Clinical trial NCT03150082
Conditions: Infections, Bacterial
Keywords: GR37547 Cross-over Bioequivalence Ciprofloxacin
Sponsor: GlaxoSmithKline
Start date: 2017-08-01; Completion date: 2017-08-28
Enrollment: 26 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This two-period cross-over study will evaluate bioequivalence of GR37547 (ciprofloxacin 500 mg) tablet versus ciprofloxacin 500 mg reference tablet in healthy adult subjects under fasting conditions. Subjects will receive Treatment A (GR37547 tablet) and Treatment B (ciprofloxacin reference tablet) in crossover manner, separated by a washout period of at least 7 days and not more than 14 days. The total duration of study for each subject will be approximately 5-7 weeks. This study will enroll approximately 26 healthy adult subjects at a single center.

Detailed description:

Arms: arm 1: Eligible subjects will be randomized to receive a single dose of Treatment A (GR37547 500 mg tablet) followed by Treatment B (ciprofloxacin 500 mg reference tablet) administered orally on Day 1 in each treatment period. The washout period will be of at least 7 days and not more than 14 days. arm 2: Eligible subjects will be randomized to receive a single dose of Treatment B (ciprofloxacin 500 mg reference tablet) followed by Treatment A (GR37547 500 mg tablet) administered orally. The washout period will be of at least 7 days and not more than 14 days.
Interventions: intervention 1: GR37547 tablet intervention 2: Ciprofloxacin reference tablet
Intervention descriptions: intervention 1: A single tablet of GR37547 should be taken orally with 240 mL of water. GR37547 500 mg tablet will be a white to off white capsule shape with break line on upper side and embossed "GSK500"on lower side. intervention 2: A single tablet of ciprofloxacin reference should be taken orally with 240 mL of water. Ciprofloxacin 500 mg reference will be nearly white to slightly yellowish film coated oblong tablets with break line and ''CIP 500" marked on upper side and "BAYER" on lower side.

Protocol documents:
Prot_SAP_001.pdf: 
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TITLE PAGE
Protocol Title: An open-label, randomised, single-dose, two-period cross-over study to 
evaluate bioequivalence of GR37547 ciprofloxacin 500 mg tablet  versus ciprofloxacin 
500 mg tablet  reference product in healthy adult participants under fasting conditions
Protocol Number: 205730
Short Title: Bioequivalence study between GR37547 500 mg tablet versus 
ciprofloxacin 500mg tablet reference product in healthy adult participants under fasting 
conditions.
Compound Number:
GR37547
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: 11-APR-2017
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.


PP
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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 ............................................................................15
3.3.1.
Risk Assessment .........................................................................15
3.3.2.
Benefit Assessment.....................................................................24
3.3.3.
Overall Benefit: Risk Conclusion..................................................24
4.
OBJECTIVES AND ENDPOINTS...........................................................................24
5.
STUDY DESIGN ....................................................................................................25
5.1.
Overall Design ............................................................................................25
5.2.
Number of Participants ...............................................................................26
5.3.
Participant and Study Completion...............................................................26
5.4.
Scientific Rationale for Study Design ..........................................................26
5.5.
Dose Justification........................................................................................26
6.
STUDY POPULATION...........................................................................................26
6.1.
Inclusion Criteria.........................................................................................27
6.2.
Exclusion Criteria........................................................................................28
6.3.
Lifestyle Restrictions...................................................................................30
6.3.1.
Meals and Dietary Restrictions ....................................................30
6.3.2.
Caffeine, Alcohol, and Tobacco ...................................................30
6.3.3.
Activity .........................................................................................31
6.4.
Screen Failures...........................................................................................31
7.
TREATMENTS.......................................................................................................31
7.1.
Treatments Administered............................................................................32
7.2.
Dose Modification .......................................................................................32
7.3.
Method of Treatment Assignment ...............................................................32
7.4.
Blinding.......................................................................................................33
7.5.
Preparation/Handling/Storage/Accountability..............................................33
7.6.
Treatment Compliance................................................................................34
7.7.
Concomitant Therapy..................................................................................34
7.8.
Treatment after the End of the Study ..........................................................35
8.
DISCONTINUATION CRITERIA.............................................................................35
8.1.
Discontinuation of Study Treatment ............................................................35
8.1.1.
Liver Chemistry Stopping Criteria ................................................35
8.1.2.
QTc Stopping Criteria ..................................................................36
8.1.3.
Temporary Discontinuation ..........................................................37
8.2.
Withdrawal from the Study..........................................................................37
8.3.
Lost to Follow Up........................................................................................37
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................38


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9.1.
Efficacy Assessments.................................................................................38
9.2.
Adverse Events...........................................................................................38
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................39
9.2.2.
Method of Detecting AEs and SAEs.............................................39
9.2.3.
Follow-up of AEs and SAEs.........................................................39
9.2.4.
Regulatory Reporting Requirements for SAEs .............................39
9.2.5.
Pregnancy ...................................................................................40
9.3.
Treatment of Overdose...............................................................................40
9.4.
Safety Assessments ...................................................................................41
9.4.1.
Physical Examinations.................................................................41
9.4.2.
Vital Signs....................................................................................41
9.4.3.
Electrocardiograms......................................................................41
9.4.4.
Clinical Safety Laboratory Assessments ......................................42
9.4.5.
Suicidal Risk Monitoring...............................................................42
9.5.
Pharmacokinetics .......................................................................................43
9.6.
Pharmacodynamics ....................................................................................43
9.7.
Genetics .....................................................................................................43
9.8.
Biomarkers .................................................................................................43
9.9.
Health Economics OR Medical Resource Utilization and Health 
Economics..................................................................................................43
10. STATISTICAL CONSIDERATIONS........................................................................44
10.1.
Sample Size Determination ........................................................................45
10.2.
Populations for Analyses ............................................................................45
10.3.
Statistical Analyses.....................................................................................45
10.3.1.
PK Analyses ................................................................................46
10.3.2.
Protocol Deviations and Changes to Planned Analyses...............46
10.3.3.
PK Parameters ............................................................................47
10.3.3.1.
Primary Pharmacokinetic Parameters for 
ciprofloxacin ...............................................................47
10.3.3.2.
Secondary Pharmacokinetic Parameters for 
ciprofloxacin ...............................................................47
10.3.4.
Analysis of Bioequivalence ..........................................................47
10.3.5.
Safety Analyses...........................................................................48
10.3.6.
Other Analyses ............................................................................48
10.3.7.
Interim Analyses ..........................................................................48
11. REFERENCES.......................................................................................................49
12. APPENDICES........................................................................................................50
12.1.
Appendix 1: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................50
12.2.
Appendix 2: Study Governance Considerations..........................................54
12.3.
Appendix 3: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................58
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................60
12.5.
Appendix 5: Clinical Laboratory Tests.........................................................65
12.6.
Appendix 6:  Analysis Plan .........................................................................67
12.7.
Appendix 7: Abbreviations and Trademarks................................................73


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1.
SYNOPSIS
Protocol Title: An open-label, randomised, single-dose, two-period cross-over study to 
evaluate bioequivalence of GR37547 ciprofloxacin 500 mg tablet versus ciprofloxacin 
500mg tablet reference product in healthy adult participants under fasting conditions
Short Title: Bioequivalence study between GR37547 500 mg tablet versus ciprofloxacin
500mg tablet reference product in healthy adult participants under fasting conditions.
Rationale:
This study will determine if ciprofloxacin 500 mg tablets (test formulation: GR37547; 
CIPVALTM; GlaxoSmithKline Pakistan Limited) are bioequivalent to ciprofloxacin 500 
mg tablets (reference formulation: Ciproxin; Bayer Limited, United Kingdom).
Objectives and Endpoints:
Objectives
Endpoints
Primary
To determine if 500 mg Ciprofloxacin 
(GR37547) tablets are bioequivalent to 
reference 500 mg Ciprofloxacin tablets in 
healthy adult participants under fasting 
conditions. 
Plasma PK parameters: AUC(0-t) and Cmax, for 
ciprofloxacin in relevant treatments. 
Secondary
To assess secondary PK parameters of 500 mg 
ciprofloxacin tablets (GR37547) relative to 
reference 500 mg ciprofloxacin in healthy adult 
participants under fasting conditions. 
To compare the safety and tolerability of a 
single dose of a 500 mg ciprofloxacin tablet
(GR37547) with reference 500 mg ciprofloxacin 
tablet, in healthy adult participants under fasting 
conditions.

