Clinical Trial Results:
A single blind, randomised, multi-centre, active controlled, trial to evaluate safety, tolerability, pharmacokinetics and efficacy of ceftazidime and avibactam when given in combination with metronidazole, compared with meropenem, in children from 3 months to less than 18 years of age with complicated intra-abdominal infections (cIAIs).
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Summary
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EudraCT number |
2014-003242-28 |
Trial protocol |
HU ES CZ GR RO |
Global end of trial date |
01 Jun 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
13 Dec 2017
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First version publication date |
13 Dec 2017
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
C3591004
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02475733 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Pfizer, Inc.
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Sponsor organisation address |
235 E 42nd Street, New York, United States, NY 10017
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Public contact |
Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 18007181021, ClinicalTrials.gov_Inquiries@pfizer.com
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Scientific contact |
Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 18007181021, ClinicalTrials.gov_Inquiries@pfizer.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-001313-PIP01-12 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
29 Aug 2017
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
01 Jun 2017
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To evaluate the safety and tolerability of ceftazidime and avibactam (CAZ-AVI) plus metronidazole is given at the selected dose regimen versus meropenem in paediatric subjects aged greater than or equal to (>=)3 months to less than (<)18 years with cIAI
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Protection of trial subjects |
The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Council for Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trials subjects were followed.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
01 Aug 2015
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Hungary: 15
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Country: Number of subjects enrolled |
Poland: 1
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Country: Number of subjects enrolled |
Romania: 2
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Country: Number of subjects enrolled |
Russian Federation: 3
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Country: Number of subjects enrolled |
Spain: 16
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Country: Number of subjects enrolled |
Taiwan: 10
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Country: Number of subjects enrolled |
Turkey: 7
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Country: Number of subjects enrolled |
United States: 12
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Country: Number of subjects enrolled |
Czech Republic: 12
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Country: Number of subjects enrolled |
Greece: 5
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Worldwide total number of subjects |
83
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EEA total number of subjects |
51
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
1
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Children (2-11 years) |
52
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Adolescents (12-17 years) |
30
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
- | ||||||||||||||||||
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Pre-assignment
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Screening details |
Total 83 subjects were enrolled in multiple sites in 10 countries. Study started from 01-Aug-2015 and completed on 01-Jun-2017. | ||||||||||||||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Single blind | ||||||||||||||||||
Roles blinded |
Assessor [1] | ||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Ceftazidime- Avibactam (CAZ-AVI) plus Metronidazole | ||||||||||||||||||
Arm description |
Subjects with Creatinine clearance(CrCL) >=50 milliliter per minute (mL/min) received 10 milligram per kilogram (mg/kg) intravenous(IV) infusion of metronidazole over 20 to 30 minutes along with 2 hour IV infusion of CAZ/AVI in following manner: 1)Age 6 to less than(<)18 years: 2000 mg CAZ/500 mg AVI (body weight >=40 kg), 50 mg/kg CAZ/12.5 mg/kg AVI (body weight <40 kg), 2) Age 6 months to <6 years: 50 mg/kg CAZ/12.5 mg/kg AVI, 3)Age 3 months to <6 months: 40 mg/kg CAZ/10 mg/kg AVI. Both infusions were administered to subjects every 8 hours for a minimum of 72 hours and up to a maximum duration of 15 days. Dose of CAZ-AVI was reduced to 50% if CrCl of subject decreased to <=50mL/min, and subject was removed from study therapy, if CrCl decreased below 30mL/min. After having 72 hours of IV treatment, subjects had option to switch to an oral therapy at investigator's discretion. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Ceftazidime- Avibactam (CAZ-AVI) plus Metronidazole
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Subjects with Creatinine clearance(CrCL) >=50 milliliter per minute (mL/min) received 10 milligram per kilogram (mg/kg) intravenous(IV) infusion of metronidazole over 20 to 30 minutes along with 2 hour IV infusion of CAZ/AVI in following manner: 1)Age 6 to less than(<)18 years: 2000 mg CAZ/500 mg AVI (body weight >=40 kg), 50 mg/kg CAZ/12.5 mg/kg AVI (body weight <40 kg), 2) Age 6 months to <6 years: 50 mg/kg CAZ/12.5 mg/kg AVI, 3)Age 3 months to <6 months: 40 mg/kg CAZ/10 mg/kg AVI. Both infusions were administered to subjects every 8 hours for a minimum of 72 hours and up to a maximum duration of 15 days.
