g/ d a y 
a d mi nistere d i n t w o di vi de d d oses, e ver y 1 2 h o urs wit h f o o d f or 1 0 da ys. 
T he i nci d e nce of pr ot oc ol- defi ne d di arr h o ea will be deter mi ne d fr o m i nf or mati o n c oll ecte d fr o m 
t he Patie nt Diar y car ds, w hic h will be a p pr o priatel y tra nslate d f or all la n g u a ges re q uire d bas e d o n 
sites parti ci pati n g i n t he trial.  
 
P P D
P P D


 
Gla x o S mit h Kli ne
P har mace utic als Lt d.  
2 1 3 5 1 4  
St ati sti c al A n al y si s Pl a n  
P a g e 1 5 of 4 3  
 
D o c u m e nt:  
\\i e e d c- v n a s c 0 1\ BI O S d at a\ G S K\ B R L 2 5 0 0 0\ 
\ Bi o st ati sti c s\ D o c u m e nt ati o n\ S A P 
A ut h or: 
V er si o n N u m b er: 
V 1. 0  
 
V er si o n D at e:  
1 8 J U L 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6 
R ef er e n c e:  C S _ WI _ B S 0 0 5 
Eff e cti v e D at e: 0 2 D e c 2 0 1 9 
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
After a mi ni m u m 
-
e n d p oi nt). Safet y para meter i ncl u des treat me nt e mer ge nt a d v erse e ve nts ( T E A Es) f or pri m ar y 
st u d y o bj ecti ve. A d diti o nall y, cli nic al stat us, st u d y i nter ve nti o n c o m plia nce, c o m pleti o n of Pati e nt 
Diar y car ds, a n d c o nc o mita nt me di cati o ns use will als o be assesse d. T he I n vesti gat or will assess 
safet y p ara met ers a n d cli nical st at us w hereas st u d y c o or di nat or will c hec k ot her para meters wit h 
c o or di n ate d eff ort. 
 
S u bjects 
 5), will 
be wit h dra w n fr o m t he st u d y i nter ve nti o n (as per I n vesti gat or discreti o n) a n d treate d a p pr o priatel y. 
I n s uc h case, t h e O T visit will be c o nsi dere d as E n d of T hera p y ( E O T), a n d all e val uati o ns t hat are 
pla n ne d at sc he d ul e d E O T ( Da y 1 2 t o 1 4) will be c o m plete d i n t his visit. H o we ver, t h ese S u bjects 
will ret ur n at F U visit ( D a y 2 2 t o 2 8) f or safet y assess me nt. 
 
S u bjects 
pri or t o E O T, will be sc he d ule d t o ret ur n t o t he site f or a n i nteri m e val u ati o n, wit hi n 2 4 h o urs of 
n otificati o n t o t he I n vesti gat or. S u bjects will t h e n be wit h dra w n fr o m t he st u d y i nter ve nti o n (as 
per I n vesti gat or discreti o n) a n d treate d a p pr o pri atel y. I n s uc h case, t he i nteri m visit will be 
c o nsi dere d as E O T visit, a n d all e val uati o ns t hat are pla n ne d at sc he d ule d E O T ( Da y 1 2 t o 1 4) will 
be c o m plete d i n t his visit. H o w e ver, t hes e S u bjects will ret ur n at F U visit ( D a y 2 2 t o 2 8) f or s afet y 
assess me nt. 
T he S u bjects 
( E O T) 
e val uati o n bet w ee n Da y 1 2 a n d 1 4. T he I n vesti gat or will e n q uire t he p arti ci pa nt or p are nt/le gal 
g uar dia n a b o ut de vel o p me nt of A Es a n d use of c o nc o mita nt me dicati o n(s). 
 
T he I n vesti gat or will perf or m safet y ( pri mar y e n d p oi nt) a n d pri mar y cli nic al res p o nse (sec o n dar y 
e n d p oi nt) e val uati o n. Patie nt Diar y car ds a n d u n us e d me dicati o n will b e ret ur ne d at t his visit. 
 
S u bjects w h o e x perie nce rec urre n ce of si g ns/s y m pt o ms after E O T visit ( Da y 1 2 t o 1 4), b ut pri or 
t o sc he d ule d F U visit ( Da y 2 2 t o 2 8) will be re q uire d t o visit t he st u d y site t wice p ost E O T - o n ce 
f or t he i nteri m visit at t he ti me of a n y r ec urre nce ( Da y 1 5 t o 2 1) a n d f or t he sc he d ule d F U visit 
( Da y 2 2 t o 2 8). At t h e i nt eri m visit, all t he e val uati o ns 
w hic h are t o be p erf or me d at sc h e d ule d F U visit will be c o n d ucte d. H o we ver, i n s uc h cases, all 
e val uati o ns e x ce pt sec o n dar y cli nical res p o nse will be re p eate d at sc h e d ule d F U visit ( Da y 2 2 t o 
2 8). All S u bjects e x perie nci n g r ec urre nce p ost E O T will be treate d 
discreti o n. 
 
P P D
P P D


 
Gla x o S mit h Kli ne
P har mace utic als Lt d.  
2 1 3 5 1 4  
St ati sti c al A n al y si s Pl a n  
P a g e 1 6 of 4 3  
 
D o c u m e nt:  
\\i e e d c- v n a s c 0 1\ BI O S d at a\ G S K\ B R L 2 5 0 0 0\ 
\ Bi o st ati sti c s\ D o c u m e nt ati o n\ S A P 
A ut h or: 
V er si o n N u m b er: 
V 1. 0  
 
V er si o n D at e:  
1 8 J U L 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6 
R ef er e n c e:  C S _ WI _ B S 0 0 5 
Eff e cti v e D at e: 0 2 D e c 2 0 1 9 
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
All S u bjects, i n cl u di n g wit h dra wals 
E O T or h a d dise ase rec urre n ce aft er 
E O T, will ret ur n f or s c he d ule d F U visit o n D a y 2 2 t o 2 8. T his visit is re q uire d f or safet y assess me nt 
a n d a d mi nistrati o n of a d diti o nal me dicati o n, if warra nt e d. 
 
T he S u bjects c o nti n ui n g 
-
) visit bet w ee n 
I n vesti gat or will p erf or m 
fi nal safet y ( pri mar y e n d p oi nt) a n d sec o n d ar y cli nical res p o ns e (sec o n dar y e n d p oi nt) e v al uati o n 
(e xce pt f or rec urre nce) d uri n g t he visit. 
 
I n ge neral, F U visit at D a y 2 2 t o 2 8 i ncl u des b ot h safet y a n d effi cac y assess me nt f or S u bjects w h o 
 S u bjects w h o were cli nical 
 T hese S u bjects are, b y defi niti o n, cli nical 
fail ures at f oll o w- u p visit. 
 
Ta ble 2:  St u d y Fl o w C hart 
 
 
3. 2.  S C H E D U L E O F E V E N T S  
Sc he d ule of e v e nts ca n b e f o u n d i n S ecti o n 1. 3 of t he pr ot oc ol. 
3. 3.  C H A N G E S T O A N A L Y SI S F R O M P R O T O C O L  
T here is n o c ha n ge i n a n al ysis fr o m pr ot oc ol. 
P P D
P P D


 
Gla x o S mit h Kli ne
P har mace utic als Lt d.  
2 1 3 5 1 4  
St ati sti c al A n al y si s Pl a n  
P a g e 1 7 of 4 3  
 
D o c u m e nt:  
\\i e e d c- v n a s c 0 1\ BI O S d at a\ G S K\ B R L 2 5 0 0 0 
\ Bi o st ati sti c s\ D o c u m e nt ati o n\ S A P 
A ut h or: 
V er si o n N u m b er: 
V 1. 0  
 
V er si o n D at e:  
1 8 J U L 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6 
R ef er e n c e:  C S _ WI _ B S 0 0 5 
Eff e cti v e D at e: 0 2 D e c 2 0 1 9 
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
4.  P L A N N E D A N A L Y S E S  
4. 1.  D A T A M O NI T O RI N G C O M MI T T E E ( D M C)  
T here will be n o D M C f or t his st u d y. 
4. 2.  IN T E RI M A N A L Y SI S  
T here will be n o I nt eri m a nal ysis f or t his st u d y. 
4. 3.  F I N A L A N A L Y SI S  
All a nal ys es i d e ntifie d i n t his S A P will be perf or me d b y I Q VI A Bi ost atistics f oll o wi n g S p o ns or 
A ut h orizati o n of t his Statistic al A nal ysis Pla n a n d D ata base L oc k. 
5.  A N A L Y SI S P O P U L A TI O N S  
T he f oll o wi n g a nal ysis p o p ulati o n will be defi ne d f or t his st u d y:  
5. 1.  E N R O L L E D P O P U L A TI O N [ E N R] 
T he all s u bjects e nr olle d ( E N R) p o p ulati o n will c o ntai n all s u bjects w h o pr o vi de i nf or me d 
c o nse nt f or t his st u d y. 
T his a nal ysis p o p ulati o n will be use d t o s u m marize s u bject dis p ositi o n (scree n fail ures a n d 
reas o n f or scree n fail ure). 
5. 2.  IN T E N T T O T R E A T P O P U L A TI O N (I T T) 
All S u bjects w h o are e nr olle d a n d recei ve at least 1 a d mi nistrati o n of t he i n vesti gati o nal pr o d uct 
( A u g me nti n [ E S]- 6 0 0) will be i n cl u de d i n t he i nte nt-t o treat p o p ulati o n. T he I T T p o p ulati o n will 
be use d f or all safet y a n d efficac y a nal ys es. 
P P D
P P D


 
Gla x o S mit h Kli ne
P har mace utic als Lt d.  
2 1 3 5 1 4  
St ati sti c al A n al y si s Pl a n  
P a g e 1 8 of 4 3  
 
D o c u m e nt:  
\\i e e d c- v n a s c 0 1\ BI O S d at a\ G S K\ B R L 2 5 0 0 0\ 
\ Bi o st ati sti c s\ D o c u m e nt ati o n\ S A P 
A ut h or: 
V er si o n N u m b er: 
V 1. 0  
 
V er si o n D at e:  
1 8 J U L 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6 
R ef er e n c e:  C S _ WI _ B S 0 0 5 
Eff e cti v e D at e: 0 2 D e c 2 0 1 9 
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
6.  G E N E R A L C O N SI D E R A TI O N S  
6. 1.  R E F E R E N C E S T A R T D A T E A N D S T U D Y D A Y  
St u d y Da y will be calc ulate d fr o m t he refere n ce st art date a n d will be use d t o s h o w start/st o p da y 
of assess me nts a n d e ve nts.  
 