Plasma PK parameters: AUC(0-), tmax, 
%AUCex and t½ for ciprofloxacin in relevant 
treatments.

Adverse events (AE), clinical laboratory 
values (Haematology and Biochemistry), 
ECGs 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; t1/2= Terminal phase half-life; Cmax= 
Maximum observed concentration; Tmax= Time of occurrence of Cmax.
Overall Design:
This is a Phase I, open label, balanced, randomised, single dose, two-way crossover 
study, enrolling 26 healthy participants at a single centre. 


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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:
Approximately 26 participants will be randomized to yield at least 22 evaluable 
participants completing the study. 
Treatment Groups and Duration:
The total duration in the study for each participant is expected to be up to approximately 
5 - 7 weeks, from screening to their last visit.
Study treatments will be referred to as Test and Reference throughout the protocol:

Treatment A – Test: GR37547 (CIPVALTM), ciprofloxacin 500 mg tablets.

Treatment B - Reference: Ciproxin, ciprofloxacin 500 mg tablets.
Treatment Groups and Sequences:

Participants will be randomised to one of two sequences, 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 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 
approximately 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. and
Admission to the Unit (domiciled)
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 hour post dose PK sample, vital signs 
(VS), 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 
participants will also have an ECG and urine pregnancy test 
(females), 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 
approximately 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, VS, 
ECG, Lab assessments) are abnormal and clinically 
significant at Treatment Period 2 discharge, then a follow up 
phone call or outpatient clinic visit is required within 7 days. 
Enquiries on the participant’s general health, including any 
AEs/SAEs/concomitant medication should be recorded in the 
medical notes.
Demography and Medical history (includes 
substance usage)
X
Substances: Drugs, Alcohol, tobacco and caffeine
Full physical examination including height 
and weight
X
X
Abbreviated physical exam (excluding height and weight) 
performed at Day -1
Past and current medical conditions  
X
X
Pregnancy test (WOCBP only)
X
X
X
Serum -hCG: at screening. 
Urine -hCG: at Day-1 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 
approximately 7 
days post last 
dose or at 
discontinuation)
Notes
Day –1
Day 1
Day 2
Laboratory assessments (include liver 
chemistries) 
X
X
X
Screening: Participants are required to fast at least 10 
hours prior to the Screening Laboratory assessment. 
Haematology, Biochemistry, glucose -6-phosphate 
dehydrogenase, 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
X
X
12-lead ECG will be completed at:

Screening, 

Day 1: ECG 2h post dose ( tmax) to be completed 
before vital signs and 2 hour PK sample. 

Day 2: at discharge, at the end of Treatment Period 
2 prior to the last PK sample

Follow up: only required if the ECG at discharge 
was abnormal and clinically significant
ECGs to be taken 30min of time points specified


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Procedure
Screening 
(Day -21  
to Day -1)
Treatment Periods 1 and 2
Follow-up
(within 
approximately 7 
days post last 
dose or at 
discontinuation)
Notes
Day –1
Day 1
Day 2
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. 
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 4 hours 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.


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Procedure
Screening 
(Day -21  
to Day -1)
Treatment Periods 1 and 2
Follow-up
(within 
approximately 7 
days post last 
dose or at 
discontinuation)
Notes
Day –1
Day 1
Day 2
Concomitant medication review
==============================================
Pharmacokineticsa
X
X
Day 1:  Pre-dose,  0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 
2.50, 3.00, 3.50,  4.50, 6.00, 8.00, 12.00, 18.00 hours 
Day 2: 24.00 hours post dose
Pre-dose sample will be taken within 15 minutes before 
dose. Post dose samples for:

0.500 -2.00 hours will be taken 2 min;, ; 

2.50 – 8.00 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.

Any changes in the timing or addition of time points for any planned study assessments must be documented and approved by 
the relevant study team member and then archived in the sponsor and site study files, but will not constitute a protocol 
amendment. The Institutional review board (IRB)/ Independent ethics committee (IEC) and regulatory authority will be informed 
of any safety issues that require alteration of the safety monitoring scheme or amendment of the informed consent form (ICF).

AE= Adverse Event; aPTT= Activated Partial Thromboplastin Time; ECG= Electrocardiogram; GSK= GlaxoSmithKline; HIV= 
Human Immunodeficiency Virus;  hr= Hour; IP= Investigational Product; PK= Pharmacokinetic; PT= Prothrombin Time; SAE= 
Serious adverse event(s)


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3.
INTRODUCTION
3.1.
Study Rationale
GSK Product, GR37547 (Ciprofloxacin) 500 mg tablets is marketed in Pakistan as 
CIPVALTM.  This study is required to determine whether the test product 
GR37547/CIPVALTM is bioequivalent to the reference ciprofloxacin 500 mg tablets in 
healthy adult participants.  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
Ciprofloxacin is a synthetic fluoroquinolone antibiotic with activity against Gram 
positive and Gram negative bacteria. Ciprofloxacin exerts its bactericidal effect by 
inhibition of Topoispmerase II (DNA gyrase) and Topoisomerase IV, thus interfering 
with bacterial DNA replication, repair, transcription and recombination. The mechanism 
of action of fluoroquinolones including Ciprofloxacin differs from other antibiotic classes 
such as penicillins, cephalosporins, aminoglycosides, macrolides, and tetracyclines 
therefore, microorganisms resistant to these classes of antibiotics are usually susceptible 
to fluoroquinolones. The converse applies where microorganisms resistant to 
Ciprofloaxicin are usually susceptible to the other classes of antibiotics [APO-
CIPROFLOX Package Insert, 2012]. 
Indications and Dosing
Ciprofloxacin is used to treat a wide number of infections because of its wide 
antibacterial spectrum, extensive tissue distribution, prolonged half-life, good oral 
absorption and lack of cross-resistance with other antibacterials [Morera, 2001].
Ciprofloxacin is indicated for treatment of infections caused by susceptible strains of the 
causative microorganisms.  Factors which determine the dose include the indication,
severity, site of the infection and the renal function of the patient. In children and 
adolescents the body weight is also taken into account. The duration of treatment depends 
on the severity of the illness and on the clinical and bacteriological course. Doses may 
range from a single 500 mg dose once off  for  Gonococcal uretritis and cervicitis, to 
750 mg twice daily taken for a maximum of 3 months for bone and joint infections. In 
some infections or infection sites higher ciprofloxacin doses and co-administration with 
other appropriate antibacterial agents is required [CIPROXIN Package Insert, 2016].
Clinical Pharmacology
Ciprofloxacin tablets dissolve rapidly in the gastrointestinal tract following oral 
administration, and are absorbed in the duodenum and jejunum. Following oral dosing, 
the bioavailability of ciprofloxacin is 70-80%. Ciprofloxacin bioavailability was 
unaltered by food.[Shah, 1999]. Concurrent intake of foods and cations such as iron, 


