Trial Outcomes & Findings for Safety and Tolerability of Ceftazidime-Avibactam for Pediatric Patients With Suspected or Confirmed Infections (NCT NCT01893346)

Last Updated: 2017-09-06

Results Overview

Key PK parameters were prespecified to be calculated for cohorts 1 and 2. For cohorts 3 and 4 (where children were \<6 years of age), sparse sampling scheme was used for PK samples to limit the volume of blood required. PK parameters cannot be derived from these sparse PK samples without population PK analysis. Thus the PK is not described here, but will be reported in a separate population PK report.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

35 participants

Primary outcome timeframe

Day 1

Results posted on

2017-09-06

Participant Flow

First patient enrolled: 26 July 2013 Last patient last visit: 09 October 2014

Eligibility was determined by investigator, prior to enrollment. Patients were selected on the basis of the age requirements for the appropriate cohort and after obtaining written informed consent from the parent or legal guardian and assent from patients (as appropriate). Screening assessments were completed prior to study drug administration.

Participant milestones

Participant milestones
Measure	Cohort 1 aged ≥12 to \<18 years 2000 mg ceftazidime and 500 mg avibactam	Cohort 2 aged ≥6 to \<12 years Weight \<40 kg: 50 mg/kg ceftazidime and 12.5 mg/kg avibactam Weight ≥40 kg: 2000 mg ceftazidime and 500 mg avibactam	Cohort 3 aged ≥2 to \<6 years Normal renal function or mild renal insufficiency: 50 mg/kg ceftazidime and 12.5 mg/kg avibactam. Moderate renal insufficiency: 25 mg/kg ceftazidime and 6.25 mg/kg avibactam	Cohort 4 aged ≥3 months to \<2 years Normal renal function or mild renal insufficiency: 50 mg/kg ceftazidime and 12.5 mg/kg avibactam. Moderate renal insufficiency: 25 mg/kg ceftazidime and 6.25 mg/kg avibactam
Overall Study STARTED	11	8	8	8
Overall Study Patients Who Received Full Infusion	8	8	8	8
Overall Study COMPLETED	8	7	8	8
Overall Study NOT COMPLETED	3	1	0	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Cohort 1 aged ≥12 to \<18 years 2000 mg ceftazidime and 500 mg avibactam	Cohort 2 aged ≥6 to \<12 years Weight \<40 kg: 50 mg/kg ceftazidime and 12.5 mg/kg avibactam Weight ≥40 kg: 2000 mg ceftazidime and 500 mg avibactam
Overall Study Lost to Follow-up	0	1
Overall Study Protocol Violation	1	0
Overall Study Withdrawal by Subject	2	0

Baseline Characteristics

Safety and Tolerability of Ceftazidime-Avibactam for Pediatric Patients With Suspected or Confirmed Infections

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Cohort 1 n=8 Participants aged ≥12 to \<18 years 2000 mg ceftazidime and 500 mg avibactam	Cohort 2 n=8 Participants aged ≥6 to \<12 years Weight \<40 kg: 50 mg/kg ceftazidime and 12.5 mg/kg avibactam Weight ≥40 kg: 2000 mg ceftazidime and 500 mg avibactam	Cohort 3 n=8 Participants aged ≥2 to \<6 years Normal renal function or mild renal insufficiency: 50 mg/kg ceftazidime and 12.5 mg/kg avibactam. Moderate renal insufficiency: 25 mg/kg ceftazidime and 6.25 mg/kg avibactam	Cohort 4 n=8 Participants aged ≥3 months to \<2 years Normal renal function or mild renal insufficiency: 50 mg/kg ceftazidime and 12.5 mg/kg avibactam. Moderate renal insufficiency: 25 mg/kg ceftazidime and 6.25 mg/kg avibactam	Total n=32 Participants Total of all reporting groups
Age, Continuous	14.945 years STANDARD_DEVIATION 1.5599 • n=5 Participants	8.020 years STANDARD_DEVIATION 1.4036 • n=7 Participants	3.519 years STANDARD_DEVIATION 1.0044 • n=5 Participants	0.924 years STANDARD_DEVIATION 0.5007 • n=4 Participants	6.852 years STANDARD_DEVIATION 5.5200 • n=21 Participants
Sex: Female, Male Female	5 Participants n=5 Participants	3 Participants n=7 Participants	6 Participants n=5 Participants	3 Participants n=4 Participants	17 Participants n=21 Participants
Sex: Female, Male Male	3 Participants n=5 Participants	5 Participants n=7 Participants	2 Participants n=5 Participants	5 Participants n=4 Participants	15 Participants n=21 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants	1 Participants n=4 Participants	5 Participants n=21 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	8 Participants n=5 Participants	7 Participants n=7 Participants	5 Participants n=5 Participants	7 Participants n=4 Participants	27 Participants n=21 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	1 Participants n=21 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	0 Participants n=4 Participants	1 Participants n=21 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Black or African American	1 Participants n=5 Participants	2 Participants n=7 Participants	0 Participants n=5 Participants	3 Participants n=4 Participants	6 Participants n=21 Participants
Race (NIH/OMB) White	6 Participants n=5 Participants	6 Participants n=7 Participants	7 Participants n=5 Participants	5 Participants n=4 Participants	24 Participants n=21 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants

