Clinical trial NCT03408392
Conditions: Infections, Bacterial
Keywords: Single dose Oral suspension Bioequivalence Cefixime Two-way crossover
Sponsor: GlaxoSmithKline
Start date: 2018-02-06; Completion date: 2018-03-13
Enrollment: 28 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This study is open-label, randomized two-way cross-over study to determine if cefixime 200 mg/5 mL powder for suspension (test formulation: SKF101804) is bioequivalent to cefixime 200 mg/5 mL suspension reference formulation. Study will be conducted in 28 healthy adult subjects under fasting conditions. There will be two treatment periods and each subject will participate in both periods. The washout period between both treatment periods will be 7-14 days. Subjects will be randomized to either of treatment sequences of reference followed by test or test followed by reference to receive a single dose of test or reference formulation on Day 1 in each treatment period. The study will last for 5 to 7 weeks.

Detailed description:

Arms: arm 1: Subjects will be randomized to receive single dose of Test formulation (SKF101804: cefixime 200 mg/ 5 mL) on Day 1 of the treatment period 1 and Reference formulation (cefixime 200 mg/5 mL) on Day 1 of the treatment period 2. There will be wash out period of 7-14 days between the two treatment periods. arm 2: Subjects will be randomized to receive single dose of Reference formulation (cefixime 200 mg/5 mL) on Day 1 of the treatment period 1 and Test formulation (SKF101804: cefixime 200 mg/ 5 mL) on Day 1 of the treatment period 2. There will be wash out period of 7-14 days between the two treatment periods.
Interventions: intervention 1: Test formulation A intervention 2: Reference formulation B
Intervention descriptions: intervention 1: Test formulation: SKF101804 will be available as oral suspension supplied as powder for reconstitution (Off-white to cream coloured powder). Subjects will receive single dose of 5 mL of suspension thus receiving 200 mg dose of cefixime. The suspension is a white to off white viscous suspension with a fruit flavor and odor. intervention 2: Reference formulation will be available as oral suspension supplied as powder for reconstitution (Off-white to cream coloured powder). Subjects will receive single dose of 5 mL of suspension thus receiving 200 mg dose of cefixime. The suspension is a white to off white viscous suspension with a strawberry flavor and odor.

Protocol documents:
Prot_SAP_000.pdf: 
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TITLE PAGE
Protocol Title: An open-label, randomised, single-dose, two-period cross-over study to 
evaluate bioequivalence of SKF101804 Cefixime 200 mg/5 mL suspension versus 
Cefixime 200 mg/5 mL suspension reference product in healthy adult participants under 
fasting conditions.
Protocol Number: 205731
Short Title: Bioequivalence study between SKF101804 cefixime 200 mg/5 mL
suspension versus cefixime 200 mg/5 mL suspension reference product in healthy adult 
participants under fasting conditions
Compound Number:
SKF101804
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Medical Monitor Name and Contact Information
Refer to PAREXEL Communication plan
Regulatory Agency Identifying Number(s)
N/A
Approval Date: 13-NOV-2017
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited


PPD
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TABLE OF CONTENTS
PAGE
1.
SYNOPSIS...............................................................................................................5
2.
SCHEDULE OF ACTIVITIES (SOA).........................................................................7
3.
INTRODUCTION....................................................................................................13
3.1.
Study Rationale ..........................................................................................13
3.2.
Background ................................................................................................13
3.3.
Benefit/Risk Assessment ............................................................................13
3.3.1.
Risk Assessment .........................................................................14
3.3.2.
Benefit Assessment.....................................................................18
3.3.3.
Overall Benefit:Risk Conclusion...................................................18
4.
OBJECTIVES AND ENDPOINTS...........................................................................18
5.
STUDY DESIGN ....................................................................................................19
5.1.
Overall Design ............................................................................................19
5.2.
Number of Participants ...............................................................................20
5.3.
Participant and Study Completion...............................................................20
5.4.
Scientific Rationale for Study Design ..........................................................20
5.5.
Dose Justification........................................................................................20
6.
STUDY POPULATION...........................................................................................20
6.1.
Inclusion Criteria.........................................................................................21
6.2.
Exclusion Criteria........................................................................................22
6.3.
Lifestyle Restrictions...................................................................................24
6.3.1.
Meals and Dietary Restrictions ....................................................24
6.3.2.
Caffeine, Alcohol, and Tobacco ...................................................24
6.3.3.
Activity .........................................................................................24
6.4.
Screen Failures...........................................................................................24
7.
TREATMENTS.......................................................................................................25
7.1.
Treatments Administered............................................................................25
7.2.
Dose Modification .......................................................................................26
7.3.
Method of Treatment Assignment ...............................................................26
7.4.
Blinding.......................................................................................................26
7.5.
Preparation/Handling/Storage/Accountability..............................................26
7.6.
Treatment Compliance................................................................................27
7.7.
Concomitant Therapy..................................................................................27
7.8.
Treatment after the End of the Study ..........................................................28
8.
DISCONTINUATION CRITERIA.............................................................................28
8.1.
Discontinuation of Study Treatment ............................................................28
8.1.1.
Liver Chemistry Stopping Criteria ................................................28
8.1.2.
QTc Stopping Criteria ..................................................................29
8.1.3.
Temporary Discontinuation ..........................................................30
8.2.
Withdrawal from the Study..........................................................................30
8.3.
Lost to Follow Up........................................................................................30
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................30


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9.1.
Efficacy Assessments.................................................................................31
9.2.
Adverse Events...........................................................................................31
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................31
9.2.2.
Method of Detecting AEs and SAEs.............................................32
9.2.3.
Follow-up of AEs and SAEs.........................................................32
9.2.4.
Regulatory Reporting Requirements for SAEs .............................32
9.2.5.
Pregnancy ...................................................................................33
9.3.
Treatment of Overdose...............................................................................33
9.4.
Safety Assessments ...................................................................................34
9.4.1.
Physical Examinations.................................................................34
9.4.2.
Vital Signs....................................................................................34
9.4.3.
Electrocardiograms......................................................................34
9.4.4.
Clinical Safety Laboratory Assessments ......................................34
9.5.
Pharmacokinetics .......................................................................................35
9.6.
Pharmacodynamics ....................................................................................35
9.7.
Genetics .....................................................................................................36
9.8.
Biomarkers .................................................................................................36
9.9.
Health Economics OR Medical Resource Utilization and Health 
Economics..................................................................................................36
10. STATISTICAL CONSIDERATIONS........................................................................36
10.1.
Sample Size Determination ........................................................................37
10.2.
Populations for Analyses ............................................................................37
10.3.
Statistical Analyses.....................................................................................38
10.3.1.
PK Analysis .................................................................................38
10.3.2.
Protocol Deviations and Changes to Planned Analyses...............39
10.3.3.
PK Parameters ............................................................................39
10.3.3.1.
Primary Pharmacokinetic Parameters for 
cefixime......................................................................39
10.3.3.2.
Secondary Pharmacokinetic Parameters for 
cefixime......................................................................39
10.3.4.
Analysis of Bioequivalence ..........................................................39
10.3.5.
Safety Analyses...........................................................................40
10.3.6.
Other Analyses ............................................................................40
10.3.7.
Interim Analyses ..........................................................................40
11. REFERENCES.......................................................................................................41
12. APPENDICES........................................................................................................42
12.1.
Appendix 1: Abbreviations and Trademarks................................................42
12.2.
Appendix 2: Clinical Laboratory Tests.........................................................45
12.3.
Appendix 3: Study Governance Considerations..........................................47
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................51
12.5.
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................56
12.6.
Appendix 6: Liver Safety: Required Actions and Follow-up
Assessments ..............................................................................................60
12.7.
Appendix 7: Reporting Analysis Plan ..........................................................62


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1.
SYNOPSIS
Protocol Title: An open-label, randomised, single-dose, two-period cross-over study to 
evaluate bioequivalence of SK101804 Cefixime 200 mg/5 mL suspension versus 
Cefixime 200 mg/5 mL suspension reference product in healthy adult participants under 
fasting conditions.
Short Title: Bioequivalence study between SKF101804 cefixime 200 mg/5 mL
suspension versus cefixime 200 mg/5 mL suspension reference product in healthy adult 
participants under fasting conditions
Rationale:
This study will determine if cefixime 200 mg/5 mL powder for suspension (test 
formulation: SKF101804; FIXVALTM; GlaxoSmithKline Pakistan Limited) is
bioequivalent to cefixime 200 mg/5 mL suspension (reference formulation: Cefspan, 
manufactured by Barrett Hodgson Pakistan under licence from Astellas Pharma, Japan).
Objectives and Endpoints:
Objective
Endpoint
Primary
To determine if 200 mg/5 mL cefixime 
(SKF101804) powder for suspension is
bioequivalent to reference 200 mg/5 mL
cefixime suspension in healthy adult 
participants under fasting conditions.
Plasma PK parameters: AUC(0-t) and Cmax, for 
cefixime in relevant treatments
Secondary
To assess secondary PK parameters of 200 
mg/5 mL cefixime powder for suspension 
(SKF101804) relative to reference 200 mg/5
mL cefixime suspension in healthy adult 
participants under fasting conditions. 
To compare the safety and tolerability of a 
single dose of 200 mg/5 mL cefixime powder 
for suspension (SKF101804) with reference 
200 mg/5 mL cefixime suspension, in healthy 
adult participants under fasting conditions.
Plasma PK parameters: AUC(0-), tmax, 
%AUCex and t½ for cefixime in relevant 
treatments.
Adverse events (AE), clinical laboratory 
values (Haematology and Biochemistry) and 
vital signs
AUC(0-) =  Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite 
time; %AUCex= Percentage of AUC(0-) obtained by extrapolation; AUC(0-t)= Area under the plasma 
concentration versus time curve from time zero to t, where t is the time of the last quantifiable 
concentration;Cmax= Maximum observed concentration; PK = Pharmacokinetic t½= Terminal phase 
half-life; Tmax= Time of occurrence of Cmax


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Overall Design:
This is a Phase I, open label, balanced, randomised, single dose, two-way crossover 
study, enrolling 28 healthy participants at a single centre.
Each enrolled study participant will take part in two treatment periods in accordance with 
the randomisation schedule. The treatment periods will be separated by a washout period 
of at least 7 days and no more than 14 days.
Number of Participants:
Up to 28 participants will be randomized to yield at least 24 evaluable participants 
completing the study.
Treatment Groups and Duration:
Study treatments will be referred to as Test and Reference throughout the protocol:

Treatment A – Test: SKF101804 (FIXVALTM) 200 mg cefixime (200 mg/5 mL
powder for oral suspension).