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calcium and magnesium result in prolongation of the time to reach peak serum levels 
[Morera, 2001]. It is therefore recommended that ciprofloxacin should not be taken with 
dairy products (e.g. milk, yoghurt) or mineral-fortified fruit-juice [CIPROXIN Package 
Insert, 2016].
Following a 500 mg dose, maximum serum concentrations (Cmax) ranging between 1.5 to 
2.9mg/L, are reached within 1-2 hrs following dosing. [Shah, 1999]. Protein binding is 
20-30%, and ciprofloxacin is present in the plasma in a non-ionized form, it diffuses 
freely into the extravascular space [CIPROXIN Package Insert, 2016] . After oral 
administration, ciprofloxacin is widely distributed throughout the body. Tissue 
concentrations often exceed serum concentrations in both men and women, particularly in 
genital tissue including the prostate. Ciprofloxacin is present in active form in the saliva, 
nasal and bronchial secretions, mucosa of the sinuses, sputum, skin blister fluid, lymph, 
peritoneal fluid, bile, and prostatic secretions [CIPRO Package Insert, 2011].
The total ciprofloxacin area under the serum concentration versus time curve (AUC) 
increases in proportion to dose.  Four metabolites have been reported, in the urine 
identified as desethyleneciprofloxacin (M1), sulphociprofloxacin (M2), oxociprofloxacin 
(M3) and formylciprofloxacin (M4). M1 to M3 display antibacterial activity comparable 
to or inferior to that of nalidixic acid, while M4, with the smallest quantity, is largely 
equivalent to norfloxacin in its antimicrobial activity. [APO-CIPROFLOX Package 
Insert, 2012]. 
Ciprofloxacin is an inhibitor of cytochrome P450 1A2 (CYP1A2) mediated metabolism. 
Clinically significant AEs of any drug metabolized by CYP1A2 can occur if co-
administered with ciprofloxacin, due to increased plasma concentrations of the co-
administered drug [CIPRO Package Insert, 2011]. Co-administration with tizanidine is 
contra-indicated, since co-administration may increase the serum concentrations of 
tizanidine leading to tizanidine induced side effects (hypotension, somnolence, 
drowsiness). Refer to Ciproxin label for products that are contra-indicated.
Ciprofloxacin is predominantly renally excreted with approximately 40 to 50% of an 
orally administered dose recovered as unchanged drug in the urine with excretion 
virtually complete within 24 hrs after dosing.  Renal clearance is between 180-300 
mL/kg/h and the total body clearance is between 480-600 mL/kg/h. Approximately 20 to 
35% of an oral dose is recovered from the faeces within 5 days after dosing with 1-2% of 
the dose is recovered from the bile as metabolites. In humans with normal renal function, 
the serum elimination half life (t½) is approximately 4-7 hours.  In severely renally 
impaired subjects the ciprofloxacin half-life is increased up to 12 h [CIPROXIN Package 
Insert, 2016].
A detailed description of the chemistry, pharmacology, efficacy, and safety of 
ciprofloxacin is provided in the package insert for Ciproxin .


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3.3.
Benefit/Risk Assessment
Ciprofloxacin was first approved as an antibacterial agent by the Medicines and 
Healthcare Product Regulatory Agency (MHRA), in the United Kingdom (UK) in 1987 
[CIPROXIN Package Insert, 2016]. The safety profile of ciprofloxacin is well 
established based on clinical trial safety data and unsolicited pharmacovigilence reports.   
More detailed information about the known and expected benefits and risks and 
reasonably expected AEs of Ciprofloxacin may be found in the Summary of Product 
Characteristics (SmPC) [CIPROXIN Package Insert, 2016]. 
The following section outlines the risk assessment and mitigation strategy for this 
protocol.
3.3.1.
Risk Assessment
The potential risks of clinical significance for Ciprofloxacin tablets are derived from the 
prescribing information from marketed formulations during chronic therapeutic  use. 
Most of these reported risks are uncommon, rare or very rare. The likelihood of these 
risks in a healthy volunteer population  receiving a single dose is therefore expected to be 
lower.  
Risks associated when co-administered with other medications are not included as this is 
an acute dose study in healthy participants.


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Table 2
Summary of Risks and Mitigation Strategies for Investigational Products
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) [GR37547]
Allergic reactions
Contraindication: Anaphylaxis and anaphylactic 
shock which may be life threatening may occur if a 
volunteer has an allergy to the active substance 
ciprofloxacin, excipients, or other quinolones. 
Hypersensitivity reactions have been reported
following the first dose. Some reactions reported 
include cardiovascular collapse, loss of 
consciousness, tingling, pharyngeal or facial oedema, 
dyspnoea, urticaria, and itching.
Other hypersensitivity reactions include fever, rash, 
severe dermatologic reactions (e.g. Stevens-Johnson 
syndrome); vasculitis; arthralgia; myalgia; serum 
sickness; or allergic pneumonitis.
Exclude participants with a known history of 
hypersensitivity to quinolones, ciprofloxacin, or 
excipients including cellulose microcrystalline, 
crospovidone, maize starch, magnesium stearate, 
silica colloidal anhydrous, hypromellose, macrogol 
and titanium dioxide.
Further doses must be discontinued if a participant 
develops skin rash, jaundice, or any other sign of 
hypersensitivity following the study medication, and 
supportive measures immediately instituted.
In the event of serious anaphylactic reactions, 
epinephrine must be given immediately. Oxygen, 
intravenous steroids, and airway management, 
including intubation, should be administered as 
required.


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Tendinopathy and Tendon rupture
Warning: Fluoroquinolones, including Ciprofloxacin, 
are associated with an increased risk of tendinitis and 
tendon rupture in all ages. Although reports of  this 
adverse reaction (AE) have most frequently involved
the Achilles tendon, tendonitis of other sites such 
rotator cuff (the shoulder), the hand, the biceps, the 
thumb have also occurred. The risk is higher for older 
patients (>60 years of age), patients on 
corticosteroids, patients with rheumatoid arthritis, and 
those with kidney, heart or lung transplants; however 
there have been reports of tendonitis in patients with 
no risk factors.
Cases have been reported up to several months after 
discontinuation of ciprofloxacin therapy.
Only healthy participants 60 years of age will be 
included.
Participants will be cautioned to avoid strenuous 
physical activity during participation in this study.
Photosensitivity reactions
Precaution: Ciprofloxacin may cause photosensitivity
/phototoxicity reactions of the skin including
exaggerated sunburn reactions (e.g. burning, 
erythema, exudation, vesicles, blistering and  
oedema).
Study participants will be advised to avoid direct 
exposure to sunlight and UV radiation such as 
sunbeds for 24 hours after dosing.
Safety of Ciprofloxacin has not been established in 
patients under the age of 18 years, pregnant women 
and nursing women.
Warning: Ciprofloxacin is excreted in human milk;
therefore infants of nursing mothers on ciprofloxacin 
may be at risk.
Damage to juvenile weight-bearing joints and 
lameness were observed both in rat and dog studies. 
Permanent lesions of the cartilage were observed on 
histopathological examination of weight bearing joints 
of immature dogs.
Exclude participants 18 years of age, pregnant 
women and nursing women. Contraception  guidance 
is provided in the Participant Information Leaflet.
Musculoskeletal reactions and exacerbation of
Myasthenia Gravis
Warning: Muscular skeletal pain, and arthralgia may 
Only healthy volunteers will be enrolled.


