Study to Assess the Pharmacokinetics, Safety and Tolerability of Aztreonam-Avibactam in Healthy Chinese Participants.

Study Overview
=================
Brief Summary
-----------------
A Phase 1, single center, single arm, open-label study to assess the PK, safety and tolerability of Aztreonam-Avibactam after single and repeated IV infusion of doses in healthy Chinese participants.

Official Title
-----------------
A PHASE I, SINGLE CENTER, OPEN-LABEL STUDY TO ASSESS THE PHARMACOKINETICS, SAFETY AND TOLERABILITY OF AZTREONAM-AVIBACTAM ADMINISTERED AS SINGLE AND REPEATED INTRAVENOUS DOSES IN HEALTHY CHINESE PARTICIPANTS

Conditions
-----------------
Healthy

Intervention / Treatment
-----------------
* Drug: Aztreonam-Avibactam


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Healthy Chinese male and female participants No clinical relevant abnormalities willing and able to comply with all study procedures BMI:17.5-30.5 Sign informed consent Exclusion Criteria: Any clinical significant illness History of alcohol abuse Use within 14 days prior the first study dose CL>80ml/min Abnormal vital signs, such 12-ECG, blood pressure and pulse rate Blood donation within 60days History of HIV, HBsAg, HBcAb, HCVAb Other medical or psychiatric may inappropriate for the study