Treatment B   Reference: (Cefspan), 200 mg cefixime (200 mg/5 mL powder for 
oral suspension).
Treatment periods 1 and 2 will be separated by a washout period of 7 to 14 days. 
The total duration in the study for each participant is expected to be 5 to 7 weeks, from 
screening to their last visit.
Treatment Groups and Sequences:

Participants will be randomised to one of two sequences (A-B or B-A), and 
administered a single oral dose of one of the two treatments (A or B) in each 
treatment period, such that each participant receives a dose of each treatment in 
the study.


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2.
SCHEDULE OF ACTIVITIES (SOA)
Details of study assessments and collection windows are given in the Schedule of 
Activities (SoA), Table 1.


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Table 1
Schedule of Activities
Procedure
Screening 
(Day -21  
to Day -1)
Treatment Periods 1 and 2
Follow-up
(within 7 days 
post last dose or 
at 
discontinuation)
Notes
Day –1
Day 1
Day 2
Informed consent
X
Inclusion and exclusion criteria
X
X
Refer to Section 6 . Recheck clinical status before 
randomization.
Domiciled to the Unit 
X
X
X
Participants to be admitted on Day -1 of each treatment 
period, and discharged on Day 2. 
Outpatient Visits
X
Discharge
X
Participants will be discharged from the unit after the 
collection of the 24 hours post dose PK sample, vital signs, 
lab assessments and, urinalysis; following review by a doctor 
to assess participant safety. 
At the end of treatment period 2, in addition to the other 
assessments taken at 24 hours post dose (Day 2), all female 
participants will also have a urine pregnancy test, prior to 
discharge.
Participants who have normal safety assessment results at 
the end of treatment period 2 do not require a follow up.


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Procedure
Screening 
(Day -21  
to Day -1)
Treatment Periods 1 and 2
Follow-up
(within 7 days 
post last dose or 
at 
discontinuation)
Notes
Day –1
Day 1
Day 2
Follow up (Phone Call or Outpatient Visit)
X
If a participant’s safety assessments (medical exam, vital 
signs, ECG, Lab assessments) are abnormal and clinically 
significant at Treatment Period 2 discharge or if a participant 
has an open AE, then a follow up phone call or outpatient 
clinic visit is required within 7 days  (+2 days if required). 
Enquiries on the participant’s general health, including any 
AEs/SAEs/concomitant medication must be recorded in the 
medical notes.
Demography and Medical history (includes 
substance usage)
X
Substances: Drugs, Alcohol, tobacco and caffeine
Physical examination 
X
X
Screening: Full physical examination including height and 
weight
Day -1: Abbreviated physical exam (excluding height and 
weight) 
Past and current medical conditions  
X
X
Pregnancy test (WOCBP only)
X
X
X
Serum -hCG: at screening. 
Urine -hCG: at Day-1 of both Treatment periods and at the 
end of Treatment period 2 on Day 2.
HIV, Hepatitis B and C screening
X
Testing for Hepatitis B (HBsAg) and Hepatitis C (HepC
antibody) at screening is not required if this was performed 
within 3 months prior to first dose of study treatment. 
Participants, who are positive for Hepatitis C antibody due to 
prior resolved disease, must have a confirmatory negative 
Hepatitis C RNA test. 


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Procedure
Screening 
(Day -21  
to Day -1)
Treatment Periods 1 and 2
Follow-up
(within 7 days 
post last dose or 
at 
discontinuation)
Notes
Day –1
Day 1
Day 2
Laboratory assessments (include liver 
chemistries)a
X
X
X
Screening: Participants are required to fast at least 10 hours 
prior to the Screening Laboratory assessment. Haematology, 
Biochemistry, Coagulation profile (PT and aPTT) and
Urinalysis are assessed.
Day -1: Haematology, Biochemistry and Urinalysis are 
assessed.
Day 2: Haematology, Biochemistry and Urinalysis samples 
are obtained 24 hours post dose, prior to discharge. 
Additional safety labs must be collected as deemed 
necessary at the Investigator’s discretion.
Urine Drug/Urine Cotinine/Breath alcohol
X
X
12-lead ECGa
X
12-lead ECG will be completed at screening only.
Vital signsa
X
X
X
Vitals will be taken at:

Screening,  

Day 1: pre-dose and post dose at, 2.00, 4.00, and 
6.00 hours 

Day 2: 24.00 hours post-dose. 
Post dose vitals to be taken 30min of each time point.
Randomization
X
Day 1 of treatment period 1 only. 


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Procedure
Screening 
(Day -21  
to Day -1)
Treatment Periods 1 and 2
Follow-up
(within 7 days 
post last dose or 
at 
discontinuation)
Notes
Day –1
Day 1
Day 2
Study treatment
X
Screening and Day -1 results must be reviewed by physician 
prior to randomisation and dosing. Participants to be fasted 
10.00 hours prior and 4.00 hours post dose. Dosing between 
Treatment periods will be separated by a washout of 7 -14 
days. Participants will remain in a sitting or semi-supine 
position for at least 20 minutes after dosing on Day 1 of each 
treatment period. 
AE Review
=====================================
Collected from the start of dosing (Day 1, Treatment period 
1) to the participant’s final discharge from study at the end of 
Treatment Period 2, follow up call or last outpatient visit, 
whichever is the latest. 
SAE review
================================================
Any SAEs assessed as related to study participation (e.g. 
investigational product, protocol-mandated procedures, 
invasive tests) or related to a GSK concomitant medication 
will be recorded from the time a participant consents to 
participate in the study up to and including any follow up 
contact.
Concomitant medication review
==============================================


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Procedure
Screening 
(Day -21  
to Day -1)
Treatment Periods 1 and 2
Follow-up
(within 7 days 
post last dose or 
at 
discontinuation)
Notes
Day –1
Day 1
Day 2
Pharmacokineticsa
X
X
Day 1:  Pre-dose, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 
5.0, 6.0, 7.0 8.0, 10.0, 12.0, 16.0 and 20.0 hours post dose
Day 2: 24.00 hours post dose
Pre-dose sample will be taken within 60 minutes before 
dose. Post dose samples for:

0.50 -2.00 hours will be taken 2 min; 

2.50 – 10.00 hours will be taken 5 min; and 

12.00 – 24.00 hours will be taken 10 min. 
a. The order of assessments to be followed where an ECG, Vital Signs and Blood sample for either PK or Lab assessments are required at the same time point, should always be first 
ECG, second vital signs and lastly blood sampling, whilst ensuring that the timing for PK blood samples remains within the sampling window.
Note: PK= pharmacokinetic; ECG= electrocardiogram; AE= adverse events; SAE= serious adverse events; WOCBP= woman of childbearing potential; HBsAg= Hepatitis B surface 
antigen ; RNA= ribonucleic acid; PT= prothrombin time; aPTT= activated partial thromboplastin time; GSK= GlaxoSmithKline 


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3.
INTRODUCTION
3.1.
Study Rationale
GlaxoSmithKline (GSK) Product, SKF101804 (cefixime) 200 mg/5 mL suspension is 
marketed in Pakistan as FIXVALTM.  This study is required to determine whether the test 
product SKF101804/FIXVALTM is bioequivalent to the reference cefixime 200 mg/5mL
suspension (Cefspan) in healthy adult participants under fasting conditions.  
Bioequivalence (BE) will be declared if the 90% confidence interval (CI) for the true 
ratio of test to reference geometric means falls entirely within the range of 0.80 to 1.25 
for all primary PK parameters.
3.2.
Background
Cefixime is an orally active third generation cephalosporin indicated for the treatment of 
acute exacerbations of chronic bronchitis, acute otitis media, uncomplicated acute cystitis 
and uncomplicated pyelonephritis, caused by susceptible organisms.  Like other 
cephalosporins, cefixime exerts its antibacterial activity by binding to and inhibiting the 
action of penicillin-binding proteins involved in the synthesis of bacterial cell walls.  This 
leads to bacterial cell lysis and cell death [Cefixime Summary of Product Characteristics, 
2015; Suprax Product Monograph, 2016].  
The pharmacokinetic properties of cefixime show rapid absorption with peak serum 
concentrations reached within 2-6 hours following oral administration of the tablet or 
suspension.  Cefixime has a half life of 3-4 hours and predominantly excreted in the urine 
and bile [Cefixime Summary of Product Characteristics, 2015; Suprax Product 
Monograph, 2016].  The oral bioavailability of cefixime tablets and suspension is about 
40-50% and is unaffected by food; however time to maximal absorption is increased 
approximately by 0.8 hours when administered with food.  The AUC is approximately 
26.4% greater and the Cmax approximately 20.7% greater with the oral suspension 
compared to the tablet.  Because of this lack of bioequivalence between tablet/capsule 
and suspension consideration needs to be given if the oral suspension is to be substituted 
for the tablet/capsule. 
A detailed description of the chemistry, pharmacology, efficacy and safety of cefixime is 
provided in the cefixime product label [Cefixime Summary of Product Characteristics, 
2015; Suprax Product Monograph, 2016]
3.3.
Benefit/Risk Assessment
Cefixime is an approved antibacterial agent with a well-established safety profile based 
on clinical trial safety data.  Cefixime was originally marketed as Suprax (Astellas 
Pharma, Germany) in the EU. More detailed information about the expected benefits and 
risks and reasonably expected adverse events (AE) of cefixime may be found in the 
Summary of Product Characteristics (SPC) [Cefixime Summary of Product 
Characteristics, 2015; Suprax Product Monograph, 2016].
The following section outlines the risk assessment and mitigation strategy for this 
protocol.


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3.3.1.
Risk Assessment
The potential risks of clinical significance for cefixime suspensions are derived from the 
prescribing information from marketed formulations. Most of these reported risks are 
uncommon, rare or very rare. The likelihood of these risks in a healthy population 
receiving a single dose is therefore expected to be lower.