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Potential Risk of Clinical Significance
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Mitigation Strategy
occur. Rare instances (1/10000 <1000) of myalgia, 
arthritis and increased muscle tone and cramping 
have been reported.
Fluoroquinolones, including ciprofloxacin, have 
neuromuscular blocking activity and may exacerbate 
muscle weakness in persons with myasthenia gravis 
with resultant requirement for ventilatory support, or 
resultant death. 
Prolongation of QT interval
Warning: Ciprofloxacin may cause tachycardia, 
ventricular arrhythmia or QT interval prolongation  in 
patients with risk factors for QT interval prolongation 
such as:

the elderly and women, 

patients on concomitant medication such as 
class IA or III antiarrhythmics, tricyclic 
antidepressants, macrolides, antipsychotics

those with congenital long QT syndrome

uncorrected electrolyte imbalance 
(hypokalemia and hypomagnesemia)

Cardiac disease (eg.heart failure, 
myocardial infarction, bradycardia)
Participants older than 60 years of age will be 
excluded, and those with cardiac disease, electrolye 
imbalance (Hypokalaemia, hypomagnesaemia), and 
known risk factors for Torsades des pointes. Only 
healthy participants will be included. ECG 
measurements taken during screening and post dose 
for each period where ciprofloxacin is administered.
Central Nervous System (CNS) Reactions
Warning: Ciprofloxacin could trigger headache, 
dizziness, tremors, restlessness,
sleep disorders or taste disorders. Ciprofloxacin may 
affect reaction time and thus the ability to drive or 
operate machinery may be impaired.
Rare cases (1/10000 to <1/1000 ) tremor and 
seizures (including stats epilepticus) have also been 
Only healthy volunteers will be included, participants 
with a history of psychiatric conditions (including 
depression, anxiety, psychosis) will be excluded.
Participants will be advised against driving or 
operating machinery for 24 hours following the dose 
of study medication. 


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Potential Risk of Clinical Significance
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reported.
Psychiatric reactions may occur including anxiety, 
paranoia, depression, confusion, psychoses, 
hallucinations, depression, nervousness, agitation, 
insomnia, anxiety, paranoia, nightmares and rarely, 
suicidal thoughts or acts. Depression or psychotic
reactions can progress to suicidal ideations/thoughts 
and self-injurious behaviour, such as attempted
suicide or completed suicide.
There have also been very rare cases (<1/10000) of 
migraine, disturbed coordination, gait disturbance, 
olfactory nerve disorders, intercranial hypertension 
and increased intercranial pressure (including 
pseudotumour cerebri).


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Peripheral Neuropathy
Rare cases of sensory or sensorimotor axonal 
polyneuropathy affecting small and/or large axons 
resulting in paresthesias, hypoesthesias, 
dysesthesias and weakness have been reported in 
patients receiving quinolones, including ciprofloxacin. 
Further ciprofloxacin doses will be discontinued if any 
participant experiences symptoms of neuropathy 
including pain, burning, tingling, numbness, and/or 
weakness, or is found to have deficits in light touch, 
pain, temperature, position sense, vibratory 
sensation, and/or motor strength in order to prevent 
the development of an irreversible condition.
Vision disorders
Warning: Impaired vision such as diplopia and colour 
distortions may also occur. 
Study participants will be advised to immediately 
report any signs of visual disturbances to the 
investigator. 
Hearing disorders
Precaution: There have been rare cases of tinnitis, or 
transitory deafness (especially at higher frequencies) 
with ciprofloxacin. 
Study participants will be advised to immediately 
report any signs of hearing disturbances to the 
investigator.
Metabolic reactions
Precaution: Hypoglycaemia can occur in Diabetic 
patients.
Ciprofloxacin may increase the effects of caffeine, 
and result in caffeine accumulation if consumed 
concomitantly with quinolones.
Only healthy volunteers to be enrolled. Exclude 
volunteers with known or suspected Diabetes based 
on history, and investigator discretion following 
review of fasting blood glucose results.
All participants to be advised to avoid caffeine 
containing food and beverages for  24 hours prior 
until 24 hours following dosing with ciprofloxacin. 
Gastrointestinal reactions
Warning: Nausea and diarrhoea are the most 
commonly reported adverse drug reactions with 
Ciprofloxacin treatment. Cases of painful oral 
mucosa, oral candidiasis, dysphagia, intestinal 
perforation, gastrointestinal bleeding and loss of 
Participants will be monitored closely, and 
appropriate therapy initiated immediately if any 
symptoms appear. Participants will be asked to 
contact the site if any symptoms appear within 24 
hours after discharge. 


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appetite has also been reported. Vomiting, abdominal 
pain, dyspepsia and flatulence although uncommon 
(1/1000 to , 1/100) have been reported.  Severe and 
persistent diarrhoea may occur during or after 
treatment (including several weeks after treatment). 
The antibiotic associated colitis could be life 
threatening with a fatal outcome. Very rare cases of 
pancreatitis (<1/10000) have been reported.
Renal and urinary reactions
Warning: Rare Cases  (1/10000 to <1/1000) of renal 
failure, crystalluria, haematuria, tubulointerstitial 
nephritis have been reported.
Healthy participants with normal renal function as  
determined by review of creatinine clearance, at 
screening will be enrolled.
Participants will be advised to stay well hydrated in 
the 24 hours following dosing.
Hepatobiliary reactions
Warning: Cases of hepatic necrosis and life 
threatening hepatic failure have been reported with 
ciprofloxacin.
Patients with  previous liver damage may have an 
increase in transaminases, alkaline phosphatase or 
cholestatic jaundice.
Participants will be closely monitored for 24 hours 
following treatment and advised to immediately report 
any signs and symptoms of hepatic disease such as  
anorexia, jaundice, dark urine, pruritus or tender 
abdomen. Laboratory biochemistry results will be 
reviewed for increases in transaminases, alkaline 
phosphatase or bilirubin. Any increases to > ULN 
from baseline levels,  following the first dose, will 
result in discontinuation from further dosing of study 
treatment  based on PI discretion.
Respiratory disorders: 
Precautions:  dyspnoea, epistaxis, laryngeal or 
pulmonary oedema, hiccough, haemoptysis, bron-
chospasm, pulmonary embolism have occurred in < 
1% of patients taking ciprofloxacin.
Participants will be closely monitored for any 
respiratory disorders and, treatment initiated if 
indicated.
Blood and Lymphatic system reactions
Eosinophilia, Leukopaenia, anaemia, neutropaenia, 
leukocytosis and thrombocytopenia may occur 
All potential participants will be tested for glucose -6-
phosphate dehydrogenase at screening and those 


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following ciprofloxacin.
Haemolytic reactions could occur in patients with 
glucose-6-phosphate dehydrogenase deficiency.
Very rare cases (<1/10000) of agranulocytosis, 
pancytopaenia, and bone marrow depression (life 
threatening) have been reported.
with values below normal will not be entered into the 
study.   
All participants will be examined for clinical signs and 
laboratory signs of haemolysis, so that immediate 
treatment can commence.
Physical signs of haemolysis include weakness, 
fatigue, pale skin, fainting, shortness of breath, rapid 
heart rate and dark urine. All participants will be 
asked to report any of these immediately.
Laboratory signs of haemolytic anaemia include 
hemoglobinuria, a reduction in red blood cell count 
and haemoglobin and increase in reticulocyte count, 
lactate dehydrogenase and bilirubin levels.  
Post dose haematology results will be reviewed for 
any other blood abnormalities.
Inhibition of Cytochrome P450 (CYP 450)
Ciprofloxacin is a moderate inhibitor of CYP450 and 
the CYP1A2 enzyme pathway. Co administration of 
ciprofloxacin and other medications primarily 
metabolized via the same metabolic pathways (e.g. 
theophylline,  methylxanthines, tizanidine, cloazpine, 
duloxetine and also caffeine) results in increased 
plasma concentrations of the coadministered 
medications and could lead to clinically significant 
pharmacodynamic side effects of the coadministered 
medications.
Healthy volunteer study, with no concomitant 
treatments, other than those allowed in Section 7.7
during participation in the study, therefore no 
drug/drug interactions are expected.


