Bioequivalence Study Between GR37547 500 Milligrams (mg) Tablet Versus Ciprofloxacin 500 mg Tablet Reference Product in Healthy Adult Subjects

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Infections, Bacterial

Intervention / Treatment
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* Drug: GR37547 tablet
* Drug: Ciprofloxacin reference tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject must be between 18 and 60 years of age inclusive, at the time of signing the informed consent. 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. A subject 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. Body weight >=50 kilogram (kg) and body mass index (BMI) within the range 19-30 kg per meter square (kg/m^2) (inclusive). Healthy Male or female subjects: Male subjects: A male subject must agree to use contraception 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; Female subjects: A female subject is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: Not a woman of childbearing potential (WOCBP) OR A WOCBP who agrees to follow the contraceptive guidance 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 subjects understand how to correctly use the methods of contraception. Capable of giving signed informed consent. Exclusion Criteria: History or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, neuromuscular, psychiatric, auto-immune or neurological disorders. History of convulsions. 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. 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. History of kidney, heart or lung transplants. History or presence of rheumatoid arthritis. Presence of hypocalcaemia where the serum potassium is < lower limit of normal (LLN). Presence of hypomagnesaemia where the serum magnesium is < LLN. Fasting blood glucose >=7 millimoles (mmol)/liter (L). Serum glucose-6-phosphate dehydrogenase < LLN. Abnormal renal function, as determined by creatinine clearance and considered as clinically significant by the investigator will be excluded. Alanine transaminase (ALT) >1.5x upper limit of normal (ULN). Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%). Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). Excessive alkalinity of the urine (potential of hydrogen [pH] >=9), as determined on Day -1. Abnormal BP as determined by the investigator. QT interval corrected for heart rate according to Bazett's formula (QTcB) >450 milliseconds (msec). Subjects with a known risk of QT prolongation will be excluded. For purposes of data analysis, only QTcB, will be used 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. Where participation in the study would result in loss of blood or blood products in excess of 500 milliliter (mL) within 90 days. Exposure to more than 4 new chemical entities within 12 months prior to the first dosing day. 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. Presence of Hepatitis B surface antigen (HBsAg) at screening or a Positive Hepatitis C antibody test result at screening. Positive pre-study drug/alcohol screen. Positive human immunodeficiency virus (HIV) antibody test. Regular use of known drugs of abuse. Sensitivity to heparin or heparin-induced thrombocytopenia. 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. 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 grams (g) of alcohol: a half-pint (approximately 240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits. Urinary cotinine levels indicative of smoking or history or regular use of tobacco or nicotine-containing products within 6 months prior to screening.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Crossover assignment: Subjects will receive treatment in one of the two sequences; Treatment A (GR37547 tablet) followed by Treatment B (ciprofloxacin reference tablet) or vice versa separated by a washout period of at least 7 days and not more than 14 days.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment sequence: A/B<br>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. | Drug: GR37547 tablet<br>* 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 GSK500on lower side.<br>Drug: Ciprofloxacin reference tablet<br>* 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.<br>|
| Experimental: Treatment sequence: B/A<br>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. | Drug: GR37547 tablet<br>* 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 GSK500on lower side.<br>Drug: Ciprofloxacin reference tablet<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Plasma Concentration-time Curve From Time Zero (Pre-dose) to Last Time of Quantifiable Concentration Within a Participant Across All Treatments (AUC[0-t]) for Ciprofloxacin | Blood samples were collected from participants at indicated time points in each of the treatment period 1 and 2, after administration of study treatment to investigate the pharmacokinetics of ciprofloxacin under fasted state. Pharmacokinetic analysis of ciprofloxacin was conducted using non-compartmental methods. Pharmacokinetic Population comprised of participants who completed the study and for whom primary pharmacokinetic parameters could be calculated for all treatment periods were included in the statistical pharmacokinetic analysis of the study. | Pre-dose and 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 post-dose on Day 1; 24.00 hours post-dose on Day 2 in each treatment period | 