Refere n ce start d ate is defi ne d as t he da y of t he first d ose of st u d y me dicati o n, ( Da y 1 is t he da y 
of t he first d ose of st u d y me dicati o n) a n d will a p p ear i n e ver y listi n g w here a n assess me nt date 
or e ve nt date a p p ears.  
If t he date of t h e e v e nt is o n or after t he refere nc e date, t he n: 
 
St u d y Da y = ( date of e ve nt  refere nce d ate) + 1. 
If t he date of t h e e v e nt is pri or t o t he ref ere n ce d ate t he n: 
 St u d y Da y = ( date of e ve nt  refere nce d ate). 
I n t he sit u ati o n w h ere t he e ve nt date is partial or missi n g, St u d y Da y, a n d a n y c orres p o n di n g 
d urati o ns will a p pear p artial or missi n g i n t he listi n gs. 
6. 2.  B A S E LI N E  
T he baseli ne v al ues ( n o n- missi n g) f or eac h para meter will be t he last a vaila ble assess me nt res ult 
pri or t o t he first d ose of st u d y a d mi nistrati o n. I n case first d ose ca n be gi ve n o n Da y 0 (after 
la b orat or y test res ult a vaila bilit y), t he sa me will be c o nsi dere d as Da y 1. 
 C ha n ge fr o m Baseli n e = P ost- D ose Visit Val ue 
 Baseli ne 
 Perce nta ge C h a n ge fr o m Baseli ne = 1 0 0 x [( P ost- D ose Visit Val ue 
 Baseli ne) / 
Baseli ne 
6. 3.  C O M P U T A TI O N O F A G E  
preli mi nar y 
i m p ute d wit h 3 0t h J u ne ( 3 0 J u n Y Y Y Y).  
P P D
P P D


 
Gla x o S mit h Kli ne
P har mace utic als Lt d.  
2 1 3 5 1 4  
St ati sti c al A n al y si s Pl a n  
P a g e 1 9 of 4 3  
 
D o c u m e nt:  
\\i e e d c- v n a s c 0 1\ BI O S d at a\ G S K\ B R L 2 5 0 0 0\ 
\ Bi o st ati sti c s\ D o c u m e nt ati o n\ S A P 
A ut h or: 
V er si o n N u m b er: 
V 1. 0  
 
V er si o n D at e:  
1 8 J U L 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6 
R ef er e n c e:  C S _ WI _ B S 0 0 5 
Eff e cti v e D at e: 0 2 D e c 2 0 1 9 
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
6. 4.  A N A L Y SI S P E RI O D  
T he f oll o wi n g a nal ysis p eri o ds are defi ne d f or t his st u d y: 
 
 Pre-treat m e nt p eri o d = D ate of Preli mi nar y Visit ( D a y 0) t o Dat e of first d ose - 1  
 O n-treat me nt p eri o d = D ate of first d os e t o D ate of last d ose i n cl usi ve + 1  
 P ost-treat me nt peri o d = E n d of last d ose + 1 da ys t o E n d of st u d y date  
 
Tre at me nt Peri o d  f or A d verse E v e nts: 
 
Pre- Tre at me nt 
: 
 
A n A E will be sai d t o be pre-treat m e nt A E if 
A E Start Date < St u d y Treat me nt St art Date 
 
Tre at me nt E mer ge nt A dverse Eve nt: 
A n A E will be defi ne d as Treat me nt e mer ge nt a d v erse e ve nt ( T E A E) if t he A E start d ate is o n or 
after treat me nt st art dat e & o n or b ef ore treat m e nt st o p date + 1 
 
 + 1 
 
If t h e last d ose of st u d y dr u g is missi n g a n d t he A E start date is o n or after t he first d os e of st u d y 
dr u g, t he n t he A E will be c o nsi dere d as T E A E 
 
If t he A E start date is missi n g or partial t he n t he A E will be c o nsi dere d T E A E u nless t here is 
e vi de nce t o t h e c o ntrar y (e. g. m o nt h/ year of o nset date is prese nt a n d is earlier t ha n t he m o nt h/ year 
of first d ose of st u d y me dicati o n). 
 
P ost Tr e at m e nt 
:  
A n A E will be defi ne d as p ost treat m e nt A E if t he A E start date is after t he treat me nt st o p date  
 
A E Start Date > St u d y Treat me nt St o p Date + 1 
 
D ur ati o n of a dverse eve nt: 
 
( A E res ol uti o n date  A E o nset or start date ) + 1 
 
Tre at me nt E mer ge nt A dverse Eve nt ( T E A E):  
 
P P D
P P D


 
Gla x o S mit h Kli ne
P har mace utic als Lt d.  
2 1 3 5 1 4  
St ati sti c al A n al y si s Pl a n  
P a g e 2 0 of 4 3  
 
D o c u m e nt:  
\\i e e d c- v n a s c 0 1\ BI O S d at a\ G S K\ B R L 2 5 0 0 0\ 
\ Bi o st ati sti c s\ D o c u m e nt ati o n\ S A P 
A ut h or: 
V er si o n N u m b er: 
V 1. 0  
 
V er si o n D at e:  
1 8 J U L 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6 
R ef er e n c e:  C S _ WI _ B S 0 0 5 
Eff e cti v e D at e: 0 2 D e c 2 0 1 9 
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
D uri n g treat m e nt P eri o d + la g ti me of 1 da y. 
 
O nset Ti me Si nce 1 st  D ose ( Da ys): 
 
O nset Ti me = A E O ns et Date - Treat m e nt Start D ate 
 
O nset Ti me = A E O ns et Date - Treat m e nt Start D ate + 1 
 
St u d y/ Tre at me nt P eri o d f or C o nc o mit a nt me dic ati o n  
Pre- Tre at me nt Peri o d : 
If c o n- me d st art date < d ate of Visit 1 ( or c o n- me d date is missi n g) 
 
O n- Tre at me nt Peri o d:  
If C o n- me d start date < st u d y treat me nt start date ( or C o n- me d start d ate is missi n g) a n d c o n- me d 
( or C o n- me d start date is missi n g), or 
 
-
ate + 1. 
 
If t he st u d y treat me nt st o p date is missi n g a n d t he c o n- me d start d ate is o n or after t he st u d y 
treat me nt start date, t h e n t he c o n- me d will be o n-treat m e nt.  
 
If t he c o n- me d start or st o p date is missi n g or partial, t he n t h e c o n- me d will be c o nsi dere d o n-
treat me nt u nless t here is e vi d e nce t o t h e c o ntrar y (e. g. m o nt h/ year of c o n- m e d st o p date is prese nt 
a n d is bef ore t h e m o nt h/ year of st u d y treat m e nt start date). 
 
P ost - Tre at me nt Peri o d: 
If c o n- me d st o p d ate is after t h e treat m e nt st o p date + 1  
 
C o n- me d St o p Date > St u d y Treat m e nt St o p Date + 1 
 
Defi niti o n of o n-set f or a n Eve nt : 
C o n- me d d urati o n ( Da ys): 
 
C o n- me d St o p Date 
 C o n- me d Start Date + 1 
 
Ti me Si n ce 1 st D ose ( Da ys): 
 
- me d Start Date:  
Ti me = C o n- me d Start D ate - Treat m e nt Start D at e 
 
P P D
P P D


 
Gla x o S mit h Kli ne
P har mace utic als Lt d.  
2 1 3 5 1 4  
St ati sti c al A n al y si s Pl a n  
P a g e 2 1 of 4 3  
 
D o c u m e nt:  
\\i e e d c- v n a s c 0 1\ BI O S d at a\ G S K\ B R L 2 5 0 0 0\ 
\ Bi o st ati sti c s\ D o c u m e nt ati o n\ S A P 
A ut h or: 
V er si o n N u m b er: 
V 1. 0  
 
V er si o n D at e:  
1 8 J U L 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6 
R ef er e n c e:  C S _ WI _ B S 0 0 5 
Eff e cti v e D at e: 0 2 D e c 2 0 1 9 
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
- me d Start Date:  
Ti me = C o n- me d Start D ate - Treat m e nt Start D at e + 1 
 
If Treat m e nt Start D ate or start date of C o n- m e d is missi n g  
Ti me = missi n g. 
6. 5.  R E T E S T S , U N S C H E D U L E D V I SI T S A N D E A R L Y T E R MI N A TI O N 
D A T A  
F or b y- visit s u m maries, refer Secti o n 6. 6 ( visit wi n d o ws). 
 
Listi n gs will i n cl u de sc h e d ule d, u nsc he d ule d, retest a n d earl y disc o nti n uati o n data.  
6. 6.  W
I N D O WI N G C O N V E N TI O N S  
T he f oll o wi n g visit wi n d o w will be use d f or efficac y as w ell as safet y assess m e nt. 
 
Visit 
T ar get 
D a ys 
Visit Wi n d o w 
Baseli ne 
0  
Pri or t o first d ose of st u d y me dicati o n  
Visit 1 
1  
# 1 
O n-t hera p y visit or O T visit  
3  
2- 5 
E n d of t hera p y visit or E O T visit   
1 2  
6- 1 4 
I nteri m visit rec urre nce  
1 8  
1 5- 2 1 
F oll o w- u p visit 
2 5 
2 2 
# Visit 1 will be c o nsi dere d as baseli n e f or patie nt diar y car d assess me nts if s u bject d oes n ot 
ha ve patie nt diar y d ata pri or t o Visit 1. 
* I nteri m visit ( < 2 4 hrs of n otificati o n) is re q uir e d o nl y if s u bject h a vi n g cli nical fail ure or P D D 
or ser ver A E of S A E after O T visit pri or t o E O T visit. I n t his case all assess me nt of i nteri m visit 
will b e ma p pe d t o E O T visit as sc he d ule d.  
 
If t here is m ore t ha n o ne rec or d f or a gi ve n para meter wit hi n a s pecific visit wi n d o w, t he n t he n o n-
missi n g rec or d cl osest t o t h e tar get d a y will b e s u m marize d. If t h ere are m ulti ple rec or ds o n t he 
sa me da y f or a para meter, t he n t h e a v era ge val ue will be c o nsi dere d f or c o nti n u o us para meters, 
a n d t he w orst val ue will b e c o nsi dere d f or t he cate g orical p ara m eters.  
  
P P D
P P D


 
Gla x o S mit h Kli ne
P har mace utic als Lt d.  
2 1 3 5 1 4  
St ati sti c al A n al y si s Pl a n  
P a g e 2 2 of 4 3  
 
D o c u m e nt:  
\\i e e d c- v n a s c 0 1\ BI O S d at a\ G S K\ B R L 2 5 0 0 0\ 
\ Bi o st ati sti c s\ D o c u m e nt ati o n\ S A P 
A ut h or: 
V er si o n N u m b er: 
V 1. 0  
 
V er si o n D at e:  
1 8 J U L 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6 
R ef er e n c e:  C S _ WI _ B S 0 0 5 
Eff e cti v e D at e: 0 2 D e c 2 0 1 9 
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
St u d y treat m e nt disc o nti n uati o n a n d u nsc he d ule d visit will als o be c o nsi dere d f or deri vi n g t he visit 
wi n d o w f or para meters. 
6. 7.  S T A TI S TI C A L T E S T S  
T he defa ult si g nifica nt le vel will be 5 %. All c o nfi de nce i nter vals will be c o m p ute d at 9 5 % a n d 
all tests will be t w o-si d e d, u nless ot her wise s pecifie d i n t he descri pti o n of t he a nal yses. 
6. 8.  S A M P L E S I Z E E S TI M A TI O N  
A t otal of 3 1 0 s u bjects will be e nr olle d a n d d ose d. T hese 3 1 0 partici pa nts will be e nr oll e d f or 
eac h i n dicati o n base d o n t h e res pecti v e pre v ale nc e as m e nti o ne d i n t he ta ble bel o w. 
T hese pre v ale nce val ues are base d o n all A R TIs i n I n dia. 
 