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Potential Risk of Clinical Significance
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Mitigation Strategy
Study Procedures
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 
collected by venepuncture or the cannula will be 
replaced.
Other
Not applicable
Not applicable


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3.3.2.
Benefit Assessment
Participants enrolled into this study are healthy participants. There will be no direct 
health benefits  gained from participation in this study. The participants’ involvement 
will be contributing to the PK analysis and safety profile of GR37547 compared to 
reference ciprofloxacin tablets.
3.3.3.
Overall Benefit: Risk Conclusion
Healthy volunteers 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
Table 3
Study Objectives and Endpoints
Objectives
Endpoints
Primary
To determine if 500 mg Ciprofloxacin 
(GR37547) tablets are bioequivalent to 
reference 500 mg Ciprofloxacin tablets in 
healthy adult participants under fasting 
conditions. 
Plasma PK parameters: AUC(0-t) and Cmax, for 
ciprofloxacin in relevant treatments. 
Secondary
To assess secondary PK parameters of 500 mg 
ciprofloxacin tablets (GR37547) relative to 
reference 500 mg ciprofloxacin in healthy adult 
participants under fasting conditions . 
To compare the safety and tolerability of a 
single dose of a 500 mg ciprofloxacin tablet
(GR37547) with reference 500 mg ciprofloxacin 
tablet, in healthy adult participants under fasting 
conditions.

Plasma PK parameters: AUC(0-), tmax, 
%AUCex and t½ for ciprofloxacin in relevant 
treatments.

Adverse events (AE), clinical laboratory 
values (Haematology and Biochemistry), 
ECGs 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; t1/2= Terminal phase half-life Cmax= 
Maximum observed concentration; 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 26 healthy participants at a single centre. 
Each enrolled study participant will participate 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. 
Figure 1
Study Schematic
Treatments
A = Test–GR37547 Ciprofloxacin 500 mg tablet
B = Reference  - Ciprofloxacin 500 mg tablet
SCREENING
RANDOMISATION (n=26)
Treatment Sequences 1-2
Sequence 2:  B-A  (n=13)
Sequence 1:  A-B  (n=13)
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: GR37547 (CIPVALTM), ciprofloxacin 500mg tablets.

Treatment B - Reference: Ciproxin, ciprofloxacin 500mg tablets.
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 26 participants will be randomized such that at least 22 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 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 BE 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 BE study 
design. 
5.5.
Dose Justification
The dose of ciprofloxacin  (500 mg) in GR37547 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 GR37547 ciprofloxacin strength marketed, in keeping 
with international BE 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 500 mg ciprofloxacin product 
information leaflet [CIPROXIN Package Insert, 2016]. 
PPD
PPD
PPD


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Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted, as these can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability or participant 
safety.
Therefore adherence to inclusion and exclusion criteria as stated in the protocol is 
essential.
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 between 18 and 60 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 only if the investigator 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-
30kg/m2(inclusive). 
Sex
5.
Healthy Male or female participants
a. Male participants:
A male participant must agree to use contraception as detailed in Appendix 1 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 1), 
not breastfeeding, and at least one of the following conditions applies:
(i)
Not a woman of childbearing potential (WOCBP) as defined in Appendix 1


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OR
(ii)
A WOCBP who agrees to follow the contraceptive guidance in Appendix 1
Appendix 5 during the treatment period and for at least 30 days after the last 
dose of study treatment.
The investigator is responsible for ensuring that male and female study participants 
understand how to correctly use the methods of contraception described in Appendix 1
Informed Consent
6.
Capable of giving signed informed consent as described in Appendix 2  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, haematological, neuromuscular, psychiatric, auto-immune or 
neurological disorders .
2. History of convulsions.
3. 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.
4. History of any malignancies or chemotherapy/radiation within the past 5 years 
excluding treated squamous carcinoma of the skin and adequately excised basal 
cell carcinoma
5. History of kidney, heart or lung transplants.
6. History or presence of rheumatoid arthritis.
7. Presence of hypokalaemia where the serum potassium is < lower limit of normal
(LLN).
8. Presence of hypomagnesaemia where the serum magnesium is < LLN.
9. Fasting blood glucose 7mmol/L.
10. Serum glucose-6-phosphate dehydrogenase < LLN.
11. Abnormal renal function, as determined by creatinine clearance and considered as 
clinically significant by the investigator will be excluded.
12. Alanine transaminase (ALT) >1.5x upper limit of normal (ULN) 


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13. Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%). 
14. Current or chronic history of liver disease, or known hepatic or biliary 
abnormalities (with the exception of Gilbert's syndrome or asymptomatic 
gallstones)
15. Excessive alkalinity of the urine (pH 9), as determined on Day -1.
16. Abnormal blood pressure (BP) as determined by the investigator.
17. 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.
NOTES:

For purposes of data analysis, only QTcB, will be used.
Prior/Concomitant Therapy
18. 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
19. Where participation in the study would result in loss of blood or blood products in 
excess of 500 mL within 90 days.
20. Exposure to more than 4 new chemical entities within 12 months prior to the first 
dosing day.
21. 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.
Diagnostic assessments
22. Presence of Hepatitis B surface antigen (HBsAg) at screening or a Positive 
Hepatitis C antibody test result at screening.
NOTE:  Subjects with positive Hepatitis C antibody due to prior resolved disease can be 
enrolled, only if a confirmatory negative Hepatitis C RNA test is obtained.
23. Positive pre-study drug/alcohol screen
24. Positive human immunodeficiency virus (HIV) antibody test
25. Regular use of known drugs of abuse 


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Other Exclusions
26. Sensitivity to heparin or heparin-induced thrombocytopenia
27. Sensitivity to any of the study treatments, or components thereof, or drug or other 
allergy including allergy to quinolones that, in the opinion of the investigator or 
medical monitor, contraindicates participation in the study. 
28. 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. 
29. Urinary cotinine levels indicative of smoking or history or regular use of tobacco-
or nicotine-containing products within 6 months prior to screening.
6.3.
Lifestyle Restrictions

Study participants must avoid direct exposure to sunlight and UV radiation for 24 hrs 
after dosing, due to potential for photo-toxicity reactions. 

Participants must not drive or operate machinery for 24 hours following the dose of 
study medication.  
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 
prior to the first dose of study medication 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 hr before and after 
drug administration.  Participants should receive standardized meals scheduled at the 
same time in each period of the study.

Adequate hydration must be maintained, whilst taking into consideration the 1 hr 
water restriction pre-and post study medication dosing. 
6.3.2.
Caffeine, Alcohol, and Tobacco

During each dosing session, participants will abstain from ingesting caffeine- or 
xanthine-containing products (e.g., coffee, tea, cola drinks, and chocolate) for 24 hrs 
before the start of dosing until after collection of the final PK sample.


