A Single-centre, Randomised, Double-blind, Placebo-controlled, Four Way Crossover Phase I Study to Investigate the Effect on QT/QTc Interval of Ceftazidime NXL104 or Ceftaroline Fosamil NXL104, Compared With Placebo, Using Moxifloxacin (Avelox®) as a Positive Control, in Healthy Male Volunteers

Study Overview
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Brief Summary
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This is a single dose study in healthy male volunteers to investigate the effect of high doses of ceftazidime NXL104 (CAZ104) or ceftaroline fosamil NXL104 (CXL104) on the QT interval

Official Title
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A Single-centre, Randomised, Double-blind, Placebo-controlled, Four Way Crossover Phase I Study to Investigate the Effect on QT/QTc Interval of a Single Dose of Intravenous Ceftazidime NXL104 (3000/2000 mg) or Ceftaroline Fosamil NXL104 (1500/2000 mg), Compared With Placebo, Using Open-label Moxifloxacin (Avelox®) as a Positive Control, in Healthy Male Volunteers

Conditions
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Healthy Male Volunteers

Intervention / Treatment
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* Drug: NXL104
* Drug: Ceftaroline
* Drug: Placebo Infusion
* Drug: Ceftazidime
* Drug: Moxifloxacin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of signed informed consent prior to any study specific procedures Healthy male volunteers aged 18 to 45 years (inclusive) with suitable veins for cannulation or repeated venepuncture Have a body mass index (BMI) between 19 and 30 kg/m2 and a body weight between 60 and 100 kg Be a non-smoker or ex-smoker who has stopped smoking (or using other nicotine products) for more than 3 months prior to the start of the study Exclusion Criteria: History of any clinically significant disease or disorder which, in the opinion of the Investigator, may either put the volunteer at risk because of participation in the study, or influence the results or the volunteer's ability to participate in the study Any clinically significant abnormalities in physical examination, clinical chemistry, haematology or urinalysis results as judged by the Investigator Abnormal vital signs, after 10 minutes supine rest, defined as any of the following: Systolic blood pressure (SBP) greater than 140 mmHg, Diastolic blood pressure (DBP) greater than 90 mmHg, Heart rate less than 40 or greater than 85 beats per minute - at Visit 1 Prolonged QTcF >450 ms or shortened QTcF <340 ms Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG that may interfere with the interpretation of QTc interval changes. This includes volunteers with any of the following: Clinically significant PR (PQ) interval prolongation, Intermittent second or third degree AV block (Mobitz II type 1, Wenchebach during sleep is not disqualifying), Incomplete, full or intermittent bundle branch block (QRS less than 110 ms with normal QRS and T wave morphology is acceptable if there is no evidence of left ventricular hypertrophy), Abnormal T wave morphology, particularly in the protocol defined primary lead