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Arm title
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Meropenem | ||||||||||||||||||
Arm description |
Subjects received 15 to 30 minutes IV infusion of meropenem 20 mg/kg every 8 hours for a minimum of 72 hours and up to a maximum duration of 15 days. After having 72 hours of IV treatment, subjects had option to switch to an oral therapy at the investigator's discretion. | ||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||
Investigational medicinal product name |
Meropenem
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Subjects received 15 to 30 minutes IV infusion of meropenem 20 mg/kg every 8 hours for a minimum of 72 hours and up to a
maximum duration of 15 days. After having 72 hours of IV treatment, subjects had option to switch to an oral therapy at the investigator's discretion.
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| Notes [1] - The roles blinded appear inconsistent with a simple blinded trial. Justification: The assessor was kept blinded in this study to remove any bias during clinical assessments related to safety and efficacy |
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Baseline characteristics reporting groups
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Reporting group title |
Ceftazidime- Avibactam (CAZ-AVI) plus Metronidazole
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Reporting group description |
Subjects with Creatinine clearance(CrCL) >=50 milliliter per minute (mL/min) received 10 milligram per kilogram (mg/kg) intravenous(IV) infusion of metronidazole over 20 to 30 minutes along with 2 hour IV infusion of CAZ/AVI in following manner: 1)Age 6 to less than(<)18 years: 2000 mg CAZ/500 mg AVI (body weight >=40 kg), 50 mg/kg CAZ/12.5 mg/kg AVI (body weight <40 kg), 2) Age 6 months to <6 years: 50 mg/kg CAZ/12.5 mg/kg AVI, 3)Age 3 months to <6 months: 40 mg/kg CAZ/10 mg/kg AVI. Both infusions were administered to subjects every 8 hours for a minimum of 72 hours and up to a maximum duration of 15 days. Dose of CAZ-AVI was reduced to 50% if CrCl of subject decreased to <=50mL/min, and subject was removed from study therapy, if CrCl decreased below 30mL/min. After having 72 hours of IV treatment, subjects had option to switch to an oral therapy at investigator's discretion. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Meropenem
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Reporting group description |
Subjects received 15 to 30 minutes IV infusion of meropenem 20 mg/kg every 8 hours for a minimum of 72 hours and up to a maximum duration of 15 days. After having 72 hours of IV treatment, subjects had option to switch to an oral therapy at the investigator's discretion. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Ceftazidime- Avibactam (CAZ-AVI) plus Metronidazole
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Reporting group description |
Subjects with Creatinine clearance(CrCL) >=50 milliliter per minute (mL/min) received 10 milligram per kilogram (mg/kg) intravenous(IV) infusion of metronidazole over 20 to 30 minutes along with 2 hour IV infusion of CAZ/AVI in following manner: 1)Age 6 to less than(<)18 years: 2000 mg CAZ/500 mg AVI (body weight >=40 kg), 50 mg/kg CAZ/12.5 mg/kg AVI (body weight <40 kg), 2) Age 6 months to <6 years: 50 mg/kg CAZ/12.5 mg/kg AVI, 3)Age 3 months to <6 months: 40 mg/kg CAZ/10 mg/kg AVI. Both infusions were administered to subjects every 8 hours for a minimum of 72 hours and up to a maximum duration of 15 days. Dose of CAZ-AVI was reduced to 50% if CrCl of subject decreased to <=50mL/min, and subject was removed from study therapy, if CrCl decreased below 30mL/min. After having 72 hours of IV treatment, subjects had option to switch to an oral therapy at investigator's discretion. | ||
Reporting group title |
Meropenem
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Reporting group description |
Subjects received 15 to 30 minutes IV infusion of meropenem 20 mg/kg every 8 hours for a minimum of 72 hours and up to a maximum duration of 15 days. After having 72 hours of IV treatment, subjects had option to switch to an oral therapy at the investigator's discretion. | ||
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End point title |
Percentage of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [1] | ||||||||||||||||||
End point description |
An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged in-patient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent were events between first dose of study drug and up to late follow-up (LFU) visit (Within 20 to 35 days after last dose of any study drug [IV or oral]) that were absent before treatment or that worsened relative to pretreatment state. AEs included both SAE and non-SAE. Safety analysis set included all randomized subjects who received any amount of IV study medication.