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) SKF101804
Contraindication
Hypersensitivity to the active substance cefixime, 
other cephalosporin antibiotics, penicillin or any 
betalactam antibiotic or to any of the excipients
Exclude participants with a known history of 
hypersensitivity to cefixime, other cephalosporin 
antibiotics, penicillin or any betalactam antibiotic to 
any of the excipients.
If severe hypersensitivity reactions or anaphylactic 
reactions occur after administration of cefixime, the 
use of cefixime should be discontinued immediately
and appropriate emergency measures should be 
initiated.
Hypersensitivity
Cefixime should not be given to patients who have 
shown hypersensitivity to other drugs.
Exclude participants who have shown hypersensitivity 
to other drugs.
Severe cutaneous adverse reactions
Severe cutaneous adverse reactions such as toxic 
epidermal necrolysis, Stevens-Johnson syndrome 
and drug rash with eosinophila and systemic 
symptoms (DRESS) have been reported in some 
patients on cefixime. 
If severe cutaneous adverse reactions occur, 
cefixime should be discontinued and appropriate 
therapy and/or measures should be taken.
Acute renal failure and renal impairment
As with other cephalosporins, cefixime may cause 
acute renal failure including tubulointerstitial nephritis 
as an underlying pathological condition. 
Cefixime should be administered with caution in 
patients with creatinine clearance <20 mL/ min
Exclude any participants with abnormal renal function 
as determined by review of creatinine clearance at 
screening.
If acute renal failure occurs, cefixime should be 
discontinued and appropriate therapy and/or
measures should be taken.
Pseudomembranous colitis
Treatment with broad spectrum antibiotics alters the 
normal flora of the colon and may permit overgrowth 
of clostridia. Studies indicate that a toxin produced by
Clostridium difficile is a primary cause of antibiotic-
associated diarrhoea.
Exclude subjects with a history of colitis


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Concomitant medication
Concomitant intake with potentially nephrotoxic 
substances (such as aminoglycoside
antibiotics,colistin, polymyxin and viomycin) and 
strong-acting diuretics (e.g.ethacrynic acid or 
furosemide) induce an increased risk of impairment of 
renal function.
Concomitant therapy is restricted as per Section 7.7 of 
the protocol.
Nifedipine, a calcium channel blocker, may increase 
bioavailability of cefixime up to 70%.
As common with other cephalosporins, increases in 
prothrombin time have been noted in a few patients. 
Care should therefore be taken in patients receiving 
anticoagulation therapy. Cefixime should be 
administered with caution 
Blood and Lymphatic system reactions
Cefixime should not be administered to subjects with 
a history of cephalosporin-associate haemolytic 
anaemia as the recurrence of haemolysis is much 
more severe
Exclude subjects with a history of cephalapsorin 
mediated haemolytic anaemia.  Haematology 
assessment at screening, Day-1 and at discharge.
Concomitant medication
Administration of cefixime may reduce the efficacy of 
oral contraceptives. It is therefore recommended to 
take supplemental non-hormonal contraceptive 
measures
Contraceptive guidance in Appendix 5 will exclude 
oral contraceptives as an acceptable form of control
Study Procedures
Influence on laboratory diagnostic tests:
A false positive reaction for glucose in the urine may 
occur with Benedict's or Fehling's solutions or with 
copper sulphate test tablets, but not with tests based 
on enzymatic glucose oxidase reactions.
Glucose tests based on enzymatic glucose oxidase 
reactions will be used for the study
Blood sampling
An intravenous cannula will be inserted into 
participants to obtain blood samples for testing. This 
may cause some pain, discomfort, bruising and 
redness/irritation at the site of injection.
Participants will be monitored closely by the site staff 
during the visits. The cannula will be removed if this 
is causing pain and discomfort.  If the cannula is 
removed, the subsequent blood samples will be 


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
collected by venepuncture or the cannula will be 
replaced.


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3.3.2.
Benefit Assessment
Healthy participants will be enrolled into this study who will gain no direct health 
benefits from participation. Their involvement will be contributing to the PK analysis and 
safety profile of SKF101804 compared to reference cefixime suspension.
3.3.3.
Overall Benefit:Risk Conclusion
Healthy participants will not gain any direct health benefit by participating in this study. 
Measures have been taken to minimise risk to participants in this study. 
4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
To determine if 200 mg/5 mL cefixime 
(SKF101804) powder for suspension is 
bioequivalent to reference 200 mg/5 mL 
cefixime suspension in healthy adult 
participants under fasting conditions.
Plasma PK parameters: AUC(0-t) and Cmax, for 
cefixime in relevant treatments
Secondary
To assess secondary PK parameters of 200 
mg/5 mL cefixime powder for suspension 
(SKF101804) relative to reference 200 mg/5 mL 
cefixime suspension in healthy adult 
participants under fasting conditions. 
To compare the safety and tolerability of a 
single dose of 200 mg/5 mL cefixime powder for 
suspension (SKF101804) with reference 200 
mg/5 mL cefixime suspension, in healthy adult 
participants under fasting conditions.
Plasma PK parameters: AUC(0-∞), tmax, 
%AUCex and t½ for cefixime in relevant 
treatments.
Adverse events (AE), clinical laboratory values 
(Haematology and Biochemistry and vital signs)
AUC(0-) =  Area under the concentration-time curve from time zero (pre-dose) extrapolated to 
infinite time; %AUCex= Percentage of AUC(0-) obtained by extrapolation; AUC(0-t)= Area under the 
plasma concentration versus time curve from time zero to t, where t is the time of the last 
quantifiable concentration;Cmax= Maximum observed concentration; PK = pharmacokinetic t½= 
Terminal phase half-life; Tmax= Time of occurrence of Cmax


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5.
STUDY DESIGN
5.1.
Overall Design
This is a Phase I, open label, balanced, randomised, single dose, two-way crossover 
study, enrolling approximately 28 healthy participants at a single centre. 
Each enrolled study participant will participate in two treatment periods in accordance 
with the randomisation schedule. Treatment period 2 will be separated by a washout 
period of at least 7 days and no more than 14 days from Treatment Period 1, Day 2. 
Figure 1
Study Schematic
Treatments
A = Test SKF101804 cefixime 200 mg /5 mL suspension
B = Reference  - cefixime 200 mg/5 mL suspension
SCREENING
RANDOMISATION (n=28)
Treatment Sequences 1-2
Sequence 2:  B-A  (n=14)
Sequence 1:  A-B  (n=14)
21days 
prior to 
Day -1
7-14 days 
washout 
between 
Treatment 
Periods
FOLLOW-UP
(If required at the end of the last 
Treatment period)
Study participants will be randomised to one of two treatment sequences (A-B or B-A). A 
single dose of one of the two treatments A or B, will be administered on Day 1, in each 
treatment period.  Each participant will participate in both treatment periods and receive a 
single dose of each treatment.
Study treatments will be referred to as Test and Reference throughout the protocol:

Treatment A – Test: SKF101804 (FIXVALTM) 200 mg cefixime (200 mg/5 mL 
powder for suspension).

Treatment B - Reference: (Cefspan), 200 mg cefixime (200 mg/5 mL powder 
for suspension).
Treatment periods 1 and 2 will be separated by a washout period of 7 to 14 days. 


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The total duration in the study for each participant is expected to be 5 to 7 weeks, from
screening to their last visit.
5.2.
Number of Participants
Approximately 28 participants will be randomized such that at least 24 evaluable
participants complete the study. 
Participants who withdraw or are withdrawn from the study will not be replaced, unless 
fewer complete the study than the estimated number of required evaluable participants 
(see Section 10.1). 
If a participant is replaced, the replacement will be allocated the subject number of 
 
plus the subject number being replaced (e.g., Subject 
 will be replaced by 
  The 
subject numbers being replaced will be selected such that the replacement participants 
receive the same treatment sequence as the withdrawn participants and the sequence 
balance is maintained.
5.3.
Participant and Study Completion
A participant is considered to have completed the study if he/she has completed all 
phases of the study including the last scheduled procedure shown in the SoA.
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 SoA for the last participant in the trial.
5.4.
Scientific Rationale for Study Design

This study is a standard single dose fasted bioequivalence design.

This study will assess whether the test formulation is bioequivalent to the 
reference treatment.

This is a pivotal study and meets guidelines for all major authorities on 
bioequivalence study design. 
5.5.
Dose Justification
The dose of cefixime (200 mg/5 mL) is a well established and approved dose, marketed 
for the treatment of bacterial infections in adults. This study will be conducted using a 
single dose of the highest SKF101804 cefixime suspension strength marketed, in keeping 
with international bioequivalence guidelines. [EMEA, 2010].
6.
STUDY POPULATION
Specific information regarding warnings, precautions, contra-indications, AEs, and other 
pertinent information on the test product or other study treatment that may impact 
participant eligibility is provided in the reference cefixime summary of product 
PPD
PPD
PPD


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characteristics (SPC) [Cefixime Summary of Product Characteristics, 2015; Suprax 
Product Monograph, 2016 ].  
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted.
6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
Age
1.
Participant must be 18 to 65 years of age inclusive, at the time of signing the 
informed consent.
Type of Participant and Disease Characteristics
2.
Healthy, non-smoker, as determined by the investigator or medically qualified 
designee based on a medical evaluation including medical history, physical 
examination, laboratory tests, and cardiac monitoring.
3.
A participant with a clinical abnormality or laboratory parameter(s) which is/are not 
specifically listed in the inclusion or exclusion criteria, outside the normal reference 
range for the population being studied may be included at investigator discretion in 
consultation with the Medical Monitor if required, agree and document that the 
finding is unlikely to introduce additional risk factors and will not interfere with the 
study procedures.
Weight
4.
Body weight 50 kilogram (kg) and body mass index (BMI) within the range 19-30 
kg/m2 (inclusive).
Sex
5.
Healthy male or female participants
a. Male participants:
A male participant must agree to use contraception as detailed in Appendix 5 of this
protocol during the treatment period and for at least 5 days after the last dose of 
study treatment and refrain from donating sperm during this period.
b. Female participants: 
A female participant is eligible to participate if she is not pregnant (see Appendix 5 ),
not breastfeeding, and at least one of the following conditions applies:
i.
Not a woman of childbearing potential (WOCBP) as defined in Appendix 5
OR