PRIMARY outcome

Timeframe: Day 1

Population: Pharmacokinetic analysis set

Outcome measures

Outcome measures
Measure	Cohort 1 / Avibactam n=8 Participants aged ≥12 to \<18 years	Cohort 1 / Ceftazidime n=8 Participants aged ≥12 to \<18 years / Ceftazidime	Cohort 2 / Avibactam n=8 Participants aged ≥6 to \<12 years	Cohort 2 / Ceftazidime n=8 Participants aged ≥6 to \<12 years
Pharmacokinetic Parameters of Avibactam and Ceftazidime for Cohort 1 and 2: AUC AUC(0-8)	35140 h*ng/mL Geometric Coefficient of Variation 33.11	219100 h*ng/mL Geometric Coefficient of Variation 29.69	33590 h*ng/mL Geometric Coefficient of Variation 22.15	212400 h*ng/mL Geometric Coefficient of Variation 16.28
Pharmacokinetic Parameters of Avibactam and Ceftazidime for Cohort 1 and 2: AUC AUC(0-t)	36250 h*ng/mL Geometric Coefficient of Variation 33.70	229200 h*ng/mL Geometric Coefficient of Variation 30.86	34380 h*ng/mL Geometric Coefficient of Variation 23.37	217800 h*ng/mL Geometric Coefficient of Variation 18.36
Pharmacokinetic Parameters of Avibactam and Ceftazidime for Cohort 1 and 2: AUC AUC(0-inf)	36430 h*ng/mL Geometric Coefficient of Variation 33.61	230600 h*ng/mL Geometric Coefficient of Variation 30.70	34820 h*ng/mL Geometric Coefficient of Variation 22.62	221200 h*ng/mL Geometric Coefficient of Variation 17.38

PRIMARY outcome

Timeframe: Day 1

Population: Pharmacokinetic analysis set

Key PK parameters are shown for cohorts 1 and 2. For cohorts 3 and 4 (where children were \<6 years of age), sparse sampling scheme was used for PK samples to limit the volume of blood required. PK parameters cannot be derived from these sparse PK samples without population PK analysis. Thus the PK is not described here, but will be reported in a separate population PK report.

Outcome measures

Outcome measures
Measure	Cohort 1 / Avibactam n=8 Participants aged ≥12 to \<18 years	Cohort 1 / Ceftazidime n=8 Participants aged ≥12 to \<18 years / Ceftazidime	Cohort 2 / Avibactam n=8 Participants aged ≥6 to \<12 years	Cohort 2 / Ceftazidime n=8 Participants aged ≥6 to \<12 years
Pharmacokinetic Parameters of Avibactam and Ceftazidime for Cohort 1 and 2: Cmax	15090 ng/mL Geometric Coefficient of Variation 52.42	79750 ng/mL Geometric Coefficient of Variation 41.81	14140 ng/mL Geometric Coefficient of Variation 22.96	81270 ng/mL Geometric Coefficient of Variation 17.81