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End point type |
Primary
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End point timeframe |
From signature of informed consent until the LFU visit (27 to 50 days after start of study treatment, up to a maximum study duration of 50 days)
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned for this endpoint |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Percentage of Subjects With Cephalosporin Class Effects and Additional AEs of Special Interest (AEoSI) [2] | ||||||||||||||||||||||||||||||
End point description |
Percentage of subjects with Cephalosporin class effects (defined as AeoSI within the safety topics (ST) of hypersensitivity/anaphylaxis, diarrhea, renal disorder and liver disorder) and additional AEs (which included AEs with preferred terms[PT] in the MedDRA 20.0 system organ class [SOC] of nervous system disorders and other AEs of clinical importance [such as seizures] relevant to the cephalosporin class) were reported in this outcome measure. LFU visit occurred within 27 to 50 days after start of study treatment (IV or oral).
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End point type |
Primary
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End point timeframe |
From signature of informed consent until the LFU visit (27 to 50 days after start of study treatment, up to a maximum study duration of 50 days)
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| Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned for this endpoint |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
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End point title |
Change From Baseline in Pulse Rate at End of Intravenous Therapy (EOIV) Visit [3] | ||||||||||||||||||
End point description |
EOIV visit occurred within 24 hours after completion of last infusion of the study drug. Safety analysis set included all randomized subjects who received any amount of IV study medication. Here, ‘n’ signifies those subjects who were evaluable at specified time points, for each arm respectively.
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End point type |
Primary
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End point timeframe |
Baseline, EOIV visit (Day 4 up to 16)
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| Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned for this endpoint |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at End of Intravenous Therapy (EOIV) Visit [4] | ||||||||||||||||||||||||
End point description |
EOIV visit occurred within 24 hours after completion of last infusion of the study drug. Safety analysis set included all randomized subjects who received any amount of IV study medication. Here, ‘n’ signifies those subjects who were evaluable at specified time points, for each arm respectively.
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End point type |
Primary
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End point timeframe |
Baseline, EOIV visit (Day 4 up to 16)
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| Notes [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned for this endpoint |
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Change From Baseline in Respiratory Rate at End of Intravenous Therapy (EOIV) Visit [5] | ||||||||||||||||||
End point description |
EOIV visit occurred within 24 hours after completion of last infusion of the study drug. Safety analysis set included all randomized subjects who received any amount of IV study medication. Here, ‘n’ signifies those subjects who were evaluable at specified time points, for each arm respectively.
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End point type |
Primary
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End point timeframe |
Baseline, EOIV visit (Day 4 up to 16)
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| Notes [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned for this endpoint |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Change From Baseline in Body Weight at End of Intravenous Therapy (EOIV) Visit [6] | ||||||||||||||||||
End point description |
EOIV visit occurred within 24 hours after completion of last infusion of the study drug. Safety analysis set included all randomized subjects who received any amount of IV study medication. Here, ‘n’ signifies those subjects who were evaluable at specified time points, for each arm respectively.