St u d y 
I n dicati o n 
Pre vale nce % 
K u mari et al ( 2 0 1 6)  
A O M 
1 7. 6 
Ac har ya et al ( 2 0 0 3)  
C A P 
8. 6 ( 0. 5 % se vere) 
S ha hi d et al ( 2 0 1 2) 
A B R S 
1 4 
 
T he a p pr o xi mate rati o of sa m ples i n eac h i n dicati o n will be 1 8: 9: 1 4 ( A O M: C A B P: A B R S). 
Base d o n t his rati o, at least 1 3 6 s u bjects wit h A O M, 6 8 wit h C A B P a n d 1 0 6 wit h A B R S will be 
e nr oll e d f or t he st u d y. 
If t he pr o p orti o n of p arti ci pa nts re p orti n g at least o ne T E A E is 3 7. 9 % (as o bser ve d i n Y o u n g et 
al, 2 0 0 3), a n d ass u mi n g a sa m ple siz e of 3 1 0 partici pa nts, it is esti mate d t h at t h e wi dt h of t he 
9 5 % c o nfi de n ce i nter v al w o ul d be wit hi n +/- 5. 4 3 % of t he s a m pl e pr o p orti o n (ie, [ 3 2. 5 %, 
4 3. 3 %]), w hic h e q uates t o t he l o wer a n d u p p er b o u n ds of t he 9 5 % c o nfi d e n ce i nter v al l yi n g 
wit hi n a p pr o xi matel y 1 4 % of t he esti mate d pr o p orti o n. 
T he se nsiti vit y of t he precisi o n is calc ulate d wit h res pect t o 5 differe nt pr o p orti o ns esti mate d as 
prese nte d b el o w: 
 
P r o p orti o n esti m ate  
S a m ple si ze  
P recisi o n  
9 5 % CI  
3 0 % 
3 1 0 
5. 1 0 % 
( 2 4. 9 %, 3 5. 1 %) 
3 5 % 
3 1 0 
5. 3 1 % 
( 2 9. 7 %, 4 0. 3 %) 
3 7. 9 % 
3 1 0 
5. 4 3 % 
( 3 2. 5 %, 4 3. 3 %) 
P P D
P P D


 
Gla x o S mit h Kli ne
P har mace utic als Lt d.  
2 1 3 5 1 4  
St ati sti c al A n al y si s Pl a n  
P a g e 2 3 of 4 3  
 
D o c u m e nt:  
\\i e e d c- v n a s c 0 1\ BI O S d at a\ G S K\ B R L 2 5 0 0 0\ 
\ Bi o st ati sti c s\ D o c u m e nt ati o n\ S A P 
A ut h or: 
V er si o n N u m b er: 
V 1. 0  
 
V er si o n D at e:  
1 8 J U L 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6 
R ef er e n c e:  C S _ WI _ B S 0 0 5 
Eff e cti v e D at e: 0 2 D e c 2 0 1 9 
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
4 0 % 
3 1 0 
5. 4 5 % 
( 3 4. 5 %, 4 5. 5 %) 
4 5 % 
3 1 0 
5. 5 4 % 
( 3 9. 5 %, 5 0. 5 %) 
5 0 % 
3 1 0 
5. 5 7 % 
( 4 4. 4 %, 5 5. 6 %) 
 
6. 9.  S O F T W A R E V E R SI O N  
All a nal ys es will be c o n d ucte d usi n g S A S versi o n 9. 4 or hi g h er. 
7.  S T A TI S TI C A L C O N SI D E R A TI O N S  
C o nti n u o us data will be s u m marize d usi n g t he n u m b er of s u bjects ( n), arit h metic mea n ( mea n), 
sta n dar d de viati o n ( S D), me dia n, mi ni m u m val ue ( mi n), a n d ma xi m u m val ue ( ma x) val ues 
u nless ot her wise s pecifie d. Cate g orical v aria bles will be s u m marize d usi n g t he fre q u e nc y c o u nts 
( n) a n d perce nt a ges ( %) f or eac h p ossi ble val ue. D ata fr o m u nsc he d ule d visits will be i n cl u de d i n 
t he b y-s u bj ect listi n gs. 
7. 1.  A D J U S T M E N T S F O R C O V A RI A T E S A N D F A C T O R S T O B E 
IN C L U D E D I N A N A L Y S E S  
T his secti o n is n ot a p pli ca ble f or t his st u d y. 
7. 2.  M U L TI C E N T E R S T U DI E S  
T his st u d y will be c o n d u cte d b y m ulti ple i n vesti gat ors at m ulti ple ce nters. 
7. 3.  M I S SI N G D A T A 
Missi n g data will n ot be i m p ute d i n t his st u d y.  
7. 4.  M U L TI P L E C O M P A RI S O N S / M U L TI P LI CI T Y  
T here is n o m ulti pli cit y a dj ust me nt pla n ne d f or t his st u d y. 
P P D
P P D


 
Gla x o S mit h Kli ne
P har mace utic als Lt d.  
2 1 3 5 1 4  
St ati sti c al A n al y si s Pl a n  
P a g e 2 4 of 4 3  
 
D o c u m e nt:  
\\i e e d c- v n a s c 0 1\ BI O S d at a\ G S K\ B R L 2 5 0 0 0\ 
\ Bi o st ati sti c s\ D o c u m e nt ati o n\ S A P 
A ut h or: 
V er si o n N u m b er: 
V 1. 0  
 
V er si o n D at e:  
1 8 J U L 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6 
R ef er e n c e:  C S _ WI _ B S 0 0 5 
Eff e cti v e D at e: 0 2 D e c 2 0 1 9 
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
8.  O U T P U T P R E S E N T A TI O N S  
A P P E N DI X 1 s h o ws c o n ve nti o ns f or prese ntati o n of data i n o ut p uts.  
T he te m plates pr o vi de d wit h t his S A P descri b e t h e prese nt ati o ns f or t his st u d y a n d t h eref ore t h e 
f or mat a n d c o nt e nt of t h e s u m mar y ta bles, fi g ures, a n d listi n gs t o be pr o vi d e d b y I Q VI A 
Bi ostatisti cs. 
9.  D I S P O SI TI O N A N D W
I T H D R A W A L S 
All s u bjects w h o pr o vi de i nf or me d c o nse nt will be acc o u nte d f or i n t his st u d y.  
9. 1.  D I S P O SI TI O N 
S u bject dis p ositi o n will be s u m m arize d b ase d o n t h e I T T p o p ulati o n b y o verall a n d i n di cati o n. T he 
f oll o wi n g s u m m aries will be i ncl u de d i n t he dis p ositi o n ta ble:  
 T otal n u m ber of s u bjects e nr oll e d i n t he I T T p o p ulati o n 
 N u m ber of s u bjects w h o c o m plete d t h e st u d y treat m e nt 
 N u m ber of s u bjects w h o c o m plete d t h e st u d y 
 N u m ber a n d p erce nta ge of s u bjects w h o disc o nti n ue d fr o m t he st u d y 
 
N u m ber a n d p erce nta ge of s u bjects w h o pre- mat urel y dis c o nti n ue d t he st u d y treat m e nt as 
well as fr o m t he st u d y al o n g wit h reas o n f or dis c o nti n uati o n.   
Perce nta ges will be base d o n t he n u m ber of s u bjects i n t h e I T T p o p ulati o n.  
A s u m mar y of reas o ns f or scree n fail ure a n d t h e n u m ber of s u bje cts i n cl u de d i n I T T p o p ulati o n b y 
o verall a n d i n di cati o n will be prese nte d se paratel y bas e d o n t he e nr olle d p o p ulati o n. T he 
perce nt a ges will be bas e d o n t he n u m ber of s u bjects i n t he All E nr olle d a n al ysis p o p ulati o n.  
 
I n a d diti o n, s u m mar y of visits i m pacte d b y C O VI D- 1 9 pa n de mi c will be ge nerat e d base d o n t he 
I T T p o p ul ati o n b y o v erall a n d i n dicati o n. 
S u bject listi n gs of reas o ns f or st u d y wit h dra w al, treat m e nt disc o nti n uati o n a n d reas o ns f or s cre e n 
fail ures f or eac h i n di cati o n will be pr o vi de d usi n g I T T a n d e nr olle d p o p ulati o n res p ecti vel y . 
P P D
P P D


 
Gla x o S mit h Kli ne
P har mace utic als Lt d.  
2 1 3 5 1 4  
St ati sti c al A n al y si s Pl a n  
P a g e 2 5 of 4 3  
 
D o c u m e nt:  
\\i e e d c- v n a s c 0 1\ BI O S d at a\ G S K\ B R L 2 5 0 0 0 
\ Bi o st ati sti c s\ D o c u m e nt ati o n\ S A P 
A ut h or: 
V er si o n N u m b er: 
V 1. 0  
 
V er si o n D at e:  
1 8 J U L 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6 
R ef er e n c e:  C S _ WI _ B S 0 0 5 
Eff e cti v e D at e: 0 2 D e c 2 0 1 9 
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
9. 2.  P R O T O C O L D E VI A TI O N S  
Pr ot oc ol de viati o ns are t he de viati o ns fr o m t he pr oce d ure o utli ne d i n t h e pr ot oc ol. All t he 
i m p orta nt pr ot oc ol de viati o ns ( P Ds) will be s u m marize d usi n g I T T p o p ul ati o n as o btai ne d fr o m 
Cli nical Trial Ma na ge me nt S yst e m ( C T M S) l o gs. P Ds will be i d e ntifie d a n d disc usse d wit h t he 
I n v esti gat or/ S p o ns or i n P D re vie w disc ussi o n a n d t o fi nalize a nal ysis set assi g n m e nt.  
S u m mar y of i m p orta nt pr ot o c ol de viati o ns relate d t o C O VI D- 1 9 pa n d e mic will als o be pr o vi de d 
b y o verall a n d i n di cati o n usi n g I T T p o p ulati o n.  
A s u bject listi n g of  i m p orta nt pr ot oc ol de viati o ns i de ntifie d b y t he st u d y tea m will be pr ese nte d 
eac h i n dicati o n. 
1 0.  D E M O G R A P HI C A N D O T H E R B A S E LI N E C H A R A C T E RI S TI C S  
T he f oll o wi n g d e m o gra p hic d ata a n d ot her baseli ne c haracteristics will be prese nte d f or t h e I T T 
p o p ulati o n b y o verall a n d i n dicati o n: 
 
Deri ve d A ge ( years)  
 
A ge i n cat e g ories 
s, > 6 m o nt hs a n d < 2 years,  2 years a n d < 5 years, 
5 years a n d < 8 years
 ) 
 
Se x 
 
Race  
 
Et h nicit y 
 
Wei g ht ( k g) 
 
Wei g ht i n cate g ories (
 2 3 k g, 
, > 4 0 k g ) 
 
Hei g ht (c m) 
Baseli ne c haracteristics will i ncl u de vital si g ns p ara meters, b o w el m o ve me nts, a n d ra di ol o gi cal 
assess me nts ( X- Ra y of c hest a n d nasal/ para n asal si n us), as perf or me d at t he ti m e of preli mi nar y 
visit. 
C o nti n u o us de m o gra p hi c a n d baseli ne c h aracteristics data will be s u m m arize d usi n g descri pti ve 
statisti cs. F or cat e g orical data, c o u nts a n d perce nta ge of s u bjects i n eac h cate g or y will be pr o vi de d.  
S u bjects listi n g of de m o gra p hic c haracteristics b y i n dicati o n will be pr o vi de d f or I T T p o p ulati o n. 
P P D
P P D


 
Gla x o S mit h Kli ne
P har mace utic als Lt d.  
2 1 3 5 1 4  
St ati sti c al A n al y si s Pl a n  
P a g e 2 6 of 4 3  
 
D o c u m e nt:  
\\i e e d c- v n a s c 0 1\ BI O S d at a\ G S K\ B R L 2 5 0 0 0\ 
\ Bi o st ati sti c s\ D o c u m e nt ati o n\ S A P 
A ut h or: 
V er si o n N u m b er: 
V 1. 0  
 