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ATM-AVI treatment arm<br>Chinese healthy volunteers | Drug: Aztreonam-Avibactam<br>* 500/167 mg ATM/AVI loading infusion, followed by 1500/500 mg ATM/AVI extended loading infusion, then 1500/500 mg ATM/AVI maintenance dose infusion every 6 hours<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Plasma Concentration (Cmax) on Day 1 & 4 of Aztreonam | Cmax was the maximum observed plasma concentration and was directly observed from data. Concentration values below the lower limit of quantification (LLQ) were set to zero. Geometric Mean analysis was on the log scale. Zero values were not included in geometric mean and geometric coefficient of variation calculation. The geometric coefficient of variation is expressed in percentage. | Post dose on day 1 and day 4 | 
| Maximum Observed Plasma Concentration (Cmax) on Day 1 & 4 of Avibactam | Cmax was the maximum observed plasma concentration and was directly observed from data. Concentration values below the lower limit of quantification (LLQ) were set to zero. Geometric Mean analysis was on the log scale. Zero values were not included in geometric mean and geometric coefficient of variation calculation. The geometric coefficient of variation is expressed in percentage. | Post dose on day 1 and day 4 | 
| Area Under the Plasma Concentration-Time Profile From Time 0 to 6 Hours (AUC6) on Day 1 of Aztreonam | The area under the plasma drug concentration-time curve (AUC) was estimated from time 0 to 6 hours post dose. AUC6 was computed using the Linear/Log trapezoidal method. The geometric coefficient of variation is expressed in percentage. | Post dose on day 1 | 
| Area Under the Plasma Concentration-Time Profile From Time 0 to 6 Hours (AUC6) on Day 1 of Avibactam | The area under the plasma drug concentration-time curve (AUC) was estimated from time 0 to 6 hours post dose. AUC6 was computed using the Linear/Log trapezoidal method. The geometric coefficient of variation is expressed in percentage. | Post dose on day 1 | 
| Area Under the Plasma Concentration-Time Profile From Time Zero to Time of the Last Quantifiable Concentration (AUClast) on Day 1 & 4 of Aztreonam | AUClast is area under the plasma concentration time-curve from zero (pre-dose) to the last measured concentration. The geometric coefficient of variation is expressed in percentage. | Post dose on day 1 and day 4 | 
| Area Under the Plasma Concentration-Time Profile From Time Zero to Time of the Last Quantifiable Concentration (AUClast) on Day 1 & 4 of Avibactam | AUClast is area under the plasma concentration time-curve from zero (pre-dose) to the last measured concentration. The geometric coefficient of variation is expressed in percentage. | Post dose on day 1 and day 4 | 
| Area Under the Plasma Concentration-Time Profile From Time 0 to 24 Hours (AUC24) on Day 1 & 4 of Aztreonam | AUC24 was defined as area under the plasma concentration-time profile from time zero to 24 hours post dose. The geometric coefficient of variation is expressed in percentage. | Post dose on day 1 and day 4 | 
| Area Under the Plasma Concentration-Time Profile From Time 0 to 24 Hours (AUC24) on Day 1 & 4 of Avibactam | AUC24 was defined as area under the plasma concentration-time profile from time zero to 24 hours post dose. The geometric coefficient of variation is expressed in percentage. | Post dose on day 1 and day 4 | 
| Area Under the Plasma Concentration-Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) on Day 1 & 4 of Aztreonam | AUCinf was defined as area under the plasma concentration-time curve from time zero to infinity. The geometric coefficient of variation is expressed in percentage. | Post dose on day 1 and day 4 | 
| Area Under the Plasma Concentration-Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) on Day 1 & 4 of Avibactam | AUCinf was defined as area under the plasma concentration-time curve from time zero to infinity. The geometric coefficient of variation is expressed in percentage. | Post dose on day 1 and day 4 | 
| Area Under the Plasma Concentration-Time Profile From Time 0 to the Time of the End of the Dosing Interval (τ), Where τ=6 Hours (AUCtau) on Day 4 of Aztreonam | AUCtau was defined as area under the concentration-time profile from time 0 to time tau. The geometric coefficient of variation is expressed in percentage. | Post dose on day 4 | 
| Area Under the Plasma Concentration-Time Profile From Time 0 to the Time of the End of the Dosing Interval (τ), Where τ=6 Hours (AUCtau) on Day 4 of Avibactam | AUCtau was defined as area under the concentration-time profile from time 0 to time tau. The geometric coefficient of variation is expressed in percentage. | Post dose on day 4 | 
| Total Daily Area Under the Plasma Concentration-Time Profile From Time 0 to 24 Hours at Steady-State (AUC24,ss) on Day 4 of Aztreonam | AUC24,ss was defined as total daily area under the plasma concentration-time profile from time 0 to 24 hours at steady-state. The geometric coefficient of variation is expressed in percentage. | Post dose on day 4 | 
| Total Daily Area Under the Plasma Concentration-Time Profile From Time 0 to 24 Hours at Steady-State (AUC24,ss) on Day 4 of Avibactam | AUC24,ss was defined as total daily area under the plasma concentration-time profile from time 0 to 24 hours at steady-state. The geometric coefficient of variation is expressed in percentage. | Post dose on day 4 | 
| Renal Clearance (CLr) on Day 1 & 4 of Aztreonam | CLr was calculated as cumulative amount of drug recovered unchanged in urine during the dosing interval (Ae) divided by area under the plasma concentration time-curve from time zero to end of dosing interval (AUCtau). AUCtau was defined as area under the concentration-time profile from time 0 to time tau. The geometric coefficient of variation is expressed in percentage. | Post dose on day 1 and day 4 | 
| Renal Clearance (CLr) on Day 1 & 4 of Avibactam | CLr was calculated as cumulative amount of drug recovered unchanged in urine during the dosing interval (Ae) divided by area under the plasma concentration time-curve from time zero to end of dosing interval (AUCtau). AUCtau was defined as area under the concentration-time profile from time 0 to time tau. The geometric coefficient of variation is expressed in percentage. | Post dose on day 1 and day 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Terminal Elimination Half-Life (T1/2) on Day 1 & 4 of Aztreonam | Plasma terminal elimination half-life (T1/2) is the time measured for the plasma concentration to decrease by one half at the terminal phase. | Post dose on day 1 and day 4 | 