| Maximum Observed Plasma Concentration (Cmax) of Ciprofloxacin | Blood samples were collected from participants at indicated time points in each of the treatment period 1 and 2, after administration of study treatment to investigate the pharmacokinetics of ciprofloxacin under fasted state. Pharmacokinetic analysis of ciprofloxacin was conducted using non-compartmental methods. | Pre-dose and 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 post-dose on Day 1; 24.00 hours post-dose on Day 2 in each treatment period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Concentration-time Curve From Time Zero (Pre-dose) Extrapolated to Infinite Time (AUC[0-infinity]) for Ciprofloxacin | Blood samples were collected from participants at indicated time points in each of the treatment period 1 and 2, after administration of study treatment to investigate the pharmacokinetics of ciprofloxacin under fasted state. Pharmacokinetic analysis of ciprofloxacin was conducted using non-compartmental methods. | Pre-dose and 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 post-dose on Day 1; 24.00 hours post-dose on Day 2 in each treatment period | 
| Time of Occurrence of Cmax (Tmax) for Ciprofloxacin | Blood samples were collected from participants at indicated time points in each of the treatment period 1 and 2, after administration of study treatment to investigate the pharmacokinetics of ciprofloxacin under fasted state. Pharmacokinetic analysis of ciprofloxacin was conducted using non-compartmental methods. Tmax of ciprofloxacin was analyzed using a nonparametric test to compute point estimate of the median and full range. | Pre-dose and 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 post-dose on Day 1; 24.00 hours post-dose on Day 2 in each treatment period | 
| Percentage of AUC (0-infinity) Obtained by Extrapolation (Percentage AUCex) for Ciprofloxacin | Blood samples were collected from participants at indicated time points in each of the treatment period 1 and 2, after administration of study treatment to investigate the pharmacokinetics of ciprofloxacin under fasted state. Pharmacokinetic analysis of ciprofloxacin was conducted using non-compartmental methods. | Pre-dose and 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 post-dose on Day 1; 24.00 hours post-dose on Day 2 in each treatment period | 
| Terminal Phase Half-life (t1/2) for Ciprofloxacin | Blood samples were collected from participants at indicated time points in each of the treatment period 1 and 2, after administration of study treatment to investigate the pharmacokinetics of ciprofloxacin under fasted state. Pharmacokinetic analysis of ciprofloxacin was conducted using non-compartmental methods. | Pre-dose and 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 post-dose on Day 1; 24.00 hours post-dose on Day 2 in each treatment period | 
| Number of Participants With Serious Adverse Events (SAEs) and Non-serious AEs (Non-SAEs) | 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. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/ incapacity, is a congenital anomaly/ birth defect or other situations. The analysis was performed on Safety Population which comprised of all randomized participants who received at least 1 dose of study treatment. Participants were analyzed according to the treatment they actually received. | Up to 4 weeks in each treatment period | 
| Alanine Aminotransferase (ALT), Alkaline Phosphatase (Alk Phos), Aspartate Aminotransferase (AST) and Lactate Dehydrogenase (LD) at Indicated Time-points | Blood samples were collected from participants on Day -1 and Day 2 of each treatment period 1 and 2 for the analysis of clinical chemistry parameters including ALT, Alk phos, AST and LD. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). | Up to Day 2 of each treatment period | 
| Blood Urea Nitrogen (BUN) at Indicated Time-points | Blood samples were collected from participants on Day -1 and Day 2 of each treatment period 1 and 2 for the analysis of BUN. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). | Up to Day 2 of each treatment period | 
| Calcium, Chloride, Glucose, Magnesium, Potassium and Sodium at Indicated Time-points | Blood samples were collected from participants on Day -1 and Day 2 of each treatment period 1 and 2 for the analysis of clinical chemistry parameters including calcium, chloride, glucose, magnesium, potassium and sodium. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). | Up to Day 2 of each treatment period | 