V er si o n D at e:  
1 8 J U L 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6 
R ef er e n c e:  C S _ WI _ B S 0 0 5 
Eff e cti v e D at e: 0 2 D e c 2 0 1 9 
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
Baseli ne Si g ns a n d S y m pt o ms:  
T he f oll o wi n g s u m m aries will b e ge nerate d f or baseli ne si g ns a n d s y m pt o ms wit h c o u nts a n d 
perce nt a ges - 
 
Baseli ne si g ns a n d s y m pt o ms b y i n dicati o n usi n g I T T p o p ulati o n  
 
Baseli ne si g ns a n d s y m pt o ms b y se verit y a n d i n dicati o n usi n g I T T p o p ulati o n 
B y-s u bjects listi n g of bas eli n e si g n a n d s y m pt o ms b y i n dicati o n will be ge n erat e d. 
Baseli ne B o w el Ha bits: 
T he f oll o wi n g s u m maries will b e ge nerat e d f or b aseli ne b o w el ha bits- 
 
Descri pti ve statistics ( n, mea n, sta n dar d d e viati o n, me dia n, mi ni m u m, a n d 
ma xi m u m) o n fre q ue nc y of b o wel m o ve me nts at b aseli n e b y i n dicati o n o verall a n d 
i n dicati o n usi n g I T T p o p ulati o n 
 
S u m mar y (c o u nts a n d perce nta ges) a n d D escri pti v e statistics ( n, m ea n, sta n dar d 
de viati o n, me di a n, mi ni m u m, a n d ma xi m u m) o n c o nsiste nc y of b o w el m o ve me nts 
at baseli n e b y i n dicati o n o verall a n d i n dicati o n usi n g I T T p o p ulati o n 
S u bject listi n g of ra di o gra p hic e val u ati o n b y i n dicati o n will be pr o d uce d.  
1 1.  S U R GI C A L A N D M
E DI C A L H I S T O R Y 
Me dical Hist or y c o n diti o ns are defi ne d as t h ose c o n diti o ns w hic h st o p pri or t o or at preli mi nar y 
visit. Me dical hist or y will be c o de d usi n g t he Me dical Dicti o nar y f or Re g ul at or y Acti vities 
( Me d D R A) v ersi o n 2 4. 1  a n d will be s u m mariz e d b y s yste m or ga n class ( S O C) a n d Preferre d 
Ter m ( P T) wit h c o u nts a n d perce nt a ges base d o n t he i nte nt t o treat a nal ysis p o p ulati o n. A s u bject 
ha vi n g m ore t ha n o ne me dical c o n diti o n/ disease wit hi n t he sa me S O C/ P T will be c o u nte d o nl y 
o nce f or t h at S O C or P T. 
 
Me dical hist or y will be s orte d b y desce n di n g or der of s yst e m or ga n class ( S O C) a n d t otal 
fre q ue nc y of preferre d ter m ( P T) wit hi n eac h s yst e m or ga n class ( S O C). 
 
Past a n d c urre nt me dical c o n diti o ns will als o be s u m marize d wit h c o u nts a n d perce nt a ges usi n g 
I T T p o p ul ati o n b y o v erall a n d i n dicati o n. 
P P D
P P D


 
Gla x o S mit h Kli ne
P har mace utic als Lt d.  
2 1 3 5 1 4  
St ati sti c al A n al y si s Pl a n  
P a g e 2 7 of 4 3  
 
D o c u m e nt:  
\\i e e d c- v n a s c 0 1\ BI O S d at a\ G S K\ B R L 2 5 0 0 0 
\ Bi o st ati sti c s\ D o c u m e nt ati o n\ S A P 
A ut h or: 
V er si o n N u m b er: 
V 1. 0  
 
V er si o n D at e:  
1 8 J U L 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6 
R ef er e n c e:  C S _ WI _ B S 0 0 5 
Eff e cti v e D at e: 0 2 D e c 2 0 1 9 
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
1 2.  C O N C O MI T A N T M
E DI C A TI O N S  
Pre-treat m e nt me di cati o n is defi ne d as a n y m e di cati o n t hat starte d a n d st o p pe d pri or t o t he first 
d ose of st u d y dr u g. 
C o nc o mita nt me dicati o n is defi ne d as a n y me di cati o n w hic h starte d bef ore t he first d os e of st u d y 
dr u g A N D w as o n g oi n g at t h e ti me of t he first d ose of st u d y dr u g, or starte d o n or after t h e date 
of first d ose of st u d y dr u g. 
Me dicati o ns wit h parti all y or c o m pl etel y missi n g start a n d/ or st o p dates will be ha n dle d as 
descri b e d i n Secti o n 6. 4. 
All me dicati o ns will be c o de d usi n g t he W orl d Healt h Or ga nizati o n ( W H O) Dr u g Gl o bal 
dicti o nar y v ersi o n B 3 Se pte m ber 2 0 2 1. 
C o nc o mita nt me dicati o ns will be s u m marize d usi n g a n at o mical t h era pe uti c class ( A T C) l e vel 1 
a n d i n gre die nt b y o verall a n d i n dicati o n f or pre-, o n a n d p ost- treat me nt  base d o n t he I T T 
a nal ysis p o p ulati o n. A s u bject ha vi n g m ore t h a n o ne me dicati o n wit hi n t he sa me A T C Le vel 1 or 
i n gre di e nt will be c o u nte d o nl y o nce f or t hat A T C Le v el 1 or i n gre di e nt . S u bjects listi n gs will be 
pr o vi de d f or c o nc o mita nt me dicati o ns . 
 
C o nc o mita nt me dicati o ns will be s orte d i n desce n di n g or der of t otal i nci d e nce acr oss A u g me nti n 
E S treat m e nt gr o u p f or t h e A T C le vel 1 a n d i n desce n di n g or der of t otal i nci d e nce f or t h e 
i n gre di e nt wit hi n eac h A T C l e vel 1 class. 
1 3.  S T U D Y M E DI C A TI O N E X P O S U R E  
E x p os ure t o st u d y me di cati o n i n da ys will be pres e nte d f or t he I T T p o p ulati o n. 
 
T he t otal e x p os ure t o A u g me nti n E xtra Stre n gt h ( E S)- 6 0 0 (a m o xi cilli n/ p otassi u m cla v ula nate 
1 4: 1 c o m bi nati o n) is calc ulate d base d o n deri vati o n as m e nti o ne d i n secti o n 1 3. 1. S u bjects w h o 
e ntere d tr eat m e nt peri o d b ut di d n ot re p ort a n y treat m e nt dates will be cate g orize d as h a vi n g zer o 
da ys of e x p os ure. 
 
Descri pti ve statistics s u m mar y o n e xte nt- of-e x p os ure b y o verall a n d i n di cati o n will be prese nte d 
f or st u d y m e dicati o n e x p os ure usi n g I T T p o p ulati o n. 
 
S u bject listi n g of e x p os ure f or st u d y me dicati o n b y i n dicati o n will als o be ge n erat e d.  
P P D
P P D


 
Gla x o S mit h Kli ne
P har mace utic als Lt d.  
2 1 3 5 1 4  
St ati sti c al A n al y si s Pl a n  
P a g e 2 8 of 4 3  
 
D o c u m e nt:  
\\i e e d c- v n a s c 0 1\ BI O S d at a\ G S K\ B R L 2 5 0 0 0\ 
\ Bi o st ati sti c s\ D o c u m e nt ati o n\ S A P 
A ut h or: 
V er si o n N u m b er: 
V 1. 0  
 
V er si o n D at e:  
1 8 J U L 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6 
R ef er e n c e:  C S _ WI _ B S 0 0 5 
Eff e cti v e D at e: 0 2 D e c 2 0 1 9 
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
1 3. 1.  D E RI V A TI O N S  
D urati o n of e x p os ure da ys = ( date of last st u d y dr u g a d mi nistrati o n 
 date of first st u d y dr u g 
a d mi nistrati o n) + 1.  
1 4.  S T U D Y M E DI C A TI O N C O M P LI A N C E  
S u bject c o m plia nce will be ass esse d b y meas uri n g t he n u m b er of d oses p er n u m ber of d a ys o n 
dr u g (refer s ecti o n 1 4. 1). A mi ni m u m of 8 0 % a n d a ma xi m u m of 1 2 0 % c o m plia nce wit h t he 
st u d y me di cati o n re gi me n will be re q uire d f or t h e patie nt t o c o nsi dere d e val ua ble per pr ot o c ol. 
S u bject c o m plia nce will be c hec ke d t hr o u g h patie nt di ar y car d a n d it will be ret ur n e d t o t he sit e 
at t he e n d of treat me nt ( E O T). 
S u m mar y statistics f or st u d y me dicati o n c o m plia nce will be pres e nte d b y o verall a n d i n di cati o n 
usi n g < 8 0 %, 8 0 % - 1 2 0 % a n d > 1 2 0 %  cate g ories wit h I T T p o p ulati o n. 
S u bject listi n gs of st u d y me di cati o n c o m plia nce a n d n o n-c o m plia nce b y i n dicati o n will be 
prese nte d usi n g I T T p o p ulati o n. Eac h s u bject will be c hec ke d f or p ossi ble o ver d osi n g usi n g t he 
i nf or mati o n o n ma xi m u m rec o m me n de d d os e b y b o d y w ei g ht pr o vi de d i n A P P E N DI X 4. 
I nsta n ces of o v er d osi n g, if a n y, will be liste d. 
1 4. 1.  D E RI V A TI O N S  
O verall perce nt a ge of t h e st u d y i nter ve nti o n c o m plia nce will be cal c ulate d as f oll o ws: 
C o m plia nce = n u m ber of d oses ta k e n/ ( n u m b er of da ys o n t hera p y x 2) x 1 0 0 % 
1 5.  E F FI C A C Y E N D P OI N T S  
1 5. 1.  S E C O N D A R Y E F FI C A C Y E N D P OI N T S 
T here are n o pri mar y efficac y e n d p oi nts defi ne d f or t his st u d y. T he efficac y a n al ysis is defi ne d 
i n ter ms of sec o n dar y a n d patie nt diar y e n d p oi nts. 
 
 Sec o n dar y E n d p oi nts -  
 E arly cli nic al res p o nse  at t h e o n-
P P D
P P D


 
Gla x o S mit h Kli ne
P har mace utic als Lt d.  
2 1 3 5 1 4  
St ati sti c al A n al y si s Pl a n  
P a g e 2 9 of 4 3  
 
D o c u m e nt:  
\\i e e d c- v n a s c 0 1\ BI O S d at a\ G S K\ B R L 2 5 0 0 0\ 
\ Bi o st ati sti c s\ D o c u m e nt ati o n\ S A P 
A ut h or: 
V er si o n N u m b er: 
V 1. 0  
 
V er si o n D at e:  
1 8 J U L 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6 
R ef er e n c e:  C S _ WI _ B S 0 0 5 
Eff e cti v e D at e: 0 2 D e c 2 0 1 9 
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
 
 Pri m ary cli nic al res p o nse  at t he e n d- of-t hera p y visit ( Da y 1 2 t o 1 4), defi ne d i n ter ms of 
i nter ve nti o n. 
 Sec o n d ary cli nic al res p o nse  at f oll o w- u p ( D a y 2 2 t o 2 8), defi ne d i n ter ms of 
 t o st u d y i nter v e nti o n. 
 I n ci de nce of pr ot oc ol- defi ne d diarr hea ( P D D) i n c hil dre n recei vi n g A u g me nti n ( E S)- 6 0 0 
( A M C/ C V A 1 4: 1) at 9 0/ 6. 4 m g/ k g/ da y i n t w o di vi de d d oses a d mi nistere d f or 1 0 da ys i n 
A R TIs ( A O M, A B R S or C A B P). 
 