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End point type |
Primary
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End point timeframe |
Baseline, EOIV visit (Day 4 up to 16)
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| Notes [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned for this endpoint |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Change From Baseline in Body Temperature at End of Intravenous Therapy (EOIV) Visit [7] | ||||||||||||||||||
End point description |
EOIV visit occurred within 24 hours after completion of last infusion of the study drug. Safety analysis set included all randomized subjects who received any amount of IV study medication. Here, ‘n’ signifies those subjects who were evaluable at specified time points, for each arm respectively.
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End point type |
Primary
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End point timeframe |
Baseline, EOIV visit (Day 4 up to 16)
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| Notes [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned for this endpoint |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Percentage of Subjects With Abnormal Physical Examination Findings at End of Intravenous Therapy (EOIV) Visit [8] | ||||||||||||||||||||||||||||||||||||||||||
End point description |
Physical examination included an assessment of the following: general appearance, skin, head and neck (including ears, eyes, nose and throat), lymph nodes, thyroid, respiratory system, cardiovascular system, abdomen, musculoskeletal system (including spine and extremities), and neurological system. Subjects with new or aggravated abnormal physical examination findings with regard to baseline findings were reported. Abnormality in physical examinations were based on blinded observer’s discretion. EOIV visit occurred within 24 hours after completion of last infusion of the study drug. Safety analysis set included all randomized subjects who received any amount of IV study medication.
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End point type |
Primary
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End point timeframe |
EOIV visit (Day 4 up to 16)
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| Notes [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned for this endpoint |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||
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End point title |
Percentage of Subjects With Abnormalities in Laboratory Parameters According to Potentially Clinically Significant Criteria [9] | ||||||||||||||||||||||||
End point description |
Criteria for potentially clinically significant laboratory abnormalities: Chemistry (calcium: <0.7*lower limit of normal range [LLN] and >30 percent decrease from baseline [DFB]; alanine aminotransferase [ALT]: >3*upper limit of normal range [ULN] and >300 percent IFB; alanine aminotransferase [AST]: >3*ULN and >300 percent IFB) and hematology (platelets: >2*ULN and >100 percent IFB). LFU visit occurred within 27 to 50 days after start of study treatment (IV or oral). Safety analysis set included all randomized subjects who received any amount of IV study medication. Here, ‘n’ signifies those subjects who were evaluable at specified time points, for each arm respectively.
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End point type |
Primary
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End point timeframe |
From signature of informed consent until the LFU visit (27 to 50 days after start of study treatment, up to a maximum study duration of 50 days)
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| Notes [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned for this endpoint |
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Percentage of Subjects With Electrocardiogram (ECG) Parameter QTcF: > 450, >480 and >500 Millisecond (ms) [10] | |||||||||||||||||||||
End point description |
ECG parameters included maximum QT intervals using Fridericia’s correction (QTcF). Maximum QTcF >450 millisecond (ms); maximum QTcF >480 ms; and maximum QTcF >500 ms. LFU visit occurred within 27 to 50 days after start of study treatment (IV or oral). Safety analysis set included all randomized subjects who received any amount of IV study medication.
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End point type |
Primary
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End point timeframe |
From signature of informed consent until the LFU visit (27 to 50 days after start of study treatment, up to a maximum study duration of 50 days)
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| Notes [10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned for this endpoint |
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| No statistical analyses for this end point | ||||||||||||||||||||||
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End point title |
Percentage of Subjects With Creatinine Clearance (CrCl) at Day 7 [11] | ||||||||||||||||||||||||
End point description |
CrCl is a measure of glomerular filtration rate (GMFR), an index of kidney function. It is the volume of blood plasma that is cleared of creatinine by the kidneys per unit time. Percentage of subjects with CrCl in the following categories were reported: <30 mL/min/1.73 m^2, >=30 to <50 mL/min/1.73 m^2, >=50 mL/min/1.73 m^2 to <80 mL/min/1.73 m^2, and >=80 mL/min/1.73 m^2. Safety analysis set included all randomized subjects who received any amount of IV study medication.