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ii.
A WOCBP who agrees to follow the contraceptive guidance in Appendix 5
during the treatment period and for at least 30 days after the last dose of study 
treatment. Note: Oral contraceptives are not an acceptable form of 
contraceptive for WOCBP.
The investigator is responsible for ensuring that male and female study participants 
understand how to correctly use the methods of contraception described in Appendix 5.
Informed Consent
6.
Capable of giving signed informed consent as described in Appendix 3 which
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol.
6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1.
History or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, 
endocrine, hematological, or neurological disorders capable of significantly altering 
the absorption, metabolism, or elimination of drugs; constituting a risk when taking 
the study treatment; or interfering with the interpretation of data
2.
Any other condition that is capable of significantly altering the absorption, 
metabolism, or elimination of drugs; constituting a risk when taking the study 
treatment; or interfering with the interpretation of data.
3.
Abnormal renal function, as determined by creatinine clearance and considered as 
clinically significant by the investigator will be excluded.
4.
Abnormal blood pressure (BP) as determined by the investigator.
5.
Lymphoma, leukemia, or any malignancy within the past 5 years except for basal 
cell or squamous epithelial carcinomas of the skin that have been resected with no 
evidence of metastatic disease for 3 years
6.
Breast cancer within the past 10 years
7.
Alanine transaminase (ALT) >1.5x upper limit of normal (ULN) 
8.
Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%). 
9.
Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones)
10. History of colitis
11. History of cephalosporin induced haemolytic anaemia
12. QT interval corrected for heart rate according to Bazett’s formula (QTcB) >450 
milliseconds (msec). Participants with a known risk of QT prolongation will be 
excluded.


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NOTES:

For purposes of data analysis, only QTcB, will be used.
Prior/Concomitant Therapy
13. Past or intended use of over-the-counter or prescription medication including herbal 
medications, within 14 days prior to dosing unless in the opinion of the investigator 
and sponsor, the medication will not interfere with the study. Specific medications 
listed in Section 7.7 may be allowed
Prior/Concurrent Clinical Study Experience
14. Participation in the study would result in loss of blood or blood products in excess of 
500 mL within 90 days
15. Exposure to more than 4 new chemical entities within 12 months prior to the first 
dosing day
16. Current enrolment or past participation within the last 90 days before signing of 
consent in this or any other clinical study involving an investigational study 
treatment or any other type of medical research 
Diagnostic assessments
17. Presence of Hepatitis B surface antigen (HBsAg) at screening. Positive Hepatitis C 
antibody test result at screening.
NOTE:  Participants with positive Hepatitis C antibody due to prior resolved disease can 
be enrolled, only if a confirmatory negative Hepatitis C ribonucleic acid (RNA) test is 
obtained
18. Positive pre-study drug/alcohol screen
19. Positive human immunodeficiency virus (HIV) antibody test
20. Regular use of known drugs of abuse
Other Exclusions
21. Regular alcohol consumption within 6 months prior to the study defined as:
An average weekly intake of >21 units for males or >14 units for females.  One unit 
is equivalent to 8 g of alcohol: a half-pint (~240 mL) of beer, 1 glass (125 mL) of 
wine or 1 (25 mL) measure of spirits. 
22. Urinary cotinine levels indicative of smoking or history or regular use of tobacco- or 
nicotine-containing products within 6 months prior to screening.
23. Sensitivity to heparin or heparin-induced thrombocytopenia
24. Known sensitivity to any drugs from the class of cephalosporins, or components 
thereof.
25. Known sensitivity to any drugs from the class of penicillin, or components thereof.


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26. Known sensitivity to any of the study treatments, or components thereof, or drug or 
other allergy that, in the opinion of the investigator or medical monitor, 
contraindicates participation in the study.
6.3.
Lifestyle Restrictions
6.3.1.
Meals and Dietary Restrictions

Refrain from consumption of red wine, Seville oranges, grapefruit or grapefruit 
juice, pomelos, exotic citrus fruits, grapefruit hybrids, or fruit juices from 7 days 
before the start of study treatment until after the final dose.

Participants will be administered the treatment in the fasted state.

Following an overnight fast of at least 10 hrs, participants should be administered the 
study drug with 240 mL (8 fluid ounces) of water.  No food should be allowed for at 
least 4 hrs post-dose.  Water is allowed as desired except for one hour before and 
after drug administration.  Participants should receive standardized meals scheduled 
at the same time in each period of the study.
6.3.2.
Caffeine, Alcohol, and Tobacco

During each treatment period, participants will abstain from ingesting caffeine- or 
xanthine-containing products (eg, coffee, tea, cola drinks, and chocolate) for 24 
hours before the start of dosing until after collection of the final pharmacokinetic 
(PK) sample.

During each treatment period, participants will abstain from alcohol for 24 hours 
before the start of dosing until after collection of the final PK sample. 
6.3.3.
Activity

Participants will abstain from strenuous exercise for 48 hours before each blood
collection for clinical laboratory tests. Participants may participate in light 
recreational activities during studies (eg, watching television, reading).
6.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomised. 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, and any serious adverse events 
(SAEs).
Individuals who do not meet the criteria for participation in this study (screen failure) 
may not be rescreened.


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7.
TREATMENTS
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol.
7.1.
Treatments Administered
Study Treatment
Test Product
Reference Product
Study Treatment Name:
SKF101804/Cefixime 200 mg/ 5 
mL
(FIXVALTM)
Cefixime 200 mg/5 mL 
(Cefspan)
Dosage formulation:
Suspension
(Supplied as powder for 
reconstitution)
Suspension
(Supplied as powder for 
reconstitution)
Unit dose 
strength(s)/Dosage 
level(s):
200 mg/ 5 mL
(Participants will be given 5 mL of suspension, thus receiving a 200 
mg dose)
Route of Administration 
Route: Oral
Duration: single dose
Dosing instructions:
The suspension is to be swallowed immediately. Record the time 
when the suspension has been completely swallowed. Participants will 
be given 240 mL of water to rinse the mouth and consume.
Participants must consume the entire 240 mL
Physical Description:
Off-white to cream coloured 
powder
The suspension is a white to off 
white viscous suspension with a 
fruit flavour and odour
Off white to cream coloured powder
The suspension is a white to off 
white viscous suspension with a 
strawberry flavour and odour
Manufacturer /Supplier
GlaxoSmithKline Pakistan 
Limited, Sector 21, Korangi, 
Karachi, Pakistan
Barrett Hodgson Pakistan (PVT) 
Limited (under licence from Astellas 
Pharma Inc, Japan), F/423, SITE, 
Karachi, Pakistan


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7.2.
Dose Modification
Not applicable.
7.3.
Method of Treatment Assignment
Participants will be assigned to one of two sequences (A-B or B-A) in accordance with 
the randomisation schedule generated by PAREXEL Biostatistics, prior to the start of the 
study, using validated software. Randomization numbers will be assigned sequentially. 
Possible replacements will be handled according to Section 5.2.
A description of each regimen is provided in Table 2 .  Treatments administered are as 
follows:

Treatment A – Test SKF101804 200 mg cefixime (200 mg/5 mL powder for
oral suspension (FIXVALTM))

Treatment B – Reference 200 mg (200 mg/5 mL powder for oral suspension 
(Cefspan))
On Day 1, participants will be assigned a unique randomization number.  The 
randomization number encodes the participant’s assignment to one of the 2 sequences. 
On Day 1, each participant will be administered a single dose of open label study 
treatment.  After a washout period of 7-14 days, each participant will be administered a 
single dose of the other treatment not previously received. 
Table 2
Description of each treatment sequence
Sequence
Number of 
Participants Per 
Group
Treatment Period 1
Treatment Period 2
A-B
14
Treatment A
(SKF101804)
Treatment B
Reference
B-A
14
Treatment B
Reference
Treatment A
(SKF101804)
7.4.
Blinding
This is an open label study; potential bias will be reduced by assigning treatment by 
randomization. 
7.5.
Preparation/Handling/Storage/Accountability
1.
The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study treatment received and any discrepancies 
are reported and resolved before use of the study treatment.


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2.
Only participants enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment. All study treatments 
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 treatment accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records).
4.
Further guidance and information for the final disposition of unused study treatment 
are provided by GSK after study conduct.

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.  

A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from 
GSK.

Preparation of the reconstituted suspension will be done in accordance with the 
summary of product characteristics.
7.6.
Treatment Compliance

Individual (per participant) unit doses will be prepared from bulk supply. Suspension 
is prepared from reconstituted bulk powder for suspension.  A 5 mL dose will be 
administered orally using a suitable syringe.

When participants are dosed at the site, they will receive study treatment directly 
from the investigator or designee, under medical supervision.  The date and time of 
each dose administered in the clinic will be recorded in the source documents.  The 
dose of study treatment and study participant identification will be confirmed at the 
time of dosing by a member of the study site staff other than the person 
administering the study treatment.  
7.7.
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) that the participant is receiving at the time of 
enrolment or receives during the study must be recorded along with:

reason for use

dates of administration including start and end dates

dosage information including dose and frequency
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
Participants must abstain from taking prescription or non-prescription drugs (including 
vitamins and dietary or herbal supplements) within 7 days (or 14 days if the drug is a 


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potential enzyme inducer) or 5 half-lives (whichever is longer) before the start of study 
treatment until completion of the follow-up visit, unless, in the opinion of the investigator 
and sponsor, the medication will not interfere with the study. 
Paracetamol, at doses of  2 grams/day, is permitted for use any time during the study.  
Other concomitant medication may be considered on a case-by-case basis by the 
investigator in consultation with the Medical Monitor if required.
7.8.
Treatment after the End of the Study
This is a study in healthy participants who will not receive any treatment after the end of 
the study.
8.
DISCONTINUATION CRITERIA
8.1.
Discontinuation of Study Treatment
Participants will be permanently withdrawn from study treatment, at the discretion of the 
investigator after receiving the first dose of study medication.
8.1.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology.
Discontinuation of study treatment for abnormal liver tests is required when a participant 
meet one of the conditions outlined in Figure 2 below or if the investigator believes that it 
is in the best interest of the participant.
Study treatment will be discontinued for a participant if liver chemistry stopping criteria 
are met:


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Figure 2
Phase I Liver Chemistry Stopping Criteria – Liver Stopping Event 
Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
*INR value not applicable to subjects on anticoagulants 
ALT ≥3xULN 
No
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments  section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 6.
8.1.2.
QTc Stopping Criteria

The same QT correction formula must be used for each individual participant to 
determine eligibility for and discontinuation from the study.  This formula may not 
be changed or substituted once the participant has been enrolled.