Defi niti o n of cli nical res p o nses  
Earl y or Pri mar y Cli nical Res p o nse will be defi ne d usi n g f oll o wi n g criteria: 
Ta ble 3:  
 
S uccess  
Cli nical c ure 
S ufficie nt res ol uti o n or i m pr o ve me nt of t he si g ns a n d s y m pt o ms 
s uc h t hat n o a d diti o nal a nti bi otic t h era p y is i n dic ate d. 
I m pr o v e me nt 
I m pr o v e me nt i n at least 1 pres e nti n g si g n/s y m pt o ms. N o 
a d diti o nal a nti bi otic i n dicate d. 
Fail ure  
Cli nical fail ure 
N o n-i m pr o ve me nt or det eri orati o n i n a n y si g n/s y m pt o ms after 2 
or m ore da ys of t h era p y. A d diti o nal a nti bi otic t hera p y is 
i n dicate d. 
U na bl e t o 
deter mi n e 
A vali d assess me nt of cli nical o utc o me c o ul d n ot be ma de (e g, 
partici pa nt di d n ot atte n d or c o nse nt t o cli nical e xa mi nati o n or 
l ost t o f oll o w- u p). 
 
T he pr o p orti o n of earl y a n d pri m ar y res p o ns e will be cal c ul ate d as f oll o ws- 
 
Pr o p orti o n of earl y res p o nse = T he n u m ber of s u bj ect w h o is cate g orize d as s uccess 
(cli nical c ure or i m pr o ve me nt) at o n t h era p y ( O T) visit / t he n u m ber of s u bjects i n 
I T T p o p ul ati o n 
 
Pr o p orti o n of pri mar y res p o nse = T he n u m ber of s u bje ct w h o is cate g orize d as 
s uccess (cli nical c ure or i m pr o ve me nt) at e n d of t hera p y ( E O T) visit/ t h e n u m b er of 
s u bjects i n I T T p o p ul ati o n 
Sec o n dar y Cli nical res p o nse will be descri b e d usi n g f oll o wi n g criteria: 
Ta ble 4: 
 
P P D
P P D


 
Gla x o S mit h Kli ne
P har mace utic als Lt d.  
2 1 3 5 1 4  
St ati sti c al A n al y si s Pl a n  
P a g e 3 0 of 4 3  
 
D o c u m e nt:  
\\i e e d c- v n a s c 0 1\ BI O S d at a\ G S K\ B R L 2 5 0 0 0\ 
Bi o st ati sti c s\ D o c u m e nt ati o n\ S A P 
A ut h or: 
V er si o n N u m b er: 
V 1. 0  
 
V er si o n D at e:  
1 8 J U L 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6 
R ef er e n c e:  C S _ WI _ B S 0 0 5 
Eff e cti v e D at e: 0 2 D e c 2 0 1 9 
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
S uccess 
Persiste nt cli nical 
c ure * 
S ufficie nt res ol uti o n of si g ns/s y m pt o ms f or t h os e S u bjects w h o 
were cli nicall y c ure d or i m pr o ve d at t he e n d of t h era p y. N o 
a d diti o nal a nti bi otic i n dicate d. 
Fail ure  
Cli nical 
rec urre nce 
Rea p peara nce of si g ns/s y m pt o ms f or t h ose S u bj ects w h o w ere 
cli nicall y c ure d or i m pr o ve d at t he e n d of t hera p y. A d diti o nal 
a nti bi oti c t h era p y is i n dicate d. 
U na bl e t o 
deter mi n e 
A vali d assess me nt of cli nic al o utc o me c o ul d n ot be ma de (e g, 
partici pa nt di d n ot att e n d e n d of t h era p y visit, or e xte n uati n g 
circ u msta nc es or l ost t o f oll o w- u p). 
* S u bjects 
i. e.
 sa m e at F U 
wit h o ut re q uiri n g a d diti o nal i nt er ve nti o n, will 
 
 
T he pr o p orti o n of sec o n d ar y res p o ns e will be cal c ulate d as f oll o ws- 
 
Pr o p orti o n of sec o n dar y res p o nse = T h e n u m b er of s u bject w h o is cate g orize d as 
s uccess ( persiste nt cli nical c ure) at f oll o w- u p ( F U) visit / t he n u m ber of s u bjects i n 
I T T p o p ul ati o n 
Defi niti o n of Pr ot oc ol- defi ne d diarr h o ea ( P D D)- 
 
T he i nci d e nce of Pr ot oc ol- defi n e d diarr h oea ( P D D) will be deter mi n e d b ase d o n f oll o wi n g r ules: 
 
3 or m ore wat er y st o ols i n o ne da y O R 
 
4 or m ore l o ose/ water y st o ols i n o ne da y O R  
 
2 water y st o ols per d a y f or t w o c o nsec uti ve d a ys O R  
 
3 l o ose/ water y st o ols per d a y f or t w o c o ns ec uti v e da ys 
Patie nt diar y e n d p oi nts:  
B o wel ha bits 
 Mea n m o ve me nt fre q ue nc y p er da y 
 Ma xi m u m m o ve me nt fre q ue nc y per d a y 
 Ma xi m u m si n gle c o nsiste nc y sc ore 
 
Descri pti o n of B o w el H a bits: 
B o wel ha bit ((fre q ue nc y a n d c o nsiste nc y of 
 st o ols) data will be c ollecte d usi n g p atie nt 
diar y car ds as per s c he d ule of pr ot o c ol. B o wel m o ve me nt c o nsiste nc y will be rec or de d f or eac h 
patie nt i n fi ve cate g ories  
P P D
P P D


 
Gla x o S mit h Kli ne
P har mace utic als Lt d.  
2 1 3 5 1 4  
St ati sti c al A n al y si s Pl a n  
P a g e 3 1 of 4 3  
 
D o c u m e nt:  
\\i e e d c- v n a s c 0 1\ BI O S d at a\ G S K\ B R L 2 5 0 0 0
Bi o st ati sti c s\ D o c u m e nt ati o n\ S A P 
A ut h or: 
V er si o n N u m b er: 
V 1. 0  
 
V er si o n D at e:  
1 8 J U L 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6 
R ef er e n c e:  C S _ WI _ B S 0 0 5 
Eff e cti v e D at e: 0 2 D e c 2 0 1 9 
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
= 1,
= 2,
= 3,
= 4,
= 5.  
S u m mar y meas ures of b o w el ha bit m o ve me nt fre q ue nc y a n d c o nsiste nc y are defi n e d as 
  
 
Mea n m o ve me nt fre q ue nc y p er da y: t his meas ures t he mea n n u m ber of b o wel 
m o ve me nts e x perie nce d b y eac h p atie nt d uri n g t h e st u d y 
 
Ma xi m u m m o ve me nt fre q ue nc y per da y: t his meas ures t h e m a xi m u m n u m ber of 
b o wel m o ve me nts e x perie nce d i n a d a y f or eac h p atie nt 
 
Ma xi m u m si n gle c o nsiste nc y sc ore: t his meas ures t he ma xi m u m c o nsiste nc y sc ore 
f or eac h patie nt at a n y ti me d uri n g t he st u d y 
Cli nical Rec urre nce of Dis ease - Re a p p eara nce of si g ns/s y m pt o ms f or t h ose partici p a nts w h o 
were cli nicall y c ure d or i m pr o v e d at t he e n d of t h era p y.  
1 5. 1. 1.  A N A L Y SI S O F S E C O N D A R Y E N D P OI N T  
1 5. 1. 1. 1.  
Cli nical Res p o nse  
 
Fre q u e nc y a n d pr o p orti o n of earl y, pri m ar y, a n d s ec o n dar y cli nical res p o ns e will be prese nt e d 
al o n g wit h 9 5 % CI usi n g e xact bi n o mial met h o d  
 
Sec o n dar y cli nical res p o nse statistical a nal ysis will be perf or me d b ase d o n as c ollecte d d ata.  
T he f oll o wi n g s u m maries will b e ge n erat e d f or earl y, pri m ar y, a n d sec o n dar y cli nical res p o ns e 
b y o verall a n d i n di cati o n. 
 
- Earl y cli nical res p o nse at o n-t hera p y ( O T) visit 
- Pri mar y cli nical res p o nse at e n d of t hera p y ( E O T) visit 
- Sec o n dar y cli nical res p o nse at f oll o w- u p ( F U) visit  
 
Cli nical rec urre nce of disease at f oll o w- u p will be s u m marize d wit h fre q ue nc y a n d perce nta g e b y 
o verall a n d i n dicati o n. 
1 5. 1. 1. 2.  
I n ci de nce of  pr ot oc ol- d efi ne d diarr h oea  ( P D D). 
N o i nterc urre nt e ve nt is d efi n e d f or t his e n d p oi nt. T he data will be a n al yze d as c ollecte d. 
P P D
P P D
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d b y t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d b y t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d b y t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d b y t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, 
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d b y t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.


 
Gla x o S mit h Kli ne
P har mace utic als Lt d.  
2 1 3 5 1 4  
St ati sti c al A n al y si s Pl a n  
P a g e 3 2 of 4 3  
 
D o c u m e nt:  
\\i e e d c- v n a s c 0 1\ BI O S d at a\ G S K\ B R L 2 5 0 0 0\ 
\ Bi o st ati sti c s\ D o c u m e nt ati o n\ S A P 
A ut h or: 
V er si o n N u m b er: 
V 1. 0  
 
V er si o n D at e:  
1 8 J U L 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6 
R ef er e n c e:  C S _ WI _ B S 0 0 5 
Eff e cti v e D at e: 0 2 D e c 2 0 1 9 
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
Fre q u e nc y a n d perce nta g e of s u bjects wit h i nci de n ce of pr ot o c ol- defi n e d diarr h oea ( P D D) will 
be prese nt e d al o n g wit h 9 5 % CI usi n g e x act met h o d (refer S A S c o de A P P E N DI X 3)  
T he f oll o wi n g s u m maries  will be ge n erat e d f or i n ci de nce of pr ot oc ol- d efi ne d diarr h o ea ( P D D) 
b y o verall a n d i n di cati o n. 
 
- I nci d e nce of pr ot oc ol- d efi ne d diarr h oea ( P D D) 
- I nci d e nce of pr ot oc ol d efi ne d diarr h oea ( P D D) o ver ti m e  
 
Fi g ure f or i nci d e nce of pr ot o c ol defi n e d diarr h o ea ( P D D) o ver ti me will als o be dis pl a ye d b y 
o verall a n d i n dicati o n. 
 
T he statistical a nal ysis f or i nci de nce of pr ot o c ol- d efi ne d diarr h oea ( P D D) will be base d o n as 
c ollecte d data. 
1 5. 1. 1. 3.  
Patie nt diar y e n d p oi nts 
B o wel ha bits- 
T he f oll o wi n g s u m maries will b e ge nerat e d f or p atie nt s u m mar y meas ures of b o wel ha bit 
m o ve me nt b y o v erall a n d i n dicati o n.  
 