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Male

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: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CXL104<br>2000 mg NXL104 + 1500 mg Ceftaroline (IV) | Drug: NXL104<br>* IV Solution<br>Drug: Ceftaroline<br>* IV Solution<br>|
| Experimental: CAZ104<br>Placebo Infusion (saline) + 2000 mg NXL104 + 3000 mg Ceftazidime (IV) | Drug: NXL104<br>* IV Solution<br>Drug: Placebo Infusion<br>* IV Saline<br>Drug: Ceftazidime<br>* IV Solution<br>|
| Active Comparator: Moxifloxacin<br>Moxifloxacin 400mg (1 tablet) | Drug: Moxifloxacin<br>* Tablet (1)<br>|
| Placebo Comparator: Placebo<br>Placebo Infusion (saline) | Drug: Placebo Infusion<br>* IV Saline<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To investigate the effect of supratherapeutic doses of ceftazidime NXL104 (CAZ104) or ceftaroline fosamil NXL104 (CXL104) on the QT interval (QTcF). |  | 12-lead dECG will be performed pre-dose | 
| To investigate the effect of supratherapeutic doses of ceftazidime NXL104 (CAZ104) or ceftaroline fosamil NXL104 (CXL104) on the QT interval (QTcF). |  | 12-lead dECG at 30 min after starting dosing. | 
| To investigate the effect of supratherapeutic doses of ceftazidime NXL104 (CAZ104) or ceftaroline fosamil NXL104 (CXL104) on the QT interval (QTcF). |  | 12-lead dECG at 60 min after starting dosing. | 
| To investigate the effect of supratherapeutic doses of ceftazidime NXL104 (CAZ104) or ceftaroline fosamil NXL104 (CXL104) on the QT interval (QTcF). |  | 12-lead dECG at 90 min after starting dosing. | 
| To investigate the effect of supratherapeutic doses of ceftazidime NXL104 (CAZ104) or ceftaroline fosamil NXL104 (CXL104) on the QT interval (QTcF). |  | 12-lead dECG at 2 hour after starting dosing. | 
| To investigate the effect of supratherapeutic doses of ceftazidime NXL104 (CAZ104) or ceftaroline fosamil NXL104 (CXL104) on the QT interval (QTcF). |  | 12-lead dECG at 3 hour after starting dosing. | 
| To investigate the effect of supratherapeutic doses of ceftazidime NXL104 (CAZ104) or ceftaroline fosamil NXL104 (CXL104) on the QT interval (QTcF). |  | 12-lead dECG at 4 hour after starting dosing. | 
| To investigate the effect of supratherapeutic doses of ceftazidime NXL104 (CAZ104) or ceftaroline fosamil NXL104 (CXL104) on the QT interval (QTcF). |  | 12-lead dECG at 6 hour after starting dosing. | 
| To investigate the effect of supratherapeutic doses of ceftazidime NXL104 (CAZ104) or ceftaroline fosamil NXL104 (CXL104) on the QT interval (QTcF). |  | 12-lead dECG at 8 hour after starting dosing. | 
| To investigate the effect of supratherapeutic doses of ceftazidime NXL104 (CAZ104) or ceftaroline fosamil NXL104 (CXL104) on the QT interval (QTcF). |  | 12-lead dECG at 12 hour after starting dosing. | 
| To investigate the effect of supratherapeutic doses of ceftazidime NXL104 (CAZ104) or ceftaroline fosamil NXL104 (CXL104) on the QT interval (QTcF). |  | 12-lead dECG at 24 hour after starting dosing. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To investigate the effect of CAZ104 and CXL104, on additional ECG variables (heart rate, RR, PR, QRS, QT, and QTcB). |  | 12-lead dECG will be performed pre-dose | 
| To investigate the effect of CAZ104 and CXL104, on additional ECG variables (heart rate, RR, PR, QRS, QT, and QTcB). |  | 12-lead dECG at 30 min after starting dosing. | 
| To investigate the effect of CAZ104 and CXL104, on additional ECG variables (heart rate, RR, PR, QRS, QT, and QTcB). |  | 12-lead dECG at 60 min after starting dosing. | 
| To investigate the effect of CAZ104 and CXL104, on additional ECG variables (heart rate, RR, PR, QRS, QT, and QTcB). |  | 12-lead dECG at 90 min after starting dosing. | 
| To investigate the effect of CAZ104 and CXL104, on additional ECG variables (heart rate, RR, PR, QRS, QT, and QTcB). |  | 12-lead dECG at 2 hour after starting dosing. | 
| To investigate the effect of CAZ104 and CXL104, on additional ECG variables (heart rate, RR, PR, QRS, QT, and QTcB). |  | 12-lead dECG at 3 hour after starting dosing. | 