For example, if a participant is eligible for the protocol based on QTcB, then 
QTcB must be used for discontinuation of this individual participant as well.

Once the QT correction formula has been chosen for a participant’s eligibility, 
the same formula must continue to be used for that participant for all QTc data 
being collected for data analysis.  Safety ECGs and other non-protocol specified 
ECGs are an exception.  

The QTcB should be based on single QTcB values obtained over a brief (e.g., 5-10 
minute) recording period.  
A participant that meets either of the bulleted criteria below will be withdrawn from 
study treatment.

QTc, QTcB, >500 msec,

Change from baseline: QTc >60 msec
See the SoA for data to be collected at the time of treatment discontinuation and follow-
up and for any further evaluations that need to be completed.


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8.1.3.
Temporary Discontinuation
Participants withdrawn from study treatment, will continue in the study until completion 
of their follow up visit for the study period.
8.2.
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.

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.

Refer to the 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.
8.3.
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 fail 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 or not 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, 
three (3) telephone calls and, if necessary, a certified letter to the 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 with a primary reason of lost to follow-up. 
9.
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarized in the SoA. 

Protocol waivers or exemptions are not allowed 


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
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study treatment.

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. 

During screening the following will be completed:

Demographic parameters will be captured: Year of birth, sex, race and ethnicity.

Medical /Medication /family history will be assessed as related to the 
inclusion/exclusion criteria in Section 6.

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.

Blood samples will be collected as per SoA.

The maximum amount of blood collected from each participant over the 
duration of the study, including any extra assessments that may be required, will 
not exceed 500 mL.

Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.
9.1.
Efficacy Assessments
Not applicable
9.2.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 4.
The investigator and any 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 treatment or the study,
or that caused the participant to discontinue the study treatment/study (see Section 8).
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All SAEs will be collected from the time a participant consents to participate in 
the study until the follow-up visit at the time points specified in the SoA 
(Section 2).


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
All AEs will be collected from the start of IP administration until the follow-up 
contact at the time points specified in the SoA (Section 2 ).

Medical occurrences that begin before the start of study treatment but after 
obtaining informed consent will be recorded on the Medical History/Current
Medical Conditions section of the case report form (CRF) 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 4. 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 in former study 
participants. 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 treatment or study 
participation, the investigator must promptly notify the sponsor.

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 4.
9.2.2.
Method of Detecting AEs and SAEs
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. 
9.2.3.
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 and non-serious AEs will be followed 
until the event is resolved, stabilized, otherwise explained, or the participant is lost to 
follow-up (as defined in Section 8.3). Further information on follow-up procedures is 
given in Appendix 4.
9.2.4.
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 towards the safety of 
participants and the safety of a study treatment under clinical investigation are 
met. 

The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study treatment 
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC), and 
investigators.


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
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 SAE) from the 
sponsor will review and then file it along with the Investigator’s Brochure and 
will notify the IRB/IEC, if appropriate according to local requirements.
9.2.5.
Pregnancy

Details of all pregnancies in female participants and, if indicated, female partners of 
male participants will be collected from the start of study treatment until 5 days after 
the last dose or until the follow up visit where indicated. 

If a pregnancy is reported, the investigator should inform GSK within 24 hrs of 
learning of the pregnancy and should follow the procedures outlined in Appendix 5

Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered to be a SAE.
9.3.
Treatment of Overdose
For this study, any dose of SKF101804 or reference greater than 200 mg/ 5 mL within a 
24-hour time period will be considered an overdose.
In the event of acute excessive oral over dosage, routine emergency measures must be 
followed. In addition, ECG, renal function and urine pH should be monitored.  
Administer magnesium or calcium containing antacids which reduce the absorption of 
cefixime. Adequate hydration must be maintained. The administration of activated 
charcoal as soon as possible after oral overdose may prevent excessive increase of 
systemic cefixime exposure. The principal investigator will be responsible for the 
appropriate medical management of any participant who has an overdose.
In the event of an overdose, the investigator/treating physician should:
1.
Contact the Medical Monitor immediately.
2.
Closely monitor the participant for AE/SAE and laboratory abnormalities until 
cefixime can no longer be detected systemically (at least 3 days).
3.
Obtain a plasma sample for PK analysis within 3 days from the date of the last dose 
of study treatment if requested by the Medical Monitor (determined on a case-by-
case basis).
4.
Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF.
Decisions 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.


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9.4.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA.
Additional time points for safety tests (such as vital signs, physical exams and laboratory 
safety tests) may be added during the course of the study based on newly available data 
or investigator’s discretion to ensure appropriate safety monitoring.
9.4.1.
Physical Examinations

A complete 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.

A brief physical examination will include, at a minimum, assessments of the 
skin, lungs, cardiovascular system, and abdomen (liver and spleen).

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
9.4.2.
Vital Signs

Temperature, pulse rate, respiratory rate, and blood pressure will be assessed.

Blood pressure and pulse measurements will be assessed in a supine position 
with a completely automated device. Manual techniques will be used only if an 
automated device is not available.

Blood pressure and pulse measurements should be preceded by at least 5 
minutes of rest for the participant in a quiet setting without distractions (eg, 
television, cell phones).

Vital signs will be measured in a supine position after 5 minutes rest and will 
include temperature, systolic and diastolic blood pressure, and pulse.
9.4.3.
Electrocardiograms

Single 12-lead ECGs will be obtained as outlined in the SoA using an ECG 
machine that automatically calculates the heart rate and measures PR, QRS, QT, 
and QTc intervals. Refer to Section 8.1.2 for QTc withdrawal criteria and 
additional QTc readings that may be necessary.

ECGs will be measured in a supine position after 5 minutes rest.
9.4.4.
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 investigator must review the laboratory results, document this review, and 
record any clinically relevant changes occurring during the study in the AE 


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section of the CRF or equivalent. Clinically significant abnormal laboratory 
findings are those which are not usually expected for a healthy participant.

All laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 7 days after the last dose of study 
treatment should be repeated until the values return to normal or baseline or are 
no longer considered significantly abnormal by the investigator or medical 
monitor. 

If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified.

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the PAREXEL laboratory manual, PAREXEL 
standard operating procedure (SOPs) and the SoA.

Refer to the PAREXEL SOPs for appropriate processing and handling of 
samples to avoid duplicate/ and or additional blood draws.
9.5.
Pharmacokinetics

Venous blood samples, 4 mL each, for the determination of cefixime plasma 
concentrations will be collected in lithium heparin tubes. The actual date and time 
(24-hour clock time) of each sample will be recorded.

Blood samples will be placed on ice between sample collection and centrifuging.  
Within one hour of collection, blood samples will be centrifuged at approximately 
2700 g within a range of 0°C to 8°C for 10 minutes.  Thereafter, the supernatant 
of each sample will be divided into 2 aliquots (of at least 0.8 mL plasma each, 
transferred to labeled, plastic tubes and frozen (- 20ºC).

Plasma samples will be stored at approximately -20ºC in a temperature monitored 
freezer until transfer to PAREXEL Bioanalytical Services Division (BASD).  
Pooled samples for concentration range estimation will be prepared according to 
PAREXEL standard operating procedures (SOPs).  

Unused duplicate plasma PK samples will be stored at BASD for 6 months after 
completion of the bioanalysis phase of the study.  The sponsor will be required to 
indicate whether additional storage is needed or whether the samples may be 
discarded.

Samples collected for analyses of cefixime concentration may also be used to 
evaluate safety or efficacy aspects related to concerns arising during or after the 
study.

A validated bioanalytical method, as described in the PAREXEL bioanalytical 
protocol will be used for quantitative analysis. 
9.6.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.


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9.7.
Genetics
Genetics are not evaluated in this study.
9.8.
Biomarkers
Biomarkers are not evaluated in this study.
9.9.
Health Economics OR Medical Resource Utilization and 
Health Economics
Health Economics/Medical Resource Utilization and Health Economics parameters are 
not evaluated in this study.
10.
STATISTICAL CONSIDERATIONS
Refer to Analysis Plan (Appendix 7).
Bioequivalence
The primary objective of this study is to demonstrate BE between the test 200 mg/5 mL 
suspension formulation SKF101804 and the reference formulation, based on PK 
endpoints Cmax and AUC(0-t) of cefixime. 
The null hypothesis is that the true ratio of the geometric mean of the test treatment to the 
geometric mean of the reference treatment, (Test)/ (Reference), for the Cmax, or AUC(0-t), is 
either <0.80 or >1.25 for plasma cefixime.
The alternate hypothesis is that the true ratio of the geometric mean of the test treatment 
to the geometric mean of the reference treatment for both the Cmax, and AUC(0-t), is  0.80 
and  1.25 for plasma cefixime.
Symbolically this is expressed as follows:
H0: μ(Test)/μ(Reference) <0.80 or μ(Test)/μ(Reference) >1.25
i.e., treatments are not bioequivalent.
versus
Ha: 0.80≤ μ(Test)/μ(Reference) ≤1.25
i.e., treatments are bioequivalent.
For each PK parameter designated as a primary endpoint, a two one-sided t-test 
(TOST)[Schuirmann, 1987] procedure with =0.05 for each one-sided test will be used 
to test this set of hypotheses. Bioequivalence will be declared if the 90% CI for the true 
ratio of test to reference geometric means falls entirely within the range of 0.80 to 1.25 
for all primary parameters. 