S u m mar y a n d d escri pti ve statistics f or p atie nt b o wel ha bit s u m mar y m eas ure - mea n 
m o ve me nt fre q u e nc y per da y 
 
S u m mar y a n d d escri pti ve statistics f or pati e nt b o w el ha bit s u m mar y m eas ure - 
ma xi m u m m o ve me nt fre q ue nc y p er da y 
 
S u m mar y a n d d escri pti ve statistics f or pati e nt b o w el ha bit s u m mar y m eas ure - 
ma xi m u m c o nsiste nc y sc ore 
S u bject listi n g of b o wel m o ve me nt b y i n dicati o n will be prese nte d usi n g I T T p o p ulati o n.  
1 6.  S A F E T Y E N D P OI N T S  
All a nal ysis f or safet y e n d p oi nts will be base d o n t h e I nt e nt t o treat A n al ysis Set. 
1 6. 1.  A D V E R S E E V E N T S  
T he pri mar y safet y e n d p oi nt is t he n u m ber of s u bjects re p orti n g at le ast o ne treat m e nt e m er ge nt 
P P D
P P D


 
Gla x o S mit h Kli ne
P har mace utic als Lt d.  
2 1 3 5 1 4  
St ati sti c al A n al y si s Pl a n  
P a g e 3 3 of 4 3  
 
D o c u m e nt:  
\\i e e d c- v n a s c 0 1\ BI O S d at a\ G S K\ B R L 2 5 0 0 0\ 
\ Bi o st ati sti c s\ D o c u m e nt ati o n\ S A P 
A ut h or: 
V er si o n N u m b er: 
V 1. 0  
 
V er si o n D at e:  
1 8 J U L 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6 
R ef er e n c e:  C S _ WI _ B S 0 0 5 
Eff e cti v e D at e: 0 2 D e c 2 0 1 9 
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
a d verse e ve nt ( T E A E). 
A T E A E d urati o n is d efi ne d as a n A E w hic h has its o ns et d ate d uri n g t h e tr eat m e nt peri o d + l a g 
ti m e of 1 da y. 
A d vers e E v e nts ( A Es) will be c o de d usi n g M e d D R A versi o n 2 4. 1. 
 
1 6. 1. 1.  T E A E S : P RI M A R Y S A F E T Y E N D P OI N T  
A Es occ urri n g fr o m w he n a s u bject si g n i nf or me d c o nse nt t o w he n a s u bject e xits t h e st u d y will 
be acc o u nte d f or i n t he re p orti n g. A Es o cc urri n g pre-treat me nt, treat me nt e mer ge nt a d verse e ve nt 
( o n-treat m e nt) a n d p ost-treat me nt peri o ds will be s u m mariz e d a n d liste d f or t he I T T p o p ulati o n. 
A treat m e nt -e mer ge nt a d verse e ve nt is defi ne d as a n y a d vers e e ve nt t hat de v el o ps after i nitiati o n 
of t he st u d y treat me nts or a n y a d vers e e v e nt alrea d y prese nt t hat w ors e ns f oll o wi n g e x p os ure t o 
st u d y treat me nt.  
T he pri mar y safet y e n d p oi nt will be s u m marize d wit h c o u nts a n d p erce nta ge of s u bjects 
re p orti n g a n y T E A Es a n d s u bjects wit h at least o ne or a n y T E A E wit h c orres p o n di n g 9 5 % CI 
usi n g e x act bi n o mial met h o d  
T he f oll o wi n g s u m maries will b e ge nerat e d f or a d vers e e v e nts: 
 
A d vers e e ve nt o ver vie w b y peri o d  
 
A d vers e e ve nt o ver vie w b y peri o d f or ac ute otitis me di a ( A O M) 
 
A d vers e e ve nt o ver vie w b y peri o d f or ac ute bacterial r hi n osi n usitis ( A B R S) 
 
A d vers e e ve nt o ver vie w b y peri o d f or c o m m u nit y ac q uire d b acterial p ne u m o nia 
( C A B P) 
 
Treat m e nt e mer ge nt a d v erse e ve nts b y s yste m or ga n class, preferre d ter m, o verall 
a n d i n dicati o n   
 
A d vers e e ve nts b y s yste m or ga n class, preferre d t er m, o verall a n d i n dicati o n - p ost-
treat me nt   
 
C o m m o n ( > = 1 %) treat me nt e mer ge nt a d vers e e ve nts b y preferre d ter m, o verall a n d 
i n dicati o n 
 
C o m m o n ( > = 1 %) a d v ers e e ve nts b y preferre d ter m, o verall a n d i n dicati o n - p ost-
treat me nt 
A Es a n d T E A Es will be s orte d b y d esc e n di n g or d er of s yste m or ga n class ( S O C) a n d t otal 
fre q ue nc y of preferre d ter m ( P T) wit hi n eac h s yst e m or ga n class ( S O C). 
 
P P D
P P D


 
Gla x o S mit h Kli ne
P har mace utic als Lt d.  
2 1 3 5 1 4  
St ati sti c al A n al y si s Pl a n  
P a g e 3 4 of 4 3  
 
D o c u m e nt:  
\\i e e d c- v n a s c 0 1\ BI O S d at a\ G S K\ B R L 2 5 0 0 0\ 
\ Bi o st ati sti c s\ D o c u m e nt ati o n\ S A P 
A ut h or: 
V er si o n N u m b er: 
V 1. 0  
 
V er si o n D at e:  
1 8 J U L 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6 
R ef er e n c e:  C S _ WI _ B S 0 0 5 
Eff e cti v e D at e: 0 2 D e c 2 0 1 9 
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
A Es a n d T E A Es relate d t o st u d y dr u g will pres e nte d i n decreasi n g or der of preferre d t er m ( P T). 
S u bjects listi n g of a d verse e v e nts b y i n dicati o n ( T E A E a n d p ost-treat m e nt peri o d) will b e 
pr o d uce d. 
1 6. 1. 1. 1.  
Se verit y 
Se verit y is cl assifie d as mil d, m o derate, a n d se v ere. A n A E wit h missi n g s e verit y will be 
classifie d as 
.  
S u bjects w h o e x perie nce t he sa me e ve nt s e veral ti mes, wit h differe nt i nte nsities, will o nl y be 
c o u nte d wit h t he ma xi m u m i nte nsit y. 
T he f oll o wi n g t a bles will be ge nerate d t o s u m m ari z e t he s e verit y of a d v erse e ve nt  
 Treat m e nt e mer ge nt a d v erse e ve nts b y s yste m or ga n class, preferre d ter m, m a xi m u m 
se verit y, o verall a n d i n dicati o n 
 A d vers e e ve nts b y s yste m or ga n class, preferre d t er m, ma xi m u m se verit y, o verall a n d 
i n dicati o n - p ost treat m e nt 
S orti n g or der will be prese nte d sa me as s ecti o n 1 6. 1. 1. 
1 6. 1. 1. 2.  
Relati o ns hi p t o St u d y M e dic ati o n 
S u m mar y f or dr u g-relate d treat m e nt e mer ge nt a d verse e v e nts b y preferre d t er m, o verall  a n d 
i n dicati o n will be prese nt e d. 
1 6. 1. 2.  T E A E S L E A DI N G T O P E R M A N E N T D I S C O N TI N U A TI O N O F S T U D Y M
E DI C A TI O N 
O R W
I T H D R A W A L S T U D Y  
Treat m e nt e mer ge nt a d v erse e ve nts lea di n g t o p er ma ne nt disc o nti n uati o n of st u d y me dicati o n or 
wit h dra wal fr o m st u d y b y s yste m or ga n class, preferr e d ter m, o verall a n d i n dicati o n will be 
dis pla ye d. 
A d vers e e ve nts lea di n g t o wit h dra wal fr o m st u d y will als o be prese nte d b y s yste m or ga n class, 
preferre d t er m, o verall a n d i n dicati o n. 
 
S orti n g or der will be prese nte d sa me as s ecti o n 1 6. 1. 1. 
S u bject listi n g of treat me nt e mer ge nt a d v erse e ve nts lea di n g t o per ma ne nt disc o nti n uati o n of 
st u d y me di cati o n or wit h dra wal fr o m st u d y will als o be ge nerate d. 
P P D
P P D


 
Gla x o S mit h Kli ne
P har mace utic als Lt d.  
2 1 3 5 1 4  
St ati sti c al A n al y si s Pl a n  
P a g e 3 5 of 4 3  
 
D o c u m e nt:  
\\i e e d c- v n a s c 0 1\ BI O S d at a\ G S K\ B R L 2 5 0 0 0\ 
\ Bi o st ati sti c s\ D o c u m e nt ati o n\ S A P 
A ut h or: 
V er si o n N u m b er: 
V 1. 0  
 
V er si o n D at e:  
1 8 J U L 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6 
R ef er e n c e:  C S _ WI _ B S 0 0 5 
Eff e cti v e D at e: 0 2 D e c 2 0 1 9 
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
1 6. 1. 3.  S E RI O U S A D V E R S E E V E N T S  
T he f oll o wi n g s u m maries will b e prese nte d f or seri o us a d verse e ve nts: 
 Treat m e nt e mer ge nt seri o us a d verse e ve nts b y s yste m or ga n class, preferre d ter m, o verall 
a n d i n dicati o n   
 Seri o us a d verse e ve nts b y s yste m or ga n class, preferre d ter m, o verall a n d i n dicati o n - 
p ost-treat me nt   
 Treat m e nt e mer ge nt seri o us a d verse e ve nts b y s yste m or ga n class a n d preferre d t er m, 
ma xi m u m se verit y, o v erall a n d i n dicati o n 
 Seri o us a d verse e ve nts b y s yste m or ga n class, preferr e d ter m, m a xi m u m se verit y, o v erall 
a n d i n dicati o n - p ost treat me nt 
 Dr u g-relate d treat m e nt e mer ge nt seri o us a d verse e ve nts b y preferr e d ter m, o verall a n d 
i n dicati o n 
 
S orti n g or der will be prese nte d sa me as s ecti o n 1 6. 1. 1. 
T he f oll o wi n g s eri o us a d verse e v e nt listi n gs will be pr o d uce d: 
 Listi n g of reas o ns f or c o nsi d eri n g as a seri o us a d verse e v e nt b y i n dicati o n- pre-treat me nt 
 Listi n g of fat al a n d n o n-fatal seri o us a d verse e v e nts ( T E A E a n d p ost-treat me nt peri o d) 
 Listi n g of reas o ns f or c o nsi d eri n g as a seri o us a d verse e v e nt b y i n di cati o n ( T E A E a n d 
p ost-treat me nt peri o d) 
1 6. 1. 4.  A D V E R S E E V E N T S L E A DI N G T O D E A T H  
S u bject listi n g will be ge nerate d f or a d v erse e ve nt lea di n g t o d eat h. 
1 6. 1. 5.  . C A R DI O V A S C U L A R E V E N T S  
 
 M y ocar dial i nfarcti o n/ u nsta ble a n gi na 
 C o n gesti v e heart fail ure 
 Arr h yt h mias 
 Val v ul o pat h y 
 P ul m o nar y h y perte nsi o n 
P P D
P P D


 
Gla x o S mit h Kli ne
P har mace utic als Lt d.  
2 1 3 5 1 4  
St ati sti c al A n al y si s Pl a n  
P a g e 3 6 of 4 3  
 
D o c u m e nt:  
\\i e e d c- v n a s c 0 1\ BI O S d at a\ G S K\ B R L 2 5 0 0 0\ 
\ Bi o st ati sti c s\ D o c u m e nt ati o n\ S A P 
A ut h or: 
V er si o n N u m b er: 
V 1. 0  
 