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
During each dosing session, participants will abstain from alcohol for 24 hrs 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 hrs before the start of dosing 
until after collection of the final PK sample, at each dosing session.  Participants may 
participate in light recreational activities during studies (e.g., 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 randomized in the study. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any SAEs.
Individuals who do not meet the criteria for participation in this study (screen failure) 
may not be rescreened.
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.


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7.1.
Treatments Administered
Table 4
Study Treatments
Study Treatment
Test Product
Reference Product
Study Treatment Name:
GR37547/Ciprofloxacin 500 mg 
(CIPVALTM)
Ciproxin
Dosage formulation:
Tablet
Tablet
Unit dose 
strength(s)/Dosage 
level(s):
500 mg Ciprofloxacin
Route of Administration 
Route: Oral
Duration: single dose
Dosing instructions:
1 tablet to be taken orally with 240 mL water.
Physical Description:
White to off white capsule 
shape with break line on upper 
side and embossed “GSK500”
on lower side.
Nearly white to slightly yellowish 
film coated oblong tablets with 
break line and “CIP 500” marked on 
upper side  and “BAYER” on lower 
side.
Manufacturer /Supplier
GlaxoSmithKline Pakistan 
Limited, F-268, Karachi 75700, 
Pakistan.
Bayer Pharma AG/Bayer plc, U.K.
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.


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A description of each regimen is provided in Table 5.  Treatments administered are as 
follows:

Treatment A – Test GR37547 Ciprofloxacin 500 mg tablets (CIPVALTM)

Treatment B – Reference 500 mg Ciprofloxacin tablets (Ciproxin)
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 5
Description of each treatment sequence
Sequence
Number of 
Participants Per 
Group
Treatment Period 1
Treatment Period 2
A-B
13
Treatment A
(GR37547)
Treatment B
Reference
B-A
13
Treatment B
Reference
Treatment A
(GR37547)
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
No special preparation of study treatment is required.

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.

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.

The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records).


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
The final disposition of unused study treatment  will be handled as per GSK’s 
requirements 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.
7.6.
Treatment Compliance
When the individual dose for a participant is prepared from a bulk supply, the preparation 
of the dose will be confirmed by a second member of the study site staff. 
When participants are dosed, 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.  
Study site personnel will examine each participant’s mouth to ensure that the study 
treatment was ingested.
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 ciprofloxacin SMPC [CIPROXIN Package Insert, 2016] should be consulted for 
detailed information regarding interaction with concomitant therapy.
Participants must abstain from taking prescription or non- prescription drugs (including 
vitamins and dietary or herbal supplements) for 14 days before the start of the study 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.  Please refer to the 
summary of interactions with other medicinal products in the Package Insert for 
Ciproxin.


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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 in the event of the following medical reasons after receiving the first dose of 
study medication:

anaphylaxis, 

sensitivity reactions (e.g. pharyngeal or facial oedema, dyspnoea, rash, severe 
dermatologic reactions,) 

tendinopathy and tendon rupture

liver events (see Section 8.1.1).

positive pregnancy test

vomiting within 4 hours (approximately 2 × the median tmax) of the reference 
product

other AEs related to study treatment at the investigator discretion
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 aetiology (in alignment with the Food 
and Drug Administration [FDA] premarketing clinical liver safety guidance).  These 
protocol guidelines are in alignment with FDA premarketing clinical liver safety 
guidance: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Discontinuation of study treatment for abnormal liver tests should be considered by the 
investigator when a participant meets one of the conditions outlined in the algorithm in 
Figure 2, 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 3.
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 QT 
corrected (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 of  ECGs obtained over a brief  
recording period.
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.
A participant that meets either of  the bulleted criteria below will be withdrawn from 
study treatment.

QTc, QTcB, >500 msec,


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
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.
8.1.3.
Temporary Discontinuation
Participants withdrawn from study treatment, will continue in the study until completion 
of the 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, 
behavioural, 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. Additional assessments may be performed at the discretion of the 
investigator.
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 fails to return to the clinic for a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible and counsel the participant on the importance of maintaining
the assigned visit schedule and ascertain whether 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, 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. 


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9.
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarized in the SoA. 

Protocol waivers or exemptions are not allowed 

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study 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 (e.g., 
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.

Samples will be destroyed within 6 months after the clinical execution of the
study has been completed.
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). 


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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).

AEs will be collected from the start of IP administration and 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 within 24 hrs, 
as indicated in Appendix 4. The investigator will submit any updated SAE data 
to the sponsor within 24 hrs 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 of special 
interest (as defined in Section 3.3.1), 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 


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regulatory requirements relating to safety reporting to the regulatory authority, 
IRB/ IEC, and investigators.

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 e.g., 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 1.

Abnormal pregnancy outcomes (e.g., 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 study treatment GR37547 or comparator greater than 500 mg 
ciprofloxacin within a 24-hr time period will be considered an overdose. Symptomatic 
and supportive treatment is recommended. 
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 
ciprofloxacin. Adequate hydration must be maintained. The administration of activated 
charcoal as soon as possible after oral overdose may prevent excessive increase of 
systemic ciprofloxacin 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 
ciprofloxacin 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.


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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.
9.4.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Section 2). 
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 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 BP 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.

Vital signs will be measured in a supine position after 5 minutes rest and will 
include temperature, systolic and diastolic BP, respiratory rate and pulse.  Three 
readings of BP and pulse will be taken. The first reading should be rejected. The 
second and third readings should be averaged to give the measurement to be 
recorded in the CRF.

Participants will not be dosed if their average pre-dose SBP on Day 1 is <95 mm 
Hg or their average resting ventricular rate is 45 beats per minute.

Pre-dose vital signs will be collected at -2.00 to 0.00 hrs.  Following completion 
of the pre-dose procedures the appropriate dose of study medication will be 
administered.
Vital signs post dose will be obtained within 30 min.
9.4.3.
Electrocardiograms
Single 12-lead ECGs will be obtained at the Screening visit, Day 1 (to co-incide with 
tmax), and on Day 2 at the time of discharge, as outlined in the SoA (see Section 2 ) using 
an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, 


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and QTc intervals. Refer to Section 8.1.2 for QTc withdrawal criteria and additional QTc 
readings that may be necessary.
9.4.4.
Clinical Safety Laboratory Assessments

All clinical laboratory assessments will be performed by the local laboratory.

Refer to Appendix 5 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 
section of the CRF or equivalent. Clinically significant abnormal laboratory 
findings are those which are not usually expected in a healthy volunteer.

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 aetiology should be identified and the sponsor 
notified.

All protocol-required laboratory assessments, as defined in Appendix 5, must be 
conducted in accordance with the PAREXEL laboratory manual, PAREXEL 
standard operating procedures (SOPs) and the SoA.

If laboratory values from non-protocol specified laboratory assessments 
performed at the institution’s local laboratory require a change in participant 
management or are considered clinically significant by the investigator (e.g., 
SAE or AE or dose modification), then the results must be recorded in the CRF
or equivalent.

Refer to the PAREXEL SOPs for appropriate processing and handling of 
samples to avoid duplicate/ and or additional blood draws.
9.4.5.
Suicidal Risk Monitoring
Ciprofloxacin is considered to be a CNS-active drug.  There have been some reports of
rare instances of psychiatric reactions such as depression and psychosis leading to 
suicidal ideation as reported in the product label [CIPROXIN Package Insert, 2016] in 
some patients being treated with ciprofloxacin for bacterial infections. This risk is 
expected to be lower with a single dose versus a course of treatment. Nevertheless, GSK 
considers it important to monitor for such events before and during clinical studies with 
compounds such as this.
Study participants receiving ciprofloxacin should be appropriately  observed for suicidal 
ideation and behaviour or any other unusual changes in behaviour. Consideration should 
be given to discontinuing further dosing with the study medication in participants who 
experience signs of suicidal ideation or behaviour. 