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End point type |
Primary
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End point timeframe |
Day 7
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| Notes [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned for this endpoint |
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Percentage of Subjects With Creatinine Clearance (CrCl) at End of Intravenous Therapy (EOIV) Visit [12] | ||||||||||||||||||||||||
End point description |
CrCl is a measure of GMFR, an index of kidney function. It is the volume of blood plasma that is cleared of creatinine by the kidneys per unit time. Percentage of subjects with CrCl in the following categories were reported: <30 mL/min/1.73 m^2, >=30 to <50 mL/min/1.73 m^2, >=50 mL/min/1.73 m^2 to <80 mL/min/1.73 m^2, and >=80 mL/min/1.73 m^2. EOIV visit occurred within 24 hours after completion of last infusion of the study drug. Safety analysis set included all randomized subjects who received any amount of IV study medication.
|
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End point type |
Primary
|
||||||||||||||||||||||||
End point timeframe |
EOIV visit (Day 4 up to 16)
|
||||||||||||||||||||||||
| Notes [12] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned for this endpoint |
|||||||||||||||||||||||||
|
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| No statistical analyses for this end point | |||||||||||||||||||||||||
|
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End point title |
Percentage of Subjects With Creatinine Clearance (CrCl) at Test of Cure (TOC) Visit [13] | ||||||||||||||||||||||||
End point description |
CrCl is a measure of GMFR, an index of kidney function. It is the volume of blood plasma that is cleared of creatinine by the kidneys per unit time. Percentage of subjects with CrCl in the following categories were reported: <30 mL/min/1.73 m^2, >=30 to <50 mL/min/1.73 m^2, >=50 mL/min/1.73 m^2 to <80 mL/min/1.73 m^2, and >=80 mL/min/1.73 m^2. TOC visit occurred within 8 to 15 days after last dose of any study drug (IV or oral). Safety analysis set included all randomized subjects who received any amount of IV study medication.
|
||||||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||||||
End point timeframe |
TOC is 8 to 15 days after last dose of IV or oral treatment (up to a maximum duration of 50 days)
|
||||||||||||||||||||||||
| Notes [13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned for this endpoint |
|||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
|||||||||||||||||||||||||
End point title |
Percentage of Subjects With Creatinine Clearance (CrCl) at Late Follow-up (LFU) Visit [14] | ||||||||||||||||||||||||
End point description |
CrCl is a measure of GMFR, an index of kidney function. It is the volume of blood plasma that is cleared of creatinine by the kidneys per unit time. Percentage of subjects with CrCl in the following categories were reported: <30 mL/min/1.73 m^2, >=30 to <50 mL/min/1.73 m^2, >=50 mL/min/1.73 m^2 to <80 mL/min/1.73 m^2, and >=80 mL/min/1.73 m^2. LFU visit occurred within 27 to 50 days after start of study treatment (IV or oral). Safety analysis set included all randomized subjects who received any amount of IV study medication.
