Clinical Trial Results:
A Prospective, Randomized, Double-Blind, Multicenter Study to Establish the Safety and Tolerability of Doripenem Compared With Cefepime in Hospitalized Children With Bacterial Pneumonia.
Due to a system error, the data reported in v1 is not correct and has been removed from public view.
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Summary
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EudraCT number |
2009-016069-27 |
Trial protocol |
LT LV Outside EU/EEA |
Global end of trial date |
21 Mar 2012
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Results information
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Results version number |
v2(current) |
This version publication date |
09 Jun 2016
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First version publication date |
23 Jul 2015
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Other versions |
v1 (removed from public view) |
Version creation reason |
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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 |
DORIPED3003
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01110421 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Janssen-Cilag International NV
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Sponsor organisation address |
Turnhoutseweg 30, 2340 Beerse, Belgium, Belgium,
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Public contact |
Clinical Registry Group, Janssen-Cilag International NV, ClinicalTrialsEU@its.jnj.com
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Scientific contact |
Clinical Registry Group, Janssen-Cilag International NV, ClinicalTrialsEU@its.jnj.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-000015-PIP01-07 | ||
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 |
21 Mar 2012
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
21 Mar 2012
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Global end of trial reached? |
Yes
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Global end of trial date |
21 Mar 2012
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
The primary objective of this study is to establish the safety and tolerability of doripenem compared with that of cefepime in hospitalized children 3 months to less than 18 years of age with suspected bacterial pneumonia including NP (Nosocomial Pneumonia), VAP (Ventilator-Assiociated Pneumonia), and severe CAP (Community-Acquired Pneumonia).
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Protection of trial subjects |
This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practices and applicable
regulatory requirements. An Independent Data Monitoring Committee [IDMC] monitored the safety of participants in this study as well as 2 additional Phase 3 pediatric trials being conducted by the Sponsor simultaneously. Safety evaluations included the measurement of vital signs, monitoring of reported adverse effects (AEs), including serious adverse effects (SAEs), concomitant therapy, serum
chemistry, hematology assessments, and urinalysis with microscopy.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
01 Dec 2010
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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 |
Colombia: 2
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Country: Number of subjects enrolled |
Poland: 4
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Country: Number of subjects enrolled |
Ukraine: 1
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Worldwide total number of subjects |
7
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EEA total number of subjects |
4
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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) |
0
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Children (2-11 years) |
7
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Adolescents (12-17 years) |
0
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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 |
The study was planned to enroll a minimum of 120 participants but since it was terminated early (05 August 2013), only 7 participants were enrolled in this study at 1 center each in Poland, Ukraine, and Colombia. | |||||||||||||||
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Pre-assignment
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Screening details |
A total of 7 participants (5 subjects in doripenem group and 2 subjects in cefepime group) were enrolled in this study. | |||||||||||||||
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Period 1
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Period 1 title |
Overall (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||
Roles blinded |
Subject, Investigator, Carer, Assessor | |||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Doripenem | |||||||||||||||
Arm description |
Doripenem 20 milligram per kilogram [mg/kg] per dose (up to 500 milligram per dose [mg/dose]) was administered every 8 hours as 60-minutes intravenous [IV] (at least 3 days of IV doripenem only or IV doripenem followed by oral amoxicillin/clavulanate potassium or ciprofloxacin). Total duration of treatment 10 to 14 days. | |||||||||||||||
Arm type |
Experimental | |||||||||||||||
Investigational medicinal product name |
Doripenem
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder and solvent for solution for injection/infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Doripenem 20 milligram per kilogram [mg/kg] per dose (up to 500 milligram per dose [mg/dose]) was administered every 8 hours as 60-minutes intravenous [IV] (at least 3 days of IV doripenem only or
IV doripenem followed by oral amoxicillin/clavulanate