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9.5.
Pharmacokinetics
Pharmacokinetic sampling time-points are discussed in the SoA in Section 2. 

Whole blood samples of approximately 6 mL will be collected into lithium 
heparin tubes, for measurement of plasma concentrations of ciprofloxacin as 
specified in the SoA.  A maximum of 2 samples may be collected at additional 
time points during the study if warranted and agreed upon between the 
investigator and the sponsor. Instructions for the collection and handling of 
biological samples is provided in the PAREXEL Laboratory Manual. The actual 
date and time (24-hr clock time) of each sample will be recorded.

Samples will be used to evaluate the PK of ciprofloxacin.  

Each plasma sample will be divided into 2 aliquots of not less than 1.2 mL plasma 
each (one for analysis and one backup). 

Samples collected for analyses of ciprofloxacin plasma concentration may also be 
used to evaluate safety related to concerns arising during or after the study.

Pre-dose PK samples will be collected within 15 minutes prior to dose 

Post dose samples for 0.50-2.00 hrs will be collected within 2 minutes ;  samples 
for 2.50 – 8.00 hrs will be collected within 5 min; and samples for 12.00 – 24.00 hrs 
will be collected within 10 min.

Samples collected outside these recommended time windows will be recorded as 
protocol deviations

Participant confidentiality will be maintained. At visits during which whole blood 
samples are also taken for laboratory or other tests, one sample of sufficient 
volume can be used.

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.
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.


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10.
STATISTICAL CONSIDERATIONS
Refer to Analysis Plan (Appendix 6).
Bioequivalence
The primary objective of this study is to demonstrate BE between the test 500 mg tablet 
formulation GR37547 and the reference formulation, based on PK endpoints Cmax and 
AUC(0-t) of ciprofloxacin. 
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 ciprofloxacin.
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 ciprofloxacin.
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. 
For BE to be declared, the null hypothesis must be rejected, for all primary parameters 
Cmax, and AUC(0-t), for ciprofloxacin.


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10.1.
Sample Size Determination
Sample Size Rationale:
Bioequivalence is to be determined on the basis of the endpoints Cmax and AUC(0-t) of
ciprofloxacin. 
Intra participant coefficient of variation (CVw) estimates in recent published data for 
ciprofloxacin were in the range of 12 to 18%  for the primary endpoints of ciprofloxacin 
[Hassan , 2007; Cuadrado, 2004] which are in line with older published data [Galicia , 
1998 ] .  For the oral formulation, AUC data (CVw approximately 11-12%) generally 
were less variable than Cmax data (15-18%) and thus the latter should be considered for 
sample size calculation.
Hence, the sample size for this trial was determined based on maximum observed intra 
participant CV of 18%. 
Based on a BE range of 80.00% to 125.00% for Cmax and AUC(0-t), for ciprofloxacin 
assuming intra participant CV to be 18% and a "test/reference" mean ratio of 0.95;  22
evaluable subjects are needed to achieve a power of 90% at an alpha level of 0.05 for the 
single test for testing BE.
Approximately 26 eligible participants (approximately 19% in excess of number needed 
to complete) will be entered into the study to complete the study with at least 22
evaluable participants. See Section 5.2
10.2.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Table 6
Description of Populations for Analysis
Population
Description
Enrolled 
All participants who sign the ICF
Randomized
All participants assigned to study treatment
Safety
All randomized participants who received at least 1 dose of study 
treatment. Participants will be analyzed according to the treatment 
they actually received.
PK
All subjects 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.
10.3.
Statistical Analyses
The statistical methodology below describes the statistical analysis as it is foreseen when 
the study is being planned.


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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 described in the clinical study report.
See Appendix 6 for a list of Tables, Figures and Listings to be appended in the clinical 
study report.
10.3.1.
PK Analyses
Pharmacokinetic analysis will be the responsibility of the PAREXEL Quantitative 
Clinical Development (QCD) department.  Plasma ciprofloxacin 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 
analysis and using the actual sampling time intervals (relative to 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)], 
and apparent t1/2 of ciprofloxacin.
Participants who experience emesis during the course of the study will be deleted from 
the statistical analysis if vomiting occurred within 4 hrs which is approximately twice the 
median tmax [CIPROXIN Package Insert, 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 may be dropped from all BE 
evaluations.
The available concentration data of the participants excluded due to vomiting, and of 
those who 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. All PK data will be archived by the study sponsor GSK.
Statistical analyses of the PK parameter data will be the responsibility of PAREXEL 
Biostatistics.
10.3.2.
Protocol Deviations and Changes to Planned Analyses
Permission from the sponsor in writing will be obtained should any changes be required 
to the clinical study protocol.  Should the safety of the subjects necessitate immediate 
action, which represents a deviation from the clinical study protocol, the sponsor will be 
informed as soon as possible.


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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 ciprofloxacin

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 ciprofloxacin

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 7
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 ciprofloxacin 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, 
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 


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Endpoint
Statistical Analysis Methods
seriously violated then alternative statistical methods will be considered.
Secondary
AUC(0-) of ciprofloxacin will be  analysed as per primary analysis; tmax of 
ciprofloxacin 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 chemistry 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
APO-CIPROFLOX (Ciprofloxacin Hydrochloride tablets - Apotex Standard 250mg, 
500mg and 750mg, Product Monograph) Product Information. September, 2012. 
(https://pdf.hres.ca/dpd_pm/00017811.PDF)
CIPRO (Ciprofloxacin hydrochloride tablets, Ciprofloxacin Oral Suspension, Summary 
of Product Characteristics) Product Information. November, 2011.  
(http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/019537s074,020780s032lbl.
pdf )
CIPROXIN (Ciprofloxacin 500mg, Summary of Product Characteristics) Product 
Information. April, 2016.  (https://www.medicines.org.uk/emc/medicine/20346)
Cuadrado A, Gascon AR, Solinis MA, Ramirez E, Hernandez RM, Knie U,et.al.. 
Bioquivalence of two oral ciprofloxacin tablet formulations. Int J Clin Pharmacol Ther. 
2004;42(6):336-41. 
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. 
Galicia I, Frias-Iniesta J, Carcas AJ, Soto A, Gomez E, Miranda E,et.al.. Bioequivalence 
evaluation of 2 different oral formulations of ciprofloxacin in healthy volunteers. 
International Journal of Clinical Pharmacology and Therapeutics. 1998;36(5):282-285. 
Hassan Y, Alfadly SO, Azmin MN, Peh KK, Tan TFY, Noorizan AA,et.al.. 
Bioequivalence evaluation of two different formulations of ciprofloxacin tablets in 
healthy volunteers. Singapore Med J. 2007;48(9):819. 
Morera M, Cortes J, Ramos I, Moncada J, Fonseca L. Bioequivalence of Two Oral 
Ciprofloxacin Formulations. Clin Drug Invest. 2001;21 (2):137-145. 
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. 
Shah A, Liu M-C, Vaughan D, Heller AH. Oral Bioequivalence of three ciprofloxacin 
formulations following single-dose administration: 500mg tablet compared with 
500mg/10mL or 500mg/5mL suspension and the effect of food on the absorption of 
ciprofloxacin oral suspension. Journal of Antimicrobial Chemotherapy. 1999;43, Suppl. 
A:49-54. 