|
||||||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||||||
End point timeframe |
LFU visit (27 to 50 days after start of study treatment, up to a maximum study duration of 50 days)
|
||||||||||||||||||||||||
| Notes [14] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned for this endpoint |
|||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
|||||||||||||||||||||
End point title |
Plasma Concentrations of Ceftazidime and Avibactam [15] | ||||||||||||||||||||
End point description |
CAZ and AVI pharmacokinetic (PK) parameters derived from population PK analysis. This endpoint was not planned to be analyzed for meropenem receiving cohorts, as pre-specified in protocol. PK analysis set included all subjects who received at least 1 dose of study medication and had atleast 1 CAZ and/ or AVI plasma measurement available. Here, ‘n’ signifies those subjects who were evaluable at specified time points.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
15, 30-90, 300-360 minutes post-dose on Day 3
|
||||||||||||||||||||
| Notes [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: No statistical analysis was planned for this endpoint |
|||||||||||||||||||||
|
|||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||
|
|||||||||||||
End point title |
Percentage of Subjects With Favorable Clinical Response (CR) at End of 72 Hours Treatment: Intent-to-treat (ITT) Analysis Population | ||||||||||||
End point description |
Favorable CR was defined as resolution of all acute signs and symptoms of complicated intra- abdominal infection (cIAIs), or improvement to such an extent that no further antimicrobial therapy was required, or improvement but not enough to switch to oral therapy and still on IV study drug at end of 72 hours and had met following criterion: absence of new signs and symptoms, improvement in at least 1 symptom/sign (fever, pain, tenderness, elevated White Blood Cells [WBCs], elevated c-reactive protein) from baseline and no worsening symptom/sign. ITT analysis population included all subjects who had been assigned a randomized treatment.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
After 72 hours after the start of IV study infusion on Day 1
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Percentage of Subjects With Favorable Clinical Response (CR) at End of Intravenous Therapy (EOIV) Visit: Intent-to-treat (ITT) Analysis Population | ||||||||||||
End point description |
Favorable CR was resolution of all acute signs and symptoms of cIAI or improvement to such an extent that no further antimicrobial therapy was required, or improvement in subjects who had switch to oral therapy and met the following criterion: afebrile (temperature <=38.0°C) for at least 24 hours, absence of new and improvement in at least 1 symptom or sign (fever, pain, tenderness, elevated WBCs, elevated c-reative-protein) from baseline and worsening of none. EOIV visit occurred within 24 hours after completion of last infusion of the study drug. ITT analysis population included all subjects who had been assigned a randomized treatment.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
EOIV visit (Day 4 up to 16)
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Percentage of Subjects With Favorable Clinical Response (CR) at End of Treatment (EOT) Visit: Intent-to-treat (ITT) Analysis Population | ||||||||||||
End point description |
Favorable CR was resolution of all acute signs and symptoms of cIAI, or improvement to such an extent that no further antimicrobial therapy was required. EOT visit occurred within 48 hours after completion of the last dose of oral switch therapy or at time of premature discontinuation/early withdrawal from study if on oral switch therapy (which occurred within the maximum study treatment duration of 15 days). ITT analysis population included all subjects who had been assigned a randomized treatment.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
EOT visit (up to a maximum duration of Day 17 [48 hours after maximum study treatment of 15 days])
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Percentage of Subjects With Favorable Clinical Response (CR) at Test of Cure (TOC) Visit: Intent-to-treat (ITT) Analysis Population | ||||||||||||
End point description |
Favorable CR was resolution of all acute signs and symptoms of cIAI, or improvement to such an extent that no further antimicrobial therapy was required. TOC visit occurred within 8 to 15 days after last dose of any study drug (IV or oral). ITT analysis population included all subjects who had been assigned a randomized treatment.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
TOC visit (8 to 15 days after last dose of IV or oral treatment; up to a maximum study duration of 50 days)
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||||||||||||||
End point title |
Percentage of Subjects With Favorable Clinical Response (CR): Clinically Evaluable (CE) Analysis Population | ||||||||||||||||||||||||
End point description |