| Total Bilirubin (Total Bil), Direct Bilirubin (Direct Bil) and Creatinine (Creat) at Indicated Time-points | Blood samples were collected from participants on Day -1 and Day 2 of each treatment period 1 and 2 for the analysis of clinical chemistry parameters including total bil, direct bil and creat. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). | Up to Day 2 of each treatment period | 
| Total Protein at Indicated Time-points | Blood samples were collected from participants on Day -1 and Day 2 of each treatment period 1 and 2 for the analysis of total Protein. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). | Up to Day 2 of each treatment period | 
| Platelets, Neutrophils, Monocytes, Lymphocytes, Leucocyte, Eosinophils and Basophils at Indicated Time-points | Blood samples were collected from participants on Day -1 and Day 2 of each treatment period 1 and 2 for evaluation of hematology parameters including platelets, neutrophils, monocytes, lymphocytes, leucocyte, eosinophils and basophils. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). | Up to Day 2 of each treatment period | 
| Mean Corpuscular Volume (MCV) at Indicated Time-points | Blood samples were collected from participants on Day -1 and Day 2 of each treatment period 1 and 2 for evaluation of MCV. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). | Up to Day 2 of each treatment period | 
| Mean Corpuscular Hemoglobin (MCH) at Indicated Time-points | Blood samples were collected from participants on Day -1 and Day 2 of each treatment period 1 and 2 for evaluation of MCH. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). | Up to Day 2 of each treatment period | 
| Mean Corpuscular Hemoglobin Concentration (MCHC) and Hemoglobin (Hb) at Indicated Time-points | Blood samples were collected from participants on Day -1 and Day 2 of each treatment period 1 and 2 for evaluation of hematology parameters including MCHC and Hb. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). | Up to Day 2 of each treatment period | 
| Percent Reticulocytes at Indicated Time-points | Blood samples were collected from participants on Day -1 and Day 2 of each treatment period 1 and 2 for evaluation of percent reticulocytes. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). | Up to Day 2 of each treatment period | 
| Hematocrit at Indicated Time-points | Blood samples were collected from participants on Day -1 and Day 2 of each treatment period 1 and 2 for evaluation of hematocrit. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). | Up to Day 2 of each treatment period | 
| Erythrocyte Count at Indicated Time-points | Blood samples were collected from participants on Day -1 and Day 2 of each treatment period 1 and 2 for evaluation of erythrocyte count. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). | Up to Day 2 of each treatment period | 
| Number of Participants With Clinically Significant Abnormal Findings for Urinalysis | Urine samples were collected from participants on Day -1 and Day 2 of each treatment period 1 and 2. The number of participants with abnormal (clinically significant) findings for urinalysis have been presented. | Up to Day 2 of each treatment period | 
| Number of Participants With Clinically Significant Abnormal Findings for Electrocardiogram (ECG) Parameters | A single 12-lead ECGs was obtained on Day 1 and Day 2 of each treatment period 1 and 2 using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QT corrected (QTc) intervals. The number of participants with abnormal (clinically significant) findings for ECG parameters have been presented. | Up to Day 2 of each treatment period | 
| Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Indicated Time-points | Blood pressure of participants was measured on Day 1 and Day 2 of each treatment period 1 and 2 in a supine position after 5 minutes rest. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). | Up to Day 2 of each treatment period | 
| Respiratory Rate at Indicated Time-points | Respiratory rate of participants was measured on Day 1 and Day 2 of each treatment period 1 and 2 in a supine position after 5 minutes rest. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). | Up to Day 2 of each treatment period | 
| Pulse Rate at Indicated Time-points | Pulse rate of participants was measured on Day 1 and Day 2 of each treatment period 1 and 2 in a supine position after 5 minutes rest. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). | Up to Day 2 of each treatment period | 
| Body Temperature at Indicated Time-points | Body temperature of participants was measured on Day 1 and Day 2 of each treatment period 1 and 2 in a supine position after 5 minutes rest. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). | Up to Day 2 of each treatment period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GR37547, Cross-over, Bioequivalence, Ciprofloxacin