V er si o n D at e:  
1 8 J U L 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6 
R ef er e n c e:  C S _ WI _ B S 0 0 5 
Eff e cti v e D at e: 0 2 D e c 2 0 1 9 
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
 Cere br o vas c ular e ve nts/str o ke a n d tra nsie nt isc h e mic att ac k 
 Peri p heral arterial t hr o m b oe m b olis m 
 Dee p ve n o us t hr o m b osis/ p ul m o nar y e m b olis m 
 Re vasc ularizati o n 
 S u bject listi n g will be ge nerate d f or all car di o vasc ular e ve nts r ec or de d i n t he st u d y. 
1 6. 2.  D E A T H S  
S u bject listi n g will be ge nerate d f or a n y d eat h t hat ha p pe ns d uri n g t he st u d y.  
1 6. 3.  L A B O R A T O R Y E V A L U A TI O N S  
La b orat or y p ara m eters assesse d f or t he st u d y are liste d bel o w:  
Ta ble 5: 
Assess me nts  
Para meters 
He mat ol o g y  
Platelet 
C o u nt 
R B C C o u nt 
He m o gl o bi n 
He mat ocrit 
R B C I n di ces: 
M C V 
M C H 
% Retic ul oc yt es 
W B C c o u nt wit h 
Differ e nti al: 
Ne utr o p hils 
L y m p h oc ytes 
M o n oc yt es 
E osi n o p hils 
Bas o p hils 
Cli nical 
C he mistr y 
Plas ma 
creati ni ne 
As partate 
A mi n otra nsferase ( A S T) 
Ala ni ne 
A mi n otra nsferase 
( A L T) 
T otal a n d direct 
bilir u bi n 
Ra di o gra p h y  
C hest X ra y t o be perf or me d f or patie nts pr es u me d t o a dia g n osis of 
C A B P. X ra y of n asal/ para nasal si n us t o be perf or me d f or patie nts 
pres u m e d t o ha ve A B R S ( b ot h o nl y f or refere nce, as per i n vesti gat ors 
discreti o n) 
 
Cli nical la b orat or y e val u ati o ns i ncl u de he m at ol o g y, cli nical c he mistr y, A list of 
la b orat or y ass ess me nts is m e nti o ne d i n Ta ble 5 w hic h will be use d f or statistical 
a nal ysis. 
 
Descri pti ve statistics ( n, mea n, sta n dar d de viati o n ( S D), me dia n, mi ni m u m val ue 
P P D
P P D


 
Gla x o S mit h Kli ne
P har mace utic als Lt d.  
2 1 3 5 1 4  
St ati sti c al A n al y si s Pl a n  
P a g e 3 7 of 4 3  
 
D o c u m e nt:  
\\i e e d c- v n a s c 0 1\ BI O S d at a\ G S K\ B R L 2 5 0 0 0\ 
\ Bi o st ati sti c s\ D o c u m e nt ati o n\ S A P 
A ut h or: 
V er si o n N u m b er: 
V 1. 0  
 
V er si o n D at e:  
1 8 J U L 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6 
R ef er e n c e:  C S _ WI _ B S 0 0 5 
Eff e cti v e D at e: 0 2 D e c 2 0 1 9 
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
( mi n), a n d ma xi m u m val ue ( ma x)) will be prese nte d f or q ua ntitati ve meas ure me nts 
of la b orat or y p ara m eters b y o verall a n d i n di cati o n, Fre q u e nc y a n d perce nta ge will 
be dis pla ye d f or q u alitati ve m eas ure me nts of l a b orat or y para meters b y o v erall a n d 
i n dicati o n. 
 
S u bjects listi n g of baseli n e la b orat or y p ara m eters b y i n dicati o n will als o be 
ge n erat e d. 
1 6. 4.  E C G  E V A L U A TI O N S  
E C G assess me nt will n ot be perf or me d f or t his st u d y. 
1 6. 5.  V I T A L S I G N S 
T he f oll o wi n g Vital Si g ns meas ure me nts will be re p orte d f or t his st u d y: 
 
Res pirat or y Rate ( br eat hs/ mi n) 
 
Te m perat ure (
C) 
 
P uls e rate 
 
Wei g ht ( k g) 
 
Hei g ht  
Act u al vital si g ns res ults, c ha n ge fr o m baseli ne v al ues a n d perce nta g e c ha n ge fr o m baseli ne will 
be s u m mariz e d f or eac h a nal ysis visit. 
S u bjects listi n g of  vital si g ns para meters b y i n dic ati o n will als o be ge n erate d. 
1 6. 6.  O T H E R S A F E T Y A S S E S S M E N T S  
S u m mar y f or visits i m pacte d b y C O VI D- 1 9 pa n d e mic will b e prese nt e d b y o verall a n d 
i n dicati o n. 
S u bject listi n g of C o vi d- 1 9 pa n d e mic st u d y i m p act ( T E A E a n d p ost-tr eat me nt peri o d) will be 
dis pla ye d. 
S u bject listi n g of l ocal e x a mi n ati o n b y i n dicati o n will b e ge nerate d.  
P P D
P P D


 
Gla x o S mit h Kli ne
P har mace utic als Lt d.  
2 1 3 5 1 4  
St ati sti c al A n al y si s Pl a n  
P a g e 3 8 of 4 3  
 
D o c u m e nt:  
\\i e e d c- v n a s c 0 1\ BI O S d at a\ G S K\ B R L 2 5 0 0 0\ 
\ Bi o st ati sti c s\ D o c u m e nt ati o n\ S A P 
A ut h or: 
V er si o n N u m b er: 
V 1. 0  
 
V er si o n D at e:  
1 8 J U L 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6 
R ef er e n c e:  C S _ WI _ B S 0 0 5 
Eff e cti v e D at e: 0 2 D e c 2 0 1 9 
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
S u bject listi n g will be ge nerate d f or pre g na nc y. 
1 7.  D A T A N O T S U M M A RI Z E D O R P R E S E N T E D  
N ot a p plica ble 
1 8.  R E F E R E N C E S  
Pr ot oc ol n u m ber 2 1 3 5 1 4 | Pr ot oc ol A me n d m e nt 0 1 1 9 Ma y 2 0 2 1. 
 
 
P P D
P P D


 
Gla x o S mit h Kli ne
P har mace utic als Lt d.  
2 1 3 5 1 4  
St ati sti c al A n al y si s Pl a n  
P a g e 3 9 of 4 3  
 
D o c u m e nt:  
\\i e e d c- v n a s c 0 1\ BI O S d at a\ G S K\ B R L 2 5 0 0 0
Bi o st ati sti c s\ D o c u m e nt ati o n\ S A P 
A ut h or: 
V er si o n N u m b er: 
V 1. 0  
 
V er si o n D at e:  
1 8 J U L 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6 
R ef er e n c e:  C S _ WI _ B S 0 0 5 
Eff e cti v e D at e: 0 2 D e c 2 0 1 9 
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
A P P E N DI X 1.  P R O G R A M MI N G C O N V E N TI O N S F O R O U T P U T S  
I Q VI A O U T P U T C O N V E N TI O N S  
O ut p uts will be prese nte d acc or di n g t o I Q VI A Gl o bal Bi ostatisti cs St a n d ar d O ut p ut C o n ve nti o ns 
D A T E S &  T I M E S 
De pe n di n g o n d ata a vaila ble, dates a n d ti mes will ta ke t h e f or mat D D M M M Y Y Y Y; ti mes will 
ta ke 
t he 
f or m at 
H H: M M; 
c o m bi n e d 
d ates 
a n d 
ti m es 
will 
ta k e 
t he 
f or mat 
D D M M M Y Y Y Y/ H H: M M. Ti me will be base d o n a 2 4 h o ur cl oc k.  
S P E L LI N G F O R M A T  
E n glis h U K, i n cl u di n g f or M e d D R A w here Britis h E n glis h is use d. 
L I S TI N G S 
All listi n gs will be or dere d b y t he f oll o wi n g ( u nless ot her wis e i n dicate d i n t he te m plate): 
 S u bject I D 
 Date a n d ti me ( w h ere a p plica ble) 
P R E S E N T A TI O N O F T R E A T M E N T G R O U P S  
F or o ut p uts, treat m e nt gr o u ps will be re prese nte d as f oll o ws: 
Tre at me nt Gr o u p 
A u g me nti n ( E S) 
 6 0 0 
D E S C RI P TI V E S T A TI S TI C S  
If t he ori gi nal data h as N deci mal places, t h e n t h e s u m mar y statistics will ha ve t he f oll o wi n g 
deci mal places: 
P P D
P P D


 
Gla x o S mit h Kli ne
P har mace utic als Lt d.  
2 1 3 5 1 4  
St ati sti c al A n al y si s Pl a n  
P a g e 4 0 of 4 3  
 
D o c u m e nt:  
\\i e e d c- v n a s c 0 1\ BI O S d at a\ G S K\ B R L 2 5 0 0 0\ 
\ Bi o st ati sti c s\ D o c u m e nt ati o n\ S A P 
A ut h or: 
V er si o n N u m b er: 
V 1. 0  
 
V er si o n D at e:  
1 8 J U L 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6 
R ef er e n c e:  C S _ WI _ B S 0 0 5 
Eff e cti v e D at e: 0 2 D e c 2 0 1 9 
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
 Mi ni m u m a n d ma xi m u m: N; 
 Mea n, m e dia n, l o wer a n d u p per b o u n ds of t w o-si d e d 9 5 % CI: N + 1; 
 S D a n d S E: N + 2 
P E R C E N T A G E S  
Perce nta ges will be re p orte d t o o ne deci m al place.  R o u n di n g will be a p plie d, e x ce pt f or 
 
 
W h ere c o u nts are zer o, n o perce nt a ges will a p p ear i n t he o ut p ut. 
 
 
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Gla x o S mit h Kli ne
P har mace utic als Lt d.  
2 1 3 5 1 4  
St ati sti c al A n al y si s Pl a n  
P a g e 4 1 of 4 3  
 
D o c u m e nt:  
\\i e e d c- v n a s c 0 1\ BI O S d at a\ G S K\ B R L 2 5 0 0 0\ 
\ Bi o st ati sti c s\ D o c u m e nt ati o n\ S A P 
A ut h or: 
V er si o n N u m b er: 
V 1. 0  
 
V er si o n D at e:  
1 8 J U L 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6 
R ef er e n c e:  C S _ WI _ B S 0 0 5 
Eff e cti v e D at e: 0 2 D e c 2 0 1 9 
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
A P P E N DI X 2.  P A R TI A L D A T E C O N V E N TI O N S  
Date I m p utati o n R ule f or a d verse e ve nts a n d c o nc o mita nt me dicati o n f or assi g ni n g t h e e ve nt i n 
partic ular p eri o d : 
 
Missi n g da y i n a start dat e, e. g. - -J U N 2 0 2 1, set t o t he first of t he m o nt h, 0 1J U N 2 0 2 1.  
Missi n g m o nt h i n a start date, e. g., 1 5- - - 2 0 0 6, set t o J a n uar y, 1 5J A N 2 0 2 1.  
Missi n g da y i n a st o p dat e, e. g. - - A P R 2 0 2 1, set t o t h e last of t he m o nt h, 3 0 A P R 2 0 2 1.  
Missi n g m o nt h i n a st o p date, e. g., 2 3- - - 2 0 0 6, set t o Dece m ber, 2 3 D E C 2 0 2 1.  
If b ot h da y a n d m o nt h are missi n g, e. g. - - - - - 2 0 2 1, a p pl y b ot h r ules gi vi n g 0 1J A N 2 0 2 1 f or a 
partial start date, or 3 1 D E C 2 0 2 1 f or a partial st o p date 
 