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For BE to be declared, the null hypothesis must be rejected, for all primary parameters 
Cmax, and AUC(0-t), for cefixime.
10.1.
Sample Size Determination
Sample Size Rationale:
Bioequivalence is to be determined on the basis of the primary endpoints Cmax and 
AUC(0-t) of cefixime. 
Intra participant coefficient of variation (CVw) estimates in recent published data for 
cefixime with highest CV% was reported as approximately 19.5% for Cmax of cefixime
[Asiri, 2005].  
Hence, the sample size for this trial was determined based on maximum observed intra 
participant CV of 19.5%. 
Based on a BE range of 80.00% to 125.00% for Cmax and AUC(0-t), for cefixime assuming 
intra participant CV to be 20% and a "test/reference" mean ratio of 0.95; 24 evaluable 
participants are needed to achieve a power of 90% at an alpha level of 0.05 for the single 
test for testing BE.
Approximately 28 eligible participants (assuming approximately 15% drop out rate) will 
be entered into the study to complete the study with at least 24 evaluable participants. See 
Section 5.2
10.2.
Populations for Analyses
For purposes of analysis, the populations are defined in Table 3:
Table 3
Populations for Analyses
Population
Description
Enrolled 
All participants who sign the ICF
Randomized
All participants assigned to study treatment
Safety
All randomized participants who take at least 1 dose of study 
treatment. Participants will be analyzed according to the treatment 
they actually received.
PK
All participants who complete the study and for whom primary PK 
parameters can be calculated for all treatment periods will be 
included in the statistical PK analysis of the study.


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10.3.
Statistical Analyses
The statistical methodology below describes the statistical analysis as it is foreseen when 
the study is being planned.
If circumstances should arise during the study rendering the analysis inappropriate, or if 
in the meantime improved methods of analysis should come to light, different analyses 
may be made. Any deviations from the statistical methodology, reasons for such 
deviations and all alternative or additional statistical analyses that may be performed, will 
be documented in the TMF and described in the clinical study report.
See Appendix 7 for a list of Tables, Figures and Listings to be appended in the clinical 
study report.
10.3.1.
PK Analysis
Pharmacokinetic analysis will be the responsibility of the PAREXEL Quantitative 
Clinical Development (QCD) department.  Plasma cefixime concentration-time data will 
be analysed by non-compartmental methods with Phoenix WinNonlin 6.3.  The PK 
parameters will be calculated for each participant and treatment using non-compartmental 
methods and using the actual sampling time intervals (relative to investigational 
medicinal product [IMP] administration) recorded during the study. 
From the plasma concentration-time data, the following PK parameters will be 
determined, as data permit: maximum observed plasma concentration (Cmax), time to 
Cmax (tmax), area under the plasma concentration-time curve [AUC(0-∞) and AUC(0-t)], 
%AUCex, and apparent t1/2 of cefixime.
Participants who experience emesis during the course of the study will be deleted from 
the statistical analysis if vomiting occurred within 9 hrs of dosing which is approximately 
twice the mean cefixime tmax [Suprax Product Monograph, 2016]. For participants with 
pre-dose plasma concentrations, their data may be included without any adjustments in 
all PK measurements and calculations if the pre-dose concentration is ≤5% of Cmax. If 
the pre-dose value is > 5% of Cmax, the participant’s data will be dropped from all BE 
evaluations.
The available concentration data of the participants excluded due to vomiting, and of 
those who in the opinion of the pharmacokineticist did not complete the PK sampling will 
only be listed; it will not be presented in descriptive statistics or included in PK 
evaluations or formal statistical analysis.
Pharmacokinetic data will be presented in graphical and/or tabular form and will be 
summarized descriptively.
Statistical analyses of the PK parameter data will be the responsibility of PAREXEL 
Biostatistics.


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10.3.2.
Protocol Deviations and Changes to Planned Analyses
Should the safety of the participants necessitate immediate action, which represents a 
deviation from the clinical study protocol, the sponsor will be informed as soon as 
possible.
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan.
Protocol deviations and changes to planned analyses will be described in the clinical 
study report.
10.3.3.
PK Parameters
Calculation of the PK parameters will be made with Phoenix WinNonlin 6.3 (Certara, 
L.P., 1699 South Hanley Road, St Louis, Missouri 63144, USA). The PK parameters will 
be calculated for each subject and treatment using non compartmental analysis and using 
the actual sampling time intervals (relative to IMP administration).
10.3.3.1.
Primary Pharmacokinetic Parameters for cefixime

Maximum observed plasma concentration (Cmax)

Area under the plasma concentration versus time curve, from time zero to t, where t is 
the time of the last quantifiable concentration (AUC(0-t)).
10.3.3.2.
Secondary Pharmacokinetic Parameters for cefixime

Time to maximum observed plasma concentration (tmax)

Area under the plasma concentration versus time curve, with extrapolation to infinity 
(AUC(0-))

Apparent terminal elimination half-life (t½)

Percent area under the curve extrapolated (%AUCex). 
10.3.4.
Analysis of Bioequivalence
Table 4
Statistical Analysis Methods to be used for Endpoints
Endpoint
Statistical Analysis Methods
Primary
Following log-transformation of derived pharmacokinetic parameters Cmax and 
AUC(0-t) of cefixime will be analysed by using analysis of variance with sequence, 
subject (sequence), treatment and period effects. Point estimates for the adjusted 
means on the loge scale, the mean difference between treatments and associated 
90% CIs for the difference Treatment A - Treatment B will be constructed using 
the residual variance.
These point estimates and confidence intervals will then be exponentially back-
transformed to obtain adjusted (least square) geometric means for each treatment 
and point estimates and associated 90% confidence intervals for the ratio, 


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Endpoint
Statistical Analysis Methods
Treatment A/Treatment B.
Distributional assumptions underlying the statistical analyses will be assessed by 
visual inspection of residual plots. Normality will be examined by normal 
probability plots, while homogeneity of variance will be assessed by plotting the 
residuals against the predicted values for the model. If the assumptions are 
seriously violated then alternative statistical methods will be considered.
Secondary
AUC(0-) of cefixime will be analysed as per primary analysis; tmax of cefixime will 
be analysed using a  nonparametric test to compute point estimate of the median 
and associated 90% confidence intervals for the median differences, Treatment A 
–Treatment B
%AUCex will not be statistically analysed. A summary will be created.
For  t½  the n, median, minimum, and maximum values will be presented
10.3.5.
Safety Analyses
All safety analyses will be performed on the Safety Population. 
Safety variables will include vital signs and clinical laboratory results.  Adverse events 
and concomitant medication will also be listed and summarized by treatment.
10.3.6.
Other Analyses
No other analyses are planned.
10.3.7.
Interim Analyses
No interim analysis is planned.


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11.
REFERENCES
Asiri, Y, Al-Said M, Al-Khamis K, Niazy E, El-Sayed Y, Al-Rashood K, et al. 
Comparative bioavailability study of cefixime (equivalent to 100 mg/5 ml) suspension 
(Winex vs Suprax) in healthy male volunteers. Int J Clin Pharmacol Ther, 2005, 43, 499-
504.
Cefixime Summary of Product Characteristics, Cefixime 100 mg/5 ml Powder for Oral 
Suspension; 2015. 
http://www.mhra.gov.uk/home/groups/spcpil/documents/spcpil/con1498197773962.pdf
European Medicines Agency (EMEA). Guideline on the Investigation of Bioequivalence. 
Committee for Medicinal Products for Human Use (CHMP), London; 2010. 
CPMP/EWP/QWP/1401/98/Rev.1/Corr.
Schuirmann DJ. A comparison of the two one sided tests procedure and the power 
approach for assessing the equivalence of average bioavailability. J Pharmacokinet and 
Biopharm. 1987;15:657-680. 
Suprax Product Monograph, Sanofi Aventis; Submission Control No. 188553; 2016; 
http://products.sanofi.ca/en/suprax.pdf


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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
AE
Adverse Event
ALT
Alanine aminotransferase (SGPT)
aPTT
Activated Partial Thromboplastin Time 
AST
Aspartate aminotransferase (SGOT)
AUC
Area under concentration-time curve
AUC(0-)
Area under the concentration-time curve from time zero 
(pre-dose) extrapolated to infinite time
%AUCex
Percentage of AUC(0-) obtained by extrapolation
AUC(0-t)
Area under the concentration-time curve from time zero 
(pre-dose) to last time of quantifiable concentration within a 
participant across all treatments
BASD
Bioanalytical Services Division 
BE
Bioequivalence
BMI
Body mass index
BP
Blood pressure
BUN
Blood urea nitrogen
CI
Confidence Interval
CIOMS
Council for International Organizations of Medical Sciences 
CONSORT
Consolidated Standards of Reporting Trials
CV
Coefficient of variation
Cmax
Maximum observed concentration 
CPK
Creatine phosphokinase
CRF
Case Report Form
DRESS
Drug rash with eosinophila and systemic symptoms
ECG
Electrocardiogram
FDA
Food and Drug Administration
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
GSK
GlaxoSmithKline
HBsAg
Hepatitis B surface antigen
HRT 
Hormone replacement therapy
hCG
Human chorionic gonadotropin
HIV
Human Immunodeficiency Virus
HIPAA
Health Insurance Portability and Accountability Act 
h or hr
Hour(s)
HPLC
High Performance Liquid Chromatography 
ICF
Informed consent form
ICH
International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for 
Human Use
IMP
Investigational Medicinal Product
INR
International Normalized Ratio


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IEC
Independent Ethics Committee
IgG
Immunoglobulin G
IP
Investigational Product
IRB
Institutional Review Board
IUD
Intrauterine device 
IUS
Intrauterine hormone-releasing system 
Kg
Kilogram
LAM
Local Affiliate Module
LDH
Lactate Dehydrogenase
MCV
Mean corpuscular volume
MCH
Mean corpuscular hemoglobin 
MCHC
Mean corpuscular hemoglobin concentration
MedDRA
Medical Dictionary for Regulatory Activities
Mg
Milligrams
mL
Milliliter
MSDS
Material Safety Data Sheet
Msec
Milliseconds
PK
Pharmacokinetic
PM
Product Monograph
PT
Prothrombin Time
QCD
Quantitative Clinical Development 
QTc
QT corrected
QTcB
QT interval corrected for heart rate according to Bazett’s 
formula
RBC
Red blood cells
RNA
Ribonucleic acid
SAE
Serious adverse event(s)
SD
Standard deviation
SoA
Schedule of Activities
SOP
Standard Operating Procedure
SGOT
Serum glutamic-oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SPC
Summary of Product Characteristics
SUSAR
Suspected unexpected serious adverse reactions
t½
Terminal phase half-life
Tmax
Time of occurrence of Cmax
TOST
Two one-sided t-test 
ULN
Upper limit of normal
WBC
White blood cells
WOCBP
Women of Childbearing Potential


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Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
FIXVAL
Cefspan
Phoenix
SAS
Suprax
WinNonlin


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12.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 5 will be performed by the local laboratory. 

Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 6 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 5
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
MCV
MCH
MCHC
%Reticulocytes
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Clinical 
Chemistry1
BUN
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase
(SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase
(SGPT)
Total Protein
Glucose, fasting
Calcium
Alkaline 
phosphatase
Coagulation 
Profile 
PT and aPTT
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, 
leukocyte esterase by dipstick

Microscopic examination (if blood or protein is abnormal)
Other Screening 
Tests

Follicle-stimulating hormone (as needed in women of non-childbearing 
potential only)

Breath alcohol and urine drug screen (to include at minimum: 
amphetamines, barbiturates, benzodiazepines, cocaine, opiates, 


2 0 1 7 N 3 2 6 8 6 6 _ 0 0 
C O N FI D E N TI A L 
 
 
 
2 0 5 7 3 1 
 
4 6 
 
L a b or at or y 
A s s e s s m e nt s 
P ar a m et er s 
p h e ncycli di n e ( p h e nylcycl o h ex al pi p eri di n e), t etr a hy dr oc a n n a bi n ol, 
m et h a d o n e, m et h a m p h et a mi n e, tricyc lic a nti d e pr ess a nts, oxyc o d o n e a n d 
pr o p oxy p h e n e 
•  C oti ni n e 
•  S er u m or uri n e h u m a n c h ori o nic g o n a d otr o pi n ( h C G) pr e g n a ncy t est ( as 
n e e d e d f or w o m e n of c hil d b e ari n g p ot e nti al) 
•  S er ol o gy ( HI V a nti b o dy, h e p atitis B s urf ac e a nti g e n [ H Bs A g], a n d h e p atitis 
C vir us a nti b o dy)  
•  H e p atitis C R N A t est f or H e p atit is C a nti b o dy p ositiv e p artici p a nts 
T h e r es ults of e ac h t est m ust b e e nt er e d i nt o t h e C R F or e q uiv al e nt. 
N O T E S : 
1.  
D et ails of liv er c h e mistry st o p pi n g crit eri a a n d r e q uir e d acti o ns a n d f oll ow- u p ass ess m e nts aft er liv er st o p pi n g or 
m o nit ori n g ev e nt ar e giv e n i n S ecti o n 8. 1  a n d A p p e n dix 6  All ev e nts of A L T ≥3 × u pp er li mit of n or m al ( U L N) a n d 
bilir u bi n ≥2 × U L N ( > 3 5 % dir ect bilir u bi n) or A L T ≥3 × U L N a n d i nter n ati o n al n or m aliz e d r ati o (I N R) > 1. 5, if I N R 
m e as ur e d, w hic h m ay i n dic at e s ev er e liv er i nj ury ( p ossi bl e Hy’s L a w), m ust b e r e p ort e d as a n S A E ( excl u di n g 
st u di es of h e p atic i m p air m e nt or cirr h osis). 
2.  
L oc al uri n e t esti n g will b e st a n d ar d f or t h e pr ot ocol u nl ess s e r u m t esti n g is r e q uir e d by l oc al r e g ul ati o n or I R B/I E C. 
 


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12.3.
Appendix 3: Study Governance Considerations
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
Financial Disclosure
Financial disclosure will not be collected for this study, as data will not be used to 
support any marketing applications with any regulatory authorities.
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 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, 


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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 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. 
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. 

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. 

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.
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.
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 


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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 results summary and for 
development of a manuscript for publication will be in accordance with GSK 
Policy.

A manuscript will be progressed for publication in the scientific literature if the 
results provide important scientific or medical knowledge.
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic 
CRF 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 CRF. 

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 

The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF 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. 
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.


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
Data reported on the CRF 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 the PAREXEL SOPs .

SOP-EP.CL-WW-009-01: Data Collection, Transcription, Quality Control 
and Clarification

MAN-EP.CL-WW-044-01: Data Collection, First Time Quality and 
Correction of Data Entries
Study and Site Closure
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 treatment development


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12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
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 treatment, whether or not considered related to the 
study treatment.

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 treatment.
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 treatment 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 
treatment 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.
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 


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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.
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:
a.
Results in death
b.
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.
c.
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 serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d.
Results in persistent 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.
e.
Is a congenital anomaly/birth defect
f.
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 


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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.
Recording 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 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 GSK /AE/SAE CRF 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 sufficiently 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.
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 


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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 treatment 
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 CRF.

The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information.


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Reporting of SAE to GSK
SAE Reporting to GSK via Paper CRF

The primary mechanism for the Investigator to report SAEs and updated data on 
previously reported SAEs to GSK, will be the SAE paper data collection tool (form).

Facsimile transmission of the GSK SAE reporting form (paper) is the preferred 
method to transmit this information from the Investigator site to the LOC 
Pharmacovigilance team /medical monitor .

The LOC Pharmacovigilance team will enter the SAE into the Local Affiliate 
Module (LAM) with the SAE copy attached. The SAE will then be visible to Central 
Pharmacovigilance.

The Pharmocovigilance assistant will report the SAE to the Regulatory Authority 
(MCC)

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.

The Investigator must ensure that SAEs are reported to the local ethics committee, 
within the required timelines.

Contact for SAE reporting:
GSK, South Africa - Pharmacovigilance

Facsimile: PPD


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12.5.
Appendix 5: Contraceptive Guidance and Collection of 
Pregnancy Information
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below)
Women in the following categories are not considered WOCBP
1. Premenarchal
2. Premenopausal female with ONE of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview.
3. 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, a single FSH 
measurement is insufficient. 

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they wish 
to continue their HRT during the study. Otherwise, they must discontinue HRT 
to allow confirmation of postmenopausal status before study enrollment.
Contraception Guidance
Male participants

Male participants with female partners of child-bearing potential are eligible to 
participate if they agree to ONE of the following during the protocol-defined 
time frame in Section 6.1: 

Are abstinent from penile-vaginal intercourse as their usual and preferred 
lifestyle (abstinent on a long term and persistent basis) and agree to remain 
abstinent 

Agree to use a male condom plus an additional method of contraception 
with a failure rate of <1% per year as described in Table 6 when having 
penile-vaginal intercourse with a woman of childbearing potential 


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
Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of 
penile penetration for 5 days after each dose of study treatment. 

In addition, male participants must refrain from donating sperm for duration of 
study and for 5 days after each dose of study treatment.
Female participants
Female participants of childbearing potential are eligible to participate if they agree to 
use a highly effective method of contraception consistently and correctly as described in 
Table 6.
Table 6
Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly.
Combined (estrogen- and progestogen-containing ) hormonal contraception associated with 
inhibition of ovulationb

oral
IMPORTANT NOTE: for female partners of Male participants only. Cefixime may interfere 
with oral contraceptives, as such WOCBP participants must agree to another method 
provided within this appendix

intravaginal 

transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulationb

injectable 
Highly Effective Methods That Are User Independent 

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationb

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

bilateral tubal occlusion
Vasectomized partner 
(A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.)
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from 


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heterosexual intercourse during the entire period of risk associated with the study drug. 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.)
NOTES: 
a.
Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants in clinical studies. 
b.
Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of 
the contraceptive method. In this case two highly effective methods of contraception should be utilized during the 
treatment period and for at least 30 days after the last dose of study treatment
Pregnancy Testing

WOCBP should only be included after a confirmed menstrual period and a negative 
highly sensitive urine or serum pregnancy test 

Additional pregnancy testing should be performed at Day -1 of each treatment period 

Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected 

Pregnancy testing, with a sensitivity of 10 mIU/mL (dipstick) and serum 0.100 to 
10 000 mIU/mL (automated) will be performed and assayed in a certified laboratory.
Collection of Pregnancy Information
Male participants with partners who become pregnant

Investigator will attempt to collect pregnancy information on any male participant’s 
female partner of a male study participant who becomes pregnant while participating 
in this study. This applies only to participants who receive study treatment.

After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the 
appropriate form and submit it to GSK within 24 hours of learning of the partner’s
pregnancy. 

Partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to GSK

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated
delivery date. Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure. 
Female Participants who become pregnant

Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study. 

Information will be recorded on the appropriate form and submitted to GSK within 
24 hours of learning of a participant's pregnancy. 


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
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 will be reported as an AE or 
SAE. 

A spontaneous abortion 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 treatment by the investigator, will be reported to GSK
as described in Appendix 4 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 treatment or be withdrawn from the study 


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12.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments
Phase I liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria 
ALT-absolute
ALT≥3xULN
If ALT≥3xULN AND bilirubin1,2 2xULN (>35% direct bilirubin) or  INR >1.5, 
Report as an SAE.
See additional Actions and Follow Up Assessments listed below
Required Actions and Follow up Assessments 
Actions
Follow Up Assessments

Report the event to GSK within 24 hours

Complete the liver event CRF, and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the participant until liver chemistries 
resolve, stabilise, or return to within baseline
(see MONITORING below)
MONITORING:
If ALT≥3xULN AND bilirubin 2xULN  or INR 
>1.5

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24 
hrs

Monitor participants twice weekly until liver 
chemistries resolve, stabilise or return to 
within baseline

A specialist or hepatology consultation is 
recommended
If ALT≥3xULN AND bilirubin < 2xULN  and 
INR ≤1.5:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform
liver event follow up assessments within 24-
72 hrs

Viral hepatitis serology3

Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend

Obtain blood sample for pharmacokinetic 
(PK) analysis, obtained within 3 days of 
last dose

Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications on 
the concomitant medications report form 
including acetaminophen, herbal remedies, 
other over the counter medications.

Record alcohol use on the liver event 
alcohol intake case report form
If ALT≥3xULN AND bilirubin 2xULN  or 
INR >1.5:

Anti-nuclear antibody, anti-smooth muscle 


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Liver Chemistry Stopping Criteria 

Monitor participants weekly until liver 
chemistries resolve, stabilize or return to 
within baseline
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG) or gamma 
globulins.