| To investigate the effect of CAZ104 and CXL104, on additional ECG variables (heart rate, RR, PR, QRS, QT, and QTcB). |  | 12-lead dECG at 4 hour after starting dosing. | 
| To investigate the effect of CAZ104 and CXL104, on additional ECG variables (heart rate, RR, PR, QRS, QT, and QTcB). |  | 12-lead dECG at 6 hour after starting dosing. | 
| To investigate the effect of CAZ104 and CXL104, on additional ECG variables (heart rate, RR, PR, QRS, QT, and QTcB). |  | 12-lead dECG at 8 hour after starting dosing. | 
| To investigate the effect of CAZ104 and CXL104, on additional ECG variables (heart rate, RR, PR, QRS, QT, and QTcB). |  | 12-lead dECG at 12 hour after starting dosing. | 
| To investigate the effect of CAZ104 and CXL104, on additional ECG variables (heart rate, RR, PR, QRS, QT, and QTcB). |  | 12-lead dECG at 24 hour after starting dosing. | 
| To assess the PK of NXL104, ceftaroline, ceftazidime and moxifloxacin by determination where applicable of Cmax, tmax, AUC(0-t), AUC, t½, CL, CL/F, Vss, and Vz/F. |  | Blood samples will be taken pre-dose | 
| To assess the PK of NXL104, ceftaroline, ceftazidime and moxifloxacin by determination where applicable of Cmax, tmax, AUC(0-t), AUC, t½, CL, CL/F, Vss, and Vz/F. |  | Blood samples will be taken at 30 min after starting dosing | 
| To assess the PK of NXL104, ceftaroline, ceftazidime and moxifloxacin by determination where applicable of Cmax, tmax, AUC(0-t), AUC, t½, CL, CL/F, Vss, and Vz/F. |  | Blood samples will be taken at 60 min after starting dosing | 
| To assess the PK of NXL104, ceftaroline, ceftazidime and moxifloxacin by determination where applicable of Cmax, tmax, AUC(0-t), AUC, t½, CL, CL/F, Vss, and Vz/F. |  | Blood samples will be taken at 75 min after starting dosing | 
| To assess the PK of NXL104, ceftaroline, ceftazidime and moxifloxacin by determination where applicable of Cmax, tmax, AUC(0-t), AUC, t½, CL, CL/F, Vss, and Vz/F. |  | Blood samples will be taken at 90 min after starting dosing | 
| To assess the PK of NXL104, ceftaroline, ceftazidime and moxifloxacin by determination where applicable of Cmax, tmax, AUC(0-t), AUC, t½, CL, CL/F, Vss, and Vz/F. |  | Blood samples will be taken at 2 hour after starting dosing | 
| To assess the PK of NXL104, ceftaroline, ceftazidime and moxifloxacin by determination where applicable of Cmax, tmax, AUC(0-t), AUC, t½, CL, CL/F, Vss, and Vz/F. |  | Blood samples will be taken at 3 hour after starting dosing | 
| To assess the PK of NXL104, ceftaroline, ceftazidime and moxifloxacin by determination where applicable of Cmax, tmax, AUC(0-t), AUC, t½, CL, CL/F, Vss, and Vz/F. |  | Blood samples will be taken at 4 hour after starting dosing | 
| To assess the PK of NXL104, ceftaroline, ceftazidime and moxifloxacin by determination where applicable of Cmax, tmax, AUC(0-t), AUC, t½, CL, CL/F, Vss, and Vz/F. |  | Blood samples will be taken at 6 hour after starting dosing | 
| To assess the PK of NXL104, ceftaroline, ceftazidime and moxifloxacin by determination where applicable of Cmax, tmax, AUC(0-t), AUC, t½, CL, CL/F, Vss, and Vz/F. |  | Blood samples will be taken at 8 hour after starting dosing | 
| To assess the PK of NXL104, ceftaroline, ceftazidime and moxifloxacin by determination where applicable of Cmax, tmax, AUC(0-t), AUC, t½, CL, CL/F, Vss, and Vz/F. |  | Blood samples will be taken at 12 hour after starting dosing | 
| To assess the PK of NXL104, ceftaroline, ceftazidime and moxifloxacin by determination where applicable of Cmax, tmax, AUC(0-t), AUC, t½, CL, CL/F, Vss, and Vz/F. |  | Blood samples will be taken at 18 hour after starting dosing | 
| To assess the PK of NXL104, ceftaroline, ceftazidime and moxifloxacin by determination where applicable of Cmax, tmax, AUC(0-t), AUC, t½, CL, CL/F, Vss, and Vz/F. |  | Blood samples will be taken at 24 hour after starting dosing. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NXL104, CAZ104, Ceftazidime, CXL104, Ceftaroline, Healthy Male Volunteers, Phase 1, OT, Single Dose Study