| Terminal Elimination Half-Life (T1/2) on Day 1 & 4 of Avibactam | Plasma terminal elimination half-life (T1/2) is the time measured for the plasma concentration to decrease by one half at the terminal phase. | Post dose on day 1 and day 4 | 
| Apparent Volume of Distribution at Steady-State (Vss) on Day 1 & 4 of Aztreonam | Apparent volume of distribution (Vz) was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Vss was the Vz at steady-state. The geometric coefficient of variation is expressed in percentage. | Post dose on day 1 and day 4 | 
| Apparent Volume of Distribution at Steady-State (Vss) on Day 1 & 4 of Avibactam | Vz was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Vss was the Vz at steady-state. The geometric coefficient of variation is expressed in percentage. | Post dose on day 1 and day 4 | 
| Apparent Volume of Distribution During Terminal Phase (Vz) on Day 1 & 4 of Aztreonam | Vz was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. The geometric coefficient of variation is expressed in percentage. | Post dose on day 1 and day 4 | 
| Apparent Volume of Distribution During Terminal Phase (Vz) on Day 1 & 4 of Avibactam | Vz was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. The geometric coefficient of variation is expressed in percentage. | Post dose on day 1 and day 4 | 
| Clearance (CL) on Day 1 & 4 of Aztreonam | CL was a quantitative measure of the rate at which a drug substance was removed from the body. The geometric coefficient of variation is expressed in percentage. | Post dose on day 1 and day 4 | 
| Clearance (CL) on Day 1 & 4 of Avibactam | CL was a quantitative measure of the rate at which a drug substance was removed from the body. The geometric coefficient of variation is expressed in percentage. | Post dose on day 1 and day 4 | 
| Time of Observed Maximum Plasma Concentration (Tmax) on Day 1 & 4 of Aztreonam | Tmax was defined as time to reach maximum observed plasma concentration. | Post dose on day 1 and day 4 | 
| Time of Observed Maximum Plasma Concentration (Tmax) on Day 1 & 4 of Avibactam | Tmax was defined as time to reach maximum observed plasma concentration. | Post dose on day 1 and day 4 | 
| Accumulation Ratio for Cmax (Rac,Cmax) on Day 4 of Aztreonam | Accumulation ratio based on maximum plasma concentration (Rac,cmax) was calculated as: Rac,Cmax = Cmax at steady state (Day 4) divided by Cmax at first dose (Day 1). The geometric coefficient of variation is expressed in percentage. | Post dose on day 4 | 
| Accumulation Ratio for Cmax (Rac,Cmax) on Day 4 of Avibactam | Accumulation ratio based on maximum plasma concentration (Rac,cmax) was calculated as: Rac,Cmax = Cmax at steady state (Day 4) divided by Cmax at first dose (Day 1). The geometric coefficient of variation is expressed in percentage. | Post dose on day 4 | 
| Accumulation Ratio for AUCτ Following Multiple Dosing (Rac) on Day 4 of Aztreonam | Rac was obtained from AUCtau at steady state (Day 4) divided by AUCtau after single dose (Day 1). AUCtau was defined as area under the concentration-time profile from time 0 to time tau. The geometric coefficient of variation is expressed in percentage. | Post dose on day 4 | 
| Accumulation Ratio for AUCτ Following Multiple Dosing (Rac) on Day 4 of Avibactam | Rac was obtained from AUCtau at steady state (Day 4) divided by AUCtau after single dose (Day 1). AUCtau was defined as area under the concentration-time profile from time 0 to time tau. The geometric coefficient of variation is expressed in percentage. | Post dose on day 4 | 
| Number of Participants With an Adverse Event (AE) | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Treatment-emergent adverse event (TEAE) means event between first dose of study treatment and up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state. An SAE was an AE resulting in any of death; inpatient hospitalization; life-threatening experience; disability; congenital anomaly or deemed significant for any other reason. Symptoms of infusion-related reactions (IRRs) may include, but were not limited to, fever, chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, and urticaria. Grade 3: severe or medically significant but not immediately life-threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence, urgent intervention indicated; Grade 5: death related to AE. | From the first dose of study treatment to the last dose of study treatment date +28 +7 days (up to 2 months) | 
| Number of Participants With Abnormal Vital Signs | Criteria for vital signs abnormalities: increase or decrease from baseline in supine Systolic Blood Pressure (SBP) >=30 mm Hg and increase or decrease from baseline in supine Diastolic Blood Pressure (DBP) >=20 mm Hg. | From the first dose of study treatment to the last dose of study treatment date +28 +7 days (up to 2 months) | 
| Number of Participants With Abnormal Electrocardiograms (ECGs) | ECG categorical summarization criteria: 1. PR interval (the interval between the start of the P wave and the start of the QRS complex, corresponding to the time between the onset of the atrial depolarization and onset of ventricular depolarization): a) greater than or equal to (>=) 300 millisecond (msec), b) >=25% increase when baseline is > 200 msec or >=50% increase when baseline is less than or equal to (<=) 200 msec. 2. QRS duration (time from ECG Q wave to the end of the S wave corresponding to ventricle depolarization): a) >=140 msec, b) >=50% increase from baseline. 3. QTcF interval (QT corrected using the Fridericia formula): a) >450 msec and <=480 msec, b) >480 msec and <=500 msec, c) >500 msec, d) >30 msec and <=60 msec increase from baseline, e) >60 msec increase from baseline. | From the first dose of study treatment to the last dose of study treatment date +28 +7 days (up to 2 months) | 
| Number of Participants With Abnormal Laboratory Assessments | Following laboratory parameters were assessed against pre-defined abnormality criteria: hematology (basophils); clinical chemistry (urate); urinalysis (urine hemoglobin, nitrite, urine erythrocytes). | From the first dose of study treatment to the last dose of study treatment date +28 +7 days (up to 2 months) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
no clinically relevant abnormalities