Adverse Events

Cohort 1

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Cohort 2

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Cohort 3

Serious events: 0 serious events

Other events: 4 other events

Deaths: 0 deaths

Cohort 4

Serious events: 0 serious events

Other events: 2 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	Cohort 1 n=8 participants at risk aged ≥12 to \<18 years 2000 mg ceftazidime and 500 mg avibactam	Cohort 2 n=8 participants at risk aged ≥6 to \<12 years Weight \<40 kg: 50 mg/kg ceftazidime and 12.5 mg/kg avibactam Weight ≥40 kg: 2000 mg ceftazidime and 500 mg avibactam	Cohort 3 n=8 participants at risk aged ≥2 to \<6 years Normal renal function or mild renal insufficiency: 50 mg/kg ceftazidime and 12.5 mg/kg avibactam. Moderate renal insufficiency: 25 mg/kg ceftazidime and 6.25 mg/kg avibactam	Cohort 4 n=8 participants at risk aged ≥3 months to \<2 years Normal renal function or mild renal insufficiency: 50 mg/kg ceftazidime and 12.5 mg/kg avibactam. Moderate renal insufficiency: 25 mg/kg ceftazidime and 6.25 mg/kg avibactam
Cardiac disorders Sinus tachycardia	0.00% 0/8 • From start of study dose infusion of CAZ AVI through the follow up period (Day 2 and Day 3)	0.00% 0/8 • From start of study dose infusion of CAZ AVI through the follow up period (Day 2 and Day 3)	0.00% 0/8 • From start of study dose infusion of CAZ AVI through the follow up period (Day 2 and Day 3)	12.5% 1/8 • From start of study dose infusion of CAZ AVI through the follow up period (Day 2 and Day 3)
Gastrointestinal disorders Constipation	0.00% 0/8 • From start of study dose infusion of CAZ AVI through the follow up period (Day 2 and Day 3)	0.00% 0/8 • From start of study dose infusion of CAZ AVI through the follow up period (Day 2 and Day 3)	12.5% 1/8 • From start of study dose infusion of CAZ AVI through the follow up period (Day 2 and Day 3)	0.00% 0/8 • From start of study dose infusion of CAZ AVI through the follow up period (Day 2 and Day 3)
Gastrointestinal disorders Diarrhoea	0.00% 0/8 • From start of study dose infusion of CAZ AVI through the follow up period (Day 2 and Day 3)	0.00% 0/8 • From start of study dose infusion of CAZ AVI through the follow up period (Day 2 and Day 3)	12.5% 1/8 • From start of study dose infusion of CAZ AVI through the follow up period (Day 2 and Day 3)	0.00% 0/8 • From start of study dose infusion of CAZ AVI through the follow up period (Day 2 and Day 3)
Gastrointestinal disorders Vomiting	0.00% 0/8 • From start of study dose infusion of CAZ AVI through the follow up period (Day 2 and Day 3)	0.00% 0/8 • From start of study dose infusion of CAZ AVI through the follow up period (Day 2 and Day 3)	12.5% 1/8 • From start of study dose infusion of CAZ AVI through the follow up period (Day 2 and Day 3)	0.00% 0/8 • From start of study dose infusion of CAZ AVI through the follow up period (Day 2 and Day 3)
Investigations Alanine aminotransferase increased	0.00% 0/8 • From start of study dose infusion of CAZ AVI through the follow up period (Day 2 and Day 3)	0.00% 0/8 • From start of study dose infusion of CAZ AVI through the follow up period (Day 2 and Day 3)	12.5% 1/8 • From start of study dose infusion of CAZ AVI through the follow up period (Day 2 and Day 3)	0.00% 0/8 • From start of study dose infusion of CAZ AVI through the follow up period (Day 2 and Day 3)
Investigations Aspartate aminotransferase increased	0.00% 0/8 • From start of study dose infusion of CAZ AVI through the follow up period (Day 2 and Day 3)	0.00% 0/8 • From start of study dose infusion of CAZ AVI through the follow up period (Day 2 and Day 3)	12.5% 1/8 • From start of study dose infusion of CAZ AVI through the follow up period (Day 2 and Day 3)	0.00% 0/8 • From start of study dose infusion of CAZ AVI through the follow up period (Day 2 and Day 3)
Investigations Blood triglycerides increased	0.00% 0/8 • From start of study dose infusion of CAZ AVI through the follow up period (Day 2 and Day 3)	0.00% 0/8 • From start of study dose infusion of CAZ AVI through the follow up period (Day 2 and Day 3)	12.5% 1/8 • From start of study dose infusion of CAZ AVI through the follow up period (Day 2 and Day 3)	0.00% 0/8 • From start of study dose infusion of CAZ AVI through the follow up period (Day 2 and Day 3)
Investigations Gamma-glutamyltransferase increased	0.00% 0/8 • From start of study dose infusion of CAZ AVI through the follow up period (Day 2 and Day 3)	0.00% 0/8 • From start of study dose infusion of CAZ AVI through the follow up period (Day 2 and Day 3)	12.5% 1/8 • From start of study dose infusion of CAZ AVI through the follow up period (Day 2 and Day 3)	0.00% 0/8 • From start of study dose infusion of CAZ AVI through the follow up period (Day 2 and Day 3)
Injury, poisoning and procedural complications Procedural site reaction	0.00% 0/8 • From start of study dose infusion of CAZ AVI through the follow up period (Day 2 and Day 3)	0.00% 0/8 • From start of study dose infusion of CAZ AVI through the follow up period (Day 2 and Day 3)	0.00% 0/8 • From start of study dose infusion of CAZ AVI through the follow up period (Day 2 and Day 3)	12.5% 1/8 • From start of study dose infusion of CAZ AVI through the follow up period (Day 2 and Day 3)

Additional Information

Paul Newell, MBBS MRCP MFPM

AstraZeneca Pharmaceuticals

Phone: +44 1625 515727

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: OTHER