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

Phase 1

Completed

• Conditions: Infections, Bacterial
• Interventions: Drug: GR37547 tablet; Drug: Ciprofloxacin reference tablet

• Registration Number: NCT03150082
• Lead Sponsor: GlaxoSmithKline

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

Not available

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2017-05-10
• Study First Submitted QC: 2017-05-10
• Study First Posted: 2017-05-11
• Study Start: 2017-08-01
• Primary Completion: 2017-08-28
• Study Completion: 2017-08-28
• Status Verified: 2018-06
• Results First Submitted: 2018-06-27
• Results First Submitted QC: 2018-06-27
• Last Update Submitted: 2018-06-27
• Results First Posted: 2018-12-19
• Last Update Posted: 2018-12-19

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 26

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.

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Treatment sequence: B/A	Ciprofloxacin reference tablet	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.
Treatment sequence: A/B	Ciprofloxacin reference tablet	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.
Treatment sequence: B/A	GR37547 tablet	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.
Treatment sequence: A/B	GR37547 tablet	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.

Primary Outcome Measures

Name	Time	Method
Maximum Observed Plasma Concentration (Cmax) of Ciprofloxacin	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	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.
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	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	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.

Secondary Outcome Measures

Name	Time	Method
Area Under the Concentration-time Curve From Time Zero (Pre-dose) Extrapolated to Infinite Time (AUC[0-infinity]) for Ciprofloxacin	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	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.
Time of Occurrence of Cmax (Tmax) for Ciprofloxacin	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	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.
Percentage of AUC (0-infinity) Obtained by Extrapolation (Percentage AUCex) for Ciprofloxacin	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	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.
Alanine Aminotransferase (ALT), Alkaline Phosphatase (Alk Phos), Aspartate Aminotransferase (AST) and Lactate Dehydrogenase (LD) at Indicated Time-points	Up to Day 2 of each treatment period	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).
Calcium, Chloride, Glucose, Magnesium, Potassium and Sodium at Indicated Time-points	Up to Day 2 of each treatment period	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).
Total Bilirubin (Total Bil), Direct Bilirubin (Direct Bil) and Creatinine (Creat) at Indicated Time-points	Up to Day 2 of each treatment period	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).
Hematocrit at Indicated Time-points	Up to Day 2 of each treatment period	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).
Pulse Rate at Indicated Time-points	Up to Day 2 of each treatment period	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).
Terminal Phase Half-life (t1/2) for Ciprofloxacin	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	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.
Mean Corpuscular Hemoglobin (MCH) at Indicated Time-points	Up to Day 2 of each treatment period	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).
Erythrocyte Count at Indicated Time-points	Up to Day 2 of each treatment period	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).
Number of Participants With Clinically Significant Abnormal Findings for Urinalysis	Up to Day 2 of each treatment period	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.
Platelets, Neutrophils, Monocytes, Lymphocytes, Leucocyte, Eosinophils and Basophils at Indicated Time-points	Up to Day 2 of each treatment period	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).
Number of Participants With Clinically Significant Abnormal Findings for Electrocardiogram (ECG) Parameters	Up to Day 2 of each treatment period	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.
Mean Corpuscular Volume (MCV) at Indicated Time-points	Up to Day 2 of each treatment period	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).
Percent Reticulocytes at Indicated Time-points	Up to Day 2 of each treatment period	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).
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Indicated Time-points	Up to Day 2 of each treatment period	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).
Body Temperature at Indicated Time-points	Up to Day 2 of each treatment period	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).
Number of Participants With Serious Adverse Events (SAEs) and Non-serious AEs (Non-SAEs)	Up to 4 weeks in each treatment period	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.
Blood Urea Nitrogen (BUN) at Indicated Time-points	Up to Day 2 of each treatment period	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).
Total Protein at Indicated Time-points	Up to Day 2 of each treatment period	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).
Mean Corpuscular Hemoglobin Concentration (MCHC) and Hemoglobin (Hb) at Indicated Time-points	Up to Day 2 of each treatment period	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).
Respiratory Rate at Indicated Time-points	Up to Day 2 of each treatment period	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).

Trial Locations

Locations (1)

GSK Investigational Site; 🇿🇦 Bloemfontein,, South Africa