Serum acetaminophen adduct high 
performance liquid chromatography 
(HPLC) assay (quantifies potential 
acetaminophen contribution to liver injury 
in participants with definite or likely 
acetaminophen use in the preceding week 
[James, 2009]. Liver imaging (ultrasound, 
magnetic resonance, or computerised 
tomography) and /or liver biopsy to 
evaluate liver disease; complete Liver 
Imaging and/or Liver Biopsy CRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that participant if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary bilirubin on 
dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured, which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated will 
not apply to participants receiving anticoagulants
3.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, et.al.. 
Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen Overdose 
and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.


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12.7.
Appendix 7: Reporting Analysis Plan
Rules for handling decimals
The following rules will be followed with regards to the number of decimal places and 
presentation of data in the tables and listings of safety data:
All data will be listed according to the number of decimal places presented in the source
data.
Mean and median will be tabulated to one more decimal place than the source data. 
Minimum and maximum values will be tabulated to the same number of decimal places 
as the source data.
Standard deviation (SD) will be tabulated to two more decimal places than the source 
data.
A maximum of three decimal places will apply to all summary statistics.
Missing data
AEs with missing start dates/times will be handled as follows for the tabulations:

Missing start date:
If the start date is completely missing but the end date is known and shows 
that the AE ended on or after the dosing date in a specific treatment period, 
then the start date will be imputed as the day of dosing in that period 
(therefore first dosing in the run-in period).
If the end date is known and shows that the AE ended before the first dosing 
date in the run-in period, then the screening date will be used for the start 
date.
If the end date is known and shows that the AE ended before the dosing date 
in the treatment period (but after dosing in the run-in period), then the first 
dosing date of the run-in period will be used for the start date.
If the end date is non-informative (i.e., is missing or does not contain enough 
information), the start date will be imputed as the date of first dosing in the 
run-in period will be used.

Missing start day:
If only the start day is missing the day will be imputed as the first day on 
which a dose was given in that month unless the end date is known and shows 
that the AE ended before a dose was given in that month; in which case the 
date will be imputed as 01.


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If the end date is non-informative (i.e., is missing or does not contain enough 
information), the start date will be imputed as the first date of dosing in the 
known month. If the month is not a dosing month the date will be imputed as 
01.

Missing start day and month:
If the start day and month are missing the date will be imputed as the first day 
of dosing in the known year unless the end date is known and shows that the 
AE ended before a dose was given in that year; in which case the start day 
and month will be imputed as 01Jan or with the date of screening if this is 
later. If the end date is non-informative (i.e., is missing or does not contain 
enough information), the start date will be imputed as the first date of dosing 
in the known year. If the year is not a year of dosing then the date will be 
imputed as 01Jan or with the date of screening if this is later.

Missing times
Missing times will be imputed as 00:00 h or with the time of dosing for 
events starting on a dosing day.
Presentation of PK Data, Descriptive Statistics and PK Assessment
This section describes outputs to be presented.
The actual blood sampling times and time deviations will be listed for each participant 
dosed, treatment and scheduled sampling time.  A listing of plasma concentrations of 
cefixime treatment will be provided.
Summary table reflecting summary statistics (n, arithmetic mean, geometric mean, 
median, coefficient of variation, standard deviation, minimum and maximum) per 
treatment will be provided for plasma concentrations of cefixime.
Concentrations below the lower limit of quantification (LLOQ) will be indicated as 
below the limit of quantification (BLQ).  These BLQ concentrations will be handled as 
follows:

For descriptive statistics, pre-dose BLQ concentrations will be substituted by 
zeros.  All other BLQ values will be substituted by ½LLOQ value before the 
calculation of the summary statistics.  Values reported as ‘NS’ (no sample) will be 
set to “missing”.

For PK assessment, all BLQ values at pre-dose and in the absorption phase, 
before the first reported concentration, will be substituted by zeros.  The BLQ 
values between evaluable concentrations will be substituted by ½LLOQ, before 
the calculation of the PK parameters.  The terminal BLQ values will be set to 
missing.  These measures are taken to prevent an over-estimation of AUC.


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
For PK calculations, missing concentrations will be deleted, resulting in an 
interpolation between the nearest two concentration values.
A listing for PK parameters of cefixime per treatment will be provided.  A summary table 
reflecting summary statistics (n, arithmetic mean, geometric mean, median, coefficient of 
variation, standard deviation, minimum and maximum) per treatment will be provided for 
PK parameters of cefixime.
The individual plasma cefixime concentration versus actual time profiles for each 
participant and treatment, as well as the mean and median (arithmetic and geometric) 
plasma cefixime concentration versus scheduled time profiles for each treatment, will be 
presented graphically on a linear-linear and log-linear scale. Individual plasma 
concentrations will be presented using actual, rather than planned, sampling times.  
Combined individual concentration versus time graphs per treatment will also be 
presented on a linear-linear scale. The adjusted geometric mean ratio with 90% CI will 
be presented graphically. The individual log-linear graphs reflecting the WinNonlin 
modelling results, will be presented using SAS.
The data listings, descriptive statistics, statistical analysis and graphs of this study will be 
generated using SAS/STAT and SAS/GRAPH software1.
Data Precision
The following rules will be followed with regards to the number of decimal places and 
presentation of data in the tables and listings concentration data.
The individual plasma concentration will be reported to the same precision as the source 
data (e.g., if the source data is presented to five significant digits, the individual values 
will be presented to five significant digits).
The mean, SD, geometric mean and median will be tabulated to one more significant 
digit compared to the source data, but with a maximum of four significant digits.
Minimum and maximum values will be tabulated to the same precision as the source 
data, but with a maximum of four significant digits.
Geometric coefficient of variation (CV) % will be presented to once decimal place.
The following rules will be followed with regards to the number of decimal places and 
presentation of data in the tables and listings of PK parameters.
Individual PK parameters will be presented to four significant digits, with the exception 
of tmax, which will be presented to two decimal places.  In addition, PK parameters 
directly derived from source data (e.g., Cmax) will be reported with the same precision as 
the source data (if this is not four significant digits).
                                                
1 SAS Version 9.2 or higher of the SAS System.  Copyright2002-2003.  SAS Institute Inc.  SAS and all 
other SAS Institute Inc. product or service names are registered trademarks or trademarks of SAS 
Institute Inc., Cary, North Carolina, USA.


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The mean, geometric mean, median and SD values will be reported to four significant 
digits, all other descriptive statistics will be reported to three significant digits except for 
CV% which will be presented to one decimal place.  For tmax the minimum and maximum 
will be presented to two decimal places and the rest of the descriptive statistics to three 
decimal places.
Estimates and confidence intervals in the form of percentages will be presented two 
decimal places.
Source data will be used in all derived PK parameter calculations without prior rounding.
Analysis of Bioequivalence
Refer to Table 3, Populations for analysis.
The following SAS code will be used, with the treatments sorted in the order reference 
first and then test:
ODS OUTPUT LSMeans=lsmean estimates=est nobs=nobs Overall ANOVA=anova;
PROC GLM DATA=pk ALPHA=0.1;
BY Analyte Parameter;
CLASS treatment period participant sequence2
MODEL var= treatment period sequence participant (sequence)/ clparm;
(where var = log [Cmax], log[AUC(0-t)])
OUTPUT OUT= routput R=res P=pred;
LSMEANS treatment / pdiff=control('A') CL;
ESTIMATE 'Test versus Reference' treatment 1 -1;
RUN;Bioequivalence of the test and reference products will be assessed on the basis of 
the 90% confidence intervals for estimates of the geometric mean ratios between the 
primary PK parameters of the test and reference products in relation to the conventional
bioequivalence range of 80.00% to 125.00%.
A non-parametric Wilcoxon signed rank test may be performed on the variable tmax for 
the test -- reference differences and the results will be tabulated. The following SAS code 
will be used:
PROC UNIVARIATE data = PK;
                                                
2SAS Version 9.2 or higher of the SAS System.  Copyright2002-2003.  SAS Institute Inc.  SAS and all 
other SAS Institute Inc. product or service names are registered trademarks or trademarks of SAS 
Institute Inc., Cary, North Carolina, USA.


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VAR diff;[where diff denotes the difference test-reference]
ODS output testsforlocation = wilcoxon;
RUN;
Presentation of Baseline Characteristics and Safety Data
Baseline characteristics and safety data will be presented as mentioned below.  Data 
captured but not presented as listed or summarized data will be available in the CRFs or 
the source data capture system.
Demographic and anthropometric data will be listed for all participants in the safety 
population.  Demographic characteristics will be tabulated by treatment (n, mean, 
median, standard deviation, minimum and maximum for age and BMI; and frequency 
counts and percentages for race, age groups and sex).
Adverse events (AEs) will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA), and listed and summarized by treatment for all participants in the 
safety population. 
Vital signs data will be listed and summarized for all participants in the safety population.
Concomitant medication will also be listed and summarized by treatment for all 
participants in the safety population.
List of Tables, Figures and Listings
The following tables, figures and listings will be provided for inclusion into the 
mentioned sections of the clinical study report.
Tables
Demographic characteristics
Statistical analyses of cefixime PK parameters (ANOVA)
Non Parametric Analysis of cefixime PK parameter
Plasma cefixime concentration (unit)
Plasma cefixime PK parameter (unit)
Adverse events summary by treatment
Concomitant Medication summary by treatment
Summary Statistics of Vital Signs Values
Summary Statistics of Chemistry Values.


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Summary Statistics of Haematology Values.
Figures
Plasma cefixime arithmetic and geometric mean concentrations (unit)
Median concentration vs. Time for cefixime
Combined individual plasma cefixime concentrations (unit)
Individual plasma cefixime concentrations (unit) (linear-linear scale and log-linear scale)
Adjusted geometric mean treatment ratio (with 90% CI) for cefixime
Listings
Protocol deviations
Statistical output
Participant disposition
Randomization
Demography and anthropometry
Adverse events
Concomitant Medication
Vitals Signs
Haematology
Chemistry
Urinalysis
12-ECG Lead 
Actual blood sampling times
Plasma cefixime concentrations (unit)
Plasma cefixime PK parameters (unit)
The bulleted lists above indicate requirements and are not necessarily the exact names of 
each table, figure or listing.  The naming conventions as provided will be adhered to as 
far as feasible, but if deemed necessary the name of the output might be changed to fit the 
data.