Favorable CR: resolution of all acute signs, symptoms of cIAI, or improvement to such an extent that no further antimicrobial therapy required, or improvement in subjects who switch to oral therapy and met following criterion: afebrile (temperature<=38.0°C) for >=24 h, absence of new and improvement in at >= symptom or sign (fever, pain, tenderness, elevated WBCs, elevated c-reative-protein)from baseline and worsening of none. EOIV visit: 24 h after completion of last infusion of study drug. EOT visit occurred within 48 hours after completion of last dose of oral switch therapy or at time of premature discontinuation/early withdrawal from study if on oral switch therapy (which occurred within the maximum study treatment duration of 15 days). TOC visit: within 8 to 15 days after last dose of any study drug. CE analysis set. Here, ‘n’= subjects evaluable at specified time points, for each arm respectively.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
After 72 hours after the start of IV study infusion on Day 1,EOIV(Day4 up to 16),EOT visit(up to a maximum duration of Day17[48h after maximum study treatment of 15days]) and TOC visit(up to a maximum study duration of 50days)
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
|||||||||||||||||||||||||
End point title |
Percentage of Subjects With Favorable Microbiological Response: Microbiological Intent-to-treat (Micro-ITT) Population | ||||||||||||||||||||||||
End point description |
Favorable microbiological response was achieved when all baseline pathogens were eradicated or presumed eradicated based on investigator's discretion. EOIV visit occurred within 24 hours after completion of last infusion of the study drug. EOIV visit occurred within 24 hours after completion of last infusion of the study drug. TOC visit occurred within 8 to 15 days after last dose of any study drug (IV or oral). LFU visit (27 to 50 days after start of study treatment, up to a maximum study duration of 50 days). Micro-ITT analysis population included all randomized subjects who had a baseline pathogen known to cause cIAI.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
EOIV visit (Day 4 up to 16), EOT visit (up to a maximum duration of Day 17 [48 hours after maximum study treatment of 15 days]) and TOC visit (up to a maximum study duration of 50 days) and LFU visit
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
|||||||||||||||||||||||||
End point title |
Percentage of Subjects With Favorable Microbiological Response: Microbiologically Evaluable (ME) Population | ||||||||||||||||||||||||
End point description |
Favorable microbiological response was achieved when all baseline pathogens were eradicated or presumed eradicated based on investigator's discretion.EOIV visit occurred within 24hours after completion of last infusion of the study drug.EOT visit occurred within 48hours after completion of last dose of oral switch therapy or at time of premature discontinuation/early withdrawal from study if on oral switch therapy (which occurred within the maximum study treatment duration of 15 days). TOC visit occurred within 8 to 15 days after last dose of any study drug (IV or oral). LFU visit (27 to 50 days after start of study treatment, up to a maximum study duration of 50 days). ME analysis population=randomized subjects with cIAI who received study medication for >=48h and clinical failure or clinical failure with treatment limiting AE and subjects with >=72h treatment and favorable microbiological response.‘n’= subjects who were evaluable at specified time points, for each arm respectively.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
EOIV visit (Day 4 up to 16), EOT visit (up to a maximum duration of Day 17 [48 hours after maximum study treatment of 15 days]), TOC visit (up to a maximum study duration of 50 days) and LFU visit
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
||||||||||
End point title |
Percentage of Subjects With Clinical Relapse at Late Follow-up (LFU) Visit: Clinically Evaluable (CE) Population | |||||||||
End point description |
A subject was said to have clinical relapse if met either 1 of the following criteria: reappearance or worsening of signs and symptoms of cIAI that required further antimicrobial therapy and/or surgery, or death after TOC in which cIAI was contributory. LFU visit occurred within 27 to 50 days after start of study treatment (IV or oral). CE analysis population included randomized subjects with cIAI who received study medication for >=48h and clinical failure or clinical failure with treatment limiting AE and subjects with >=72h treatment and favorable clinicial response. Here, number of subjects analyzed=subjects who were evaluable for this measure.
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
LFU visit (27 to 50 days after start of study treatment, up to a maximum study duration of 50 days)
|
|||||||||
|
||||||||||
| No statistical analyses for this end point | ||||||||||
|
||||||||||
End point title |
Percentage of Subjects with Clinical Relapse at Late Follow-up (LFU) Visit: Microbiologically Evaluable (ME) Population | |||||||||
End point description |
A subject was said to have clinical relapse if me either 1 of the following criteria: reappearance or worsening of signs and symptoms of cIAI that required further antimicrobial therapy and/or surgery, or death after TOC in which cIAI was contributory. LFU visit occurred within 27 to 50 days after start of study treatment (IV or oral). ME analysis population included randomized subjects with cIAI who received study medication for >=48h and clinical failure or clinical failure with treatment-limiting AE and subjects with >=72h treatment and favorable microbiological response. Number of subjects analyzed= subjects who were evaluable for this measure.
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
LFU visit (27 to 50 days after start of study treatment, up to a maximum study duration of 50 days)
|
|||||||||
|
||||||||||
| No statistical analyses for this end point | ||||||||||
|
||||||||||
End point title |
Percentage of Subjects With Emergent Infections: Microbiological Intent-to-treat (Micro-ITT) Population | |||||||||
End point description |
Emergent infections were categorized as super infections and new infections. Superinfection: An intra-abdominal culture identified pathogen other than a baseline pathogen during the course of active treatment with study therapy along with worsening signs and symptoms of infection requiring alternative antimicrobial therapy. New infection: An intra-abdominal culture identified pathogen other than a baseline pathogen at any time after study treatment had finished along with worsening signs and symptoms of infection requiring alternative antimicrobial therapy. Subjects with any (super infections or new infections) of the infections were reported. Subjects with any (super infections or new infections) of the infections were reported. Micro-ITT analysis population included all randomized subjects who had a baseline pathogen known to cause cIAI.
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
Baseline up to 50 days
|
|||||||||
|
||||||||||
| No statistical analyses for this end point | ||||||||||
|
||||||||||
End point title |
Percentage of Subjects with Emergent Infections at Test of Cure (TOC) Visit: Microbiologically Evaluable Population | |||||||||
End point description |
Emergent Infections was an intra-abdominal culture identified pathogen other than a baseline pathogen during the course of active treatment with study therapy along with worsening signs and symptoms of infection requiring alternative antimicrobial therapy, new infection was an intra-abdominal culture identified pathogen other than a baseline pathogen at any time after study treatment has finished along with worsening signs and symptoms of infection requiring alternative antimicrobial therapy. TOC visit occurred within 8 to 15 days after last dose of any study drug (IV or oral). ME analysis population included randomized subjects with cIAI who received study medication for >=48h and clinical failure or clinical failure with treatment limiting AE,and subjects with >=72h treatment and favorable microbiological response.
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
TOC visit (8 to 15 days after last dose of IV or oral treatment; up to a maximum study duration of 50 days)
|
|||||||||
|
||||||||||
| No statistical analyses for this end point | ||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
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Timeframe for reporting adverse events |
From signature of informed consent until the LFU visit (27 to 50 days after start of study treatment, up to a maximum study duration of 50 days).
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Dictionary used for adverse event reporting
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
20.0
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Reporting groups
|
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Reporting group title |
Meropenem
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Subjects received 15 to 30 minutes IV infusion of meropenem 20 mg/kg every 8 hours for a minimum of 72 hours and up to a maximum duration of 15 days. After having 72 hours of IV treatment, subjects had option to switch to an oral therapy at the investigator's discretion. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Ceftazidime- Avibactam (CAZ-AVI) plus Metronidazole
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Subjects with CrCL >=50 mL/min received 2-hour IV infusion of 2000 mg CAZ/500 mg AVI (subjects with body weight >=40 kg) or 50 mg/kg CAZ/12.5 mg/kg AVI (subjects with body weight <40 kg), followed by 10 mg/kg metronidazole IV infusion over 20 to 30 minutes. Both infusions were administered to subjects every 8 hours for a minimum of 72 hours and up to a maximum duration of 15 days. Dose of CAZ-AVI was reduced to 50 percent, if the CrCl of subject decreased to <=50 mL/min, and subject was removed from study therapy, if CrCl decreased below 30 mL/min. After having 72 hours of IV treatment, subjects had option to switch to an oral therapy at the investigator's discretion. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
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|
|||
Substantial protocol amendments (globally) |
|||
| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
07 Mar 2017 |
Added ITT and Micro-ITT analysis sets to the analysis in line
with Food and Drug Administration (FDA) feedback; Added description of oral medications table summary; Amended AEs of SI to summarize by topic; Amended approach for summarising laboratory abnormality criteria. |
||
Interruptions (globally) |
|||
| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