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12.
APPENDICES
12.1.
Appendix 1: 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 enrolment.
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 
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
Agree to use a male condom plus an additional method of contraception 
with a failure rate of <1% per year as described in Table 8 when having 
penile-vaginal intercourse with a woman of childbearing potential 

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. 

Refrain from donating sperm for duration of study and for 5 days after the last 
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 8. 
Table 8
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 (oestrogen- and progestogen-containing ) hormonal contraception associated with 
inhibition of ovulationb

oral

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 
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 


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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 serum pregnancy test 

Additional pregnancy testing should be performed on Day -1 during the 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 foetal
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.

Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on participant and neonate, which will 


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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 foetal 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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12.2.
Appendix 2: 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 (e.g., 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, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study centre. 


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
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 reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually 
agreeable location.


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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.
Study information and tabular study results, from this protocol will be posted on the US 
National Institutes of Health’s website www.ClinTrials.gov, other publically-accessible 
sites, and the GSK Clinical Trials Register. In addition, results may also be published in 
peer-reviewed publications, to ensure the scientific integrity and credibility of publication 
activities performed by or on behalf of the company. Access to analyzable datasets from 
clinical studies will be granted through a secure system, following an independent 
assessment of the scientific merit of a rigorously defined research question from a third 
party.
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 (e.g., 
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. 


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Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the 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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12.3.
Appendix 3: Liver Safety: Required Actions and Follow-up 
Assessments
Phase I Liver chemistry stopping criteria have been designed to assure participant safety 
and to evaluate liver event aetiology  (in alignment with the FDA premarketing clinical 
liver safety guidance).  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
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

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 creatinine 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, 


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Liver Chemistry Stopping Criteria 
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

Monitor participants weekly until liver 
chemistries resolve, stabilize or return to 
within baseline
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 
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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12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
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 deemed clinically significant by the investigator), 
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 (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., 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 

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.


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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 (e.g., 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 fulfils 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, diarrhoea, influenza, 
and accidental trauma (e.g., 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 
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 


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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 (egg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The investigator will then record all relevant AE/SAE information in the CRF or 
equivalent.

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 
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 


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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 - Pharmacovigilence
Facsimile: PPD


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12.5.
Appendix 5: Clinical Laboratory Tests

The tests detailed in Table 1will be performed by the local laboratory. 

If the local laboratory results are used to make either a study treatment decision 
or response evaluation, the results must be entered into the CRF.

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 9
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
glucose -6-
phosphate 
dehydrogenase 
(G6PD)
Chloride
Magnesium
Lactate 
dehydrogenase (LD)
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

Breath alcohol and urine drug screen (to include at minimum: amphetamines, barbiturates, 
benzodiazepines, cocaine, opiates, phencyclidine (phenylcyclohexalpiperidine), 
tetrahydrocannabinol, methadone, methamphetamine, tricyclic antidepressants, oxycodone 


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Laboratory 
Assessments 
Parameters 
 
 
 
 
and propoxyphene) 
• Cot
in
ine 
• Serum or ur
ine human chor
ion
ic gonadotrop
in (hCG) pregnancy test (as needed for women 
of ch
i
ldbear
ing potent
ia
l)
2 
• Sero
logy (HIV ant
ibody, hepat
it
is B surface ant
igen [HBsAg], and hepat
it
is C v
irus 
ant
ibody)] Hepat
it
is C RNA test for Hepatit
is C ant
ibody pos
it
ive Part
ic
ipants  
The resu
lts of each test must be entered 
into the CRF or equ
iva
lent. 
NOTES : 
1. Deta
i
ls of 
l
iver chem
istry stopp
ing cr
iter
ia and requ
ired act
ions and fo
l
low-up assessments after 
l
iver stopp
ing or 
mon
itor
ing event are g
iven 
in Sect
ion 8.1 and Append
ix 3. A
l
l events of ALT ≥3 × upper 
l
im
it of norma
l (ULN) and 
b
i
l
irub
in ≥2 × ULN (>35% d
irect b
i
l
irub
in) or ALT ≥3 × ULN and 
internat
iona
l norma
l
ized rat
io (INR) >1.5, 
if INR 
measured, wh
ich may 
ind
icate severe 
l
iver 
in
jury (poss
ib
le Hy
’s Law), must be reported as an SAE (exc
lud
ing 
stud
ies of hepat
ic 
impa
irment or c
irrhos
is). 
2. Loca
l ur
ine test
ing w
i
l
l be standard for the protoco
l un
less serum test
ing 
is requ
ired by 
loca
l regu
lat
ion or IRB/IEC. 
 


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12.6.
Appendix 6:  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 
ciprofloxacin 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 ciprofloxacin
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 ciprofloxacin 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 ciprofloxacin.
The individual plasma ciprofloxacin concentration versus actual time profiles for each 
participant and treatment, as well as the mean (arithmetic and geometric) plasma 
ciprofloxacin 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, together with the geometric mean values. 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 
                                                
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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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).
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 6.
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;
                                                
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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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%.
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.
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 ciprofloxacin PK parameters (ANOVA)
Non Parametric Analysis of ciprofloxacin PK parameter
Plasma ciprofloxacin concentration (unit)
Plasma ciprofloxacin PK parameter (unit)
Adverse events summary by treatment
Concomitant Medication summary by treatment
Summary Statistics of Vital Signs Values
Summary Statistics of Chemistry Values.
Summary Statistics of Haematology Values.


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Figures
Plasma ciprofloxacin arithmetic and geometric mean concentrations (unit)
Median concentration vs. Time for ciprofloxacin
Combined individual plasma ciprofloxacin concentrations (unit)
Individual plasma ciprofloxacin concentrations (unit) (linear-linear scale and log-linear 
scale)
Adjusted geometric mean treatment ratio (with 90% CI) for ciprofloxacin
Listings
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 ciprofloxacin concentrations (unit)
Plasma ciprofloxacin 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.


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12.7.
Appendix 7: 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
BE
Bioequivalence
BMI
Body mass index
BP
Blood pressure
BUN
Blood urea nitrogen
CI
Confidence Interval
CONSORT
Consolidated Standards of Reporting Trials
CV
Coefficient of variation
Cmax
Maximum observed concentration 
CPK
Creatine phosphokinase
CRF
Case Report Form
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
h/hr
Hour(s)
ICF
Informed consent form
ICH
International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for
Human Use
INR
International Normalized Ratio
IEC
Independent Ethics Committee
IgG
Immunoglobulin G
IP
Investigational Product
IRB
Institutional Review Board
kg
Kilogram
LAM
Local Affiliate Module
LDH
Lactate Dehydrogenase
LLN
Lower Limit of Normal


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MCV
Mean corpuscular volume
MCH
Mean corpuscular hemoglobin 
MedDRA
Medical Dictionary for Regulatory Activities
Mg
Milligrams
mL
Milliliter
MSDS
Material Safety Data Sheet
Msec
Milliseconds
PK
Pharmacokinetic
PT
Prothrombin Time
QTc
QT corrected
QTcB
QT interval corrected for heart rate according to Bazett’s 
formula
RBC
Red blood cells
SAE
Serious adverse event(s)
SBP
Systolic Blood Pressure
SD
Standard deviation
SoA
Schedule of Activities
SOP
Standard Operating Procedure
SGOT
Serum glutamic-oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SmPC
Summary of Product Characteristics
t½
Terminal phase half-life
Tmax
Time of occurrence of Cmax
ULN
Upper limit of normal
WBC
White blood cells
WCBP
Women of Childbearing Potential
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
CIPVAL
Ciproxin
Phoenix
SAS
WinNonlin