 
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P P D


 
Gla x o S mit h Kli ne
P har mace utic als Lt d.  
2 1 3 5 1 4  
St ati sti c al A n al y si s Pl a n  
P a g e 4 2 of 4 3  
 
D o c u m e nt:  
\\i e e d c- v n a s c 0 1\ BI O S d at a\ G S K\ B R L 2 5 0 0 0\ 
\ Bi o st ati sti c s\ D o c u m e nt ati o n\ S A P 
A ut h or: 
V er si o n N u m b er: 
V 1. 0  
 
V er si o n D at e:  
1 8 J U L 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6 
R ef er e n c e:  C S _ WI _ B S 0 0 5 
Eff e cti v e D at e: 0 2 D e c 2 0 1 9 
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
A P P E N DI X 3.  S A S  C O D E F O R A N A L Y S E S  
T he f oll o wi n g S A S c o d e will be use d t o a nal yze t h e cli nical res p o ns e:  
 
F or o v er all: 
 
pr o c  fre q d ata = m o d el data; 
ta bles res p o nse/ bi n o mi al (e xa ct ) al p ha= 0. 0 5; 
o ut p ut o ut = _ ci 9 5 bi n o mial 
r u n; 
 
F or i n dic ati o n wise a n al ysis  
 
pr o c  fre q d ata = m o d el data; 
b y i n dicati o n 
ta bles res p o nse/ bi n o mi al (e xa ct )   al p ha= 0. 0 5 ; 
o ut p ut o ut = _ ci 9 5 bi n o mial 
r u n; 
 
N ote : I n t h e a bse nce of res p o n der cate g or y (zer o res p o n der), s e parate c ate g or y wit h zer o 
res p o n der i n fi n al data set will be a d de d bef ore passi n g i n pr oc fre q usi n g Wei g ht state me nt wit h 
zer oes o pti o n as bel o w  
S A S c o de :  
pr o c fre q d ata = m o d el data ;  
b y i n dicati o n;  
ta bles res p o nse /  bi n o mial;  
wei g ht w gt/zer o es; 
 e xact bi n o mial; 
 r u n; 
 
 
P P D
P P D


 
Gla x o S mit h Kli ne
P har mace utic als Lt d.  
2 1 3 5 1 4  
St ati sti c al A n al y si s Pl a n  
P a g e 4 3 of 4 3  
 
D o c u m e nt:  
\\i e e d c- v n a s c 0 1\ BI O S d at a\ G S K\ B R L 2 5 0 0 0 
\ Bi o st ati sti c s\ D o c u m e nt ati o n\ S A P 
A ut h or: 
V er si o n N u m b er: 
V 1. 0  
 
V er si o n D at e:  
1 8 J U L 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6 
R ef er e n c e:  C S _ WI _ B S 0 0 5 
Eff e cti v e D at e: 0 2 D e c 2 0 1 9 
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
A P P E N DI X 4.  M A XI M U M R E C O M M E N D E D D O S E B Y B O D Y W
EI G H T  
 
 
B o d y wei g ht 
( k g) # 
A u g me nti n 6 0 0 
f or oral 
s us p e nsi o n ( ml) 
t wice i n 
d a y( BI D) 
Ma xi m u m 
Rec o m me n de d 
D ose 
A d mi nistere d 
b y t he Oral 
R o ute ( ml) 
T wice i n 
d a y( BI D) 
B o d y wei g ht 
( k g) # 
A u g me nti n 6 0 0 
f or oral 
s us p e nsi o n ( ml)  
t wice i n 
d a y( BI D) 
Ma xi m u m 
Rec o m me n de d 
A d mi nistere d 
b y t he Oral 
R o ute ( ml) 
T wice i n 
d a y( BI D) 
 
 
 
2 1 
8. 0 
1 0. 5 
 
 
 
2 2 
8. 4 
1 1. 0 
3 
1. 2 
1. 5  
2 3 
8. 6 
1 1. 5 
4 
1. 6 
2. 0 
2 4 
9. 0 
1 2. 0 
5 
2. 0 
2. 5 
2 5 
9. 4 
1 2. 5 
6 
2. 4 
3. 0 
2 6 
9. 8 
1 3. 0 
7 
2. 6 
3. 5 
2 7 
1 0. 2 
1 3. 5 
8 
3. 0 
4. 0 
2 8 
1 0. 6 
1 4. 0 
9 
3. 4 
4. 5 
2 9 
1 1. 0 
1 4. 5 
1 0 
3. 8 
5. 0 
3 0 
1 1. 4 
1 5. 0 
1 1 
4. 2 
5. 5 
3 1 
1 1. 6 
1 5. 5 
1 2 
4. 6 
6. 0 
3 2 
1 2. 0 
1 6. 0 
1 3 
5. 0 
6. 5 
3 3 
1 2. 4 
1 6. 5 
1 4 
5. 4 
7. 0 
3 4 
1 2. 8 
1 7. 0 
1 5 
5. 6 
7. 5 
3 5 
1 3. 2 
1 7. 5 
1 6 
6. 0 
8. 0 
3 6 
1 3. 6 
1 8. 0 
1 7 
6. 4 
8. 5 
3 7 
1 4. 0 
1 8. 5 
1 8 
6. 8 
9. 0 
3 8 
1 4. 4 
1 9. 0 
1 9 
7. 2 
9. 5 
3 9 
1 4. 6 
1 9. 5 
2 0 
7. 6 
1 0. 0 
4 0 
1 5. 0 
2 0. 0 
 
 
 
 
 
 
 
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C ertifi c at e Of C o m pl eti o n
E n v el o p e I d:
St at u s: C o m pl et e d
S u bj e ct: Pl e a s e D o c u Si g n: G S K _ 2 1 3 5 1 4 S A P Fi n al V 1. 0. d o c x
Pr oj e ct C o d e ( E nt er 0 f or n o n- bill a bl e pr oj e ct s): 
I Q VI A I D ( L o gi n I D):
B u si n e s s U nit: 
D S S R
S o ur c e E n v el o p e: 
D o c u m e nt P a g e s: 4 3
Si g n at ur e s: 5
E n v el o p e Ori gi n at or: 
C ertifi c at e P a g e s: 6
I niti al s: 0
A ut o N a v: E n a bl e d
E n v el o p eI d St a m pi n g: Di s a bl e d
Ti m e Z o n e: ( U T C- 0 5: 0 0) E a st er n Ti m e ( U S & C a n a d a)
R e c or d Tr a c ki n g
St at u s: Ori gi n al
             7/ 1 8/ 2 0 2 2 5: 4 0: 2 7 A M
L o c ati o n: D o c u Si g n
Si g n er E v e nt s
Si g n at ur e
Ti m e st a m p
Wit h Si g ni n g A ut h e nti c ati o n vi a D o c u Si g n p a s s w or d
Wit h Si g ni n g R e a s o n s ( o n e a c h t a b): 
   I a m t h e a ut h or of t hi s d o c u m e nt
S e nt: 7/ 1 8/ 2 0 2 2 5: 4 7: 4 5 A M
Vi e w e d: 7/ 1 8/ 2 0 2 2 6: 0 2: 3 3 A M 
Si g n e d: 7/ 1 8/ 2 0 2 2 6: 0 3: 1 8 A M
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e: 
      A c c e pt e d: 7/ 1 8/ 2 0 2 2 6: 0 4: 1 0 A M
      C o m p a n y N a m e: I Q VI A
I Q VI A Bi ot e c h D o c u Si g n P art 1 1
S e c urit y L e v el: E m ail, A c c o u nt A ut h e nti c ati o n 
( R e q uir e d), L o g g e d i n
Si g n at ur e A d o pti o n: Pr e- s el e ct e d St yl e
Wit h Si g ni n g A ut h e nti c ati o n vi a D o c u Si g n p a s s w or d
Wit h Si g ni n g R e a s o n s ( o n e a c h t a b): 
   I a m t h e a ut h or of t hi s d o c u m e nt
S e nt: 7/ 1 8/ 2 0 2 2 5: 4 7: 4 7 A M
Vi e w e d: 7/ 1 8/ 2 0 2 2 5: 5 3: 4 1 A M 
Si g n e d: 7/ 1 8/ 2 0 2 2 5: 5 4: 0 5 A M
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e: 
      N ot Off er e d vi a D o c u Si g n
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
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Si g n er E v e nt s
Si g n at ur e
Ti m e st a m p
Wit h Si g ni n g A ut h e nti c ati o n vi a D o c u Si g n p a s s w or d
Wit h Si g ni n g R e a s o n s ( o n e a c h t a b): 
   I a p pr o v e t hi s d o c u m e nt
S e nt: 7/ 1 8/ 2 0 2 2 5: 4 7: 4 7 A M
Vi e w e d: 7/ 1 8/ 2 0 2 2 8: 4 5: 2 4 A M 
Si g n e d: 7/ 1 8/ 2 0 2 2 8: 4 9: 2 9 A M
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e: 
      A c c e pt e d: 7/ 1 8/ 2 0 2 2 8: 4 5: 2 4 A M
  
      C o m p a n y N a m e: I Q VI A
Wit h Si g ni n g A ut h e nti c ati o n vi a D o c u Si g n p a s s w or d
Wit h Si g ni n g R e a s o n s ( o n e a c h t a b): 
   I a m t h e a ut h or of t hi s d o c u m e nt
S e nt: 7/ 1 8/ 2 0 2 2 5: 4 7: 4 9 A M
Vi e w e d: 7/ 1 8/ 2 0 2 2 6: 2 8: 0 2 A M 
Si g n e d: 7/ 1 8/ 2 0 2 2 6: 2 9: 3 3 A M
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e: 
      A c c e pt e d: 7/ 1 8/ 2 0 2 2 6: 2 8: 0 2 A M
   
      C o m p a n y N a m e: I Q VI A
Wit h Si g ni n g A ut h e nti c ati o n vi a D o c u Si g n p a s s w or d
Wit h Si g ni n g R e a s o n s ( o n e a c h t a b): 
   I a p pr o v e t hi s d o c u m e nt
S e nt: 7/ 1 8/ 2 0 2 2 5: 4 7: 4 9 A M
Vi e w e d: 7/ 2 0/ 2 0 2 2 6: 1 5: 2 5 A M 
Si g n e d: 7/ 2 0/ 2 0 2 2 6: 1 6: 4 7 A M
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e: 
      A c c e pt e d: 7/ 2 0/ 2 0 2 2 6: 1 5: 2 5 A M
    
      C o m p a n y N a m e: I Q VI A
I n P er s o n Si g n er E v e nt s
Si g n at ur e
Ti m e st a m p
E dit or D eli v er y E v e nt s
St at u s
Ti m e st a m p
A g e nt D eli v er y E v e nt s
St at u s
Ti m e st a m p
I nt er m e di ar y D eli v er y E v e nt s
St at u s
Ti m e st a m p
C ertifi e d D eli v er y E v e nt s
St at u s
Ti m e st a m p
P P D
P P D
P P D
P P D
P P D
P P D


Carbon Copy Events
Status
Timestamp
Witness Events
Signature
Timestamp
Notary Events
Signature
Timestamp
Envelope Summary Events
Status
Timestamps
Envelope Sent
Hashed/Encrypted
7/18/2022 5:47:49 AM
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Security Checked
7/20/2022 6:15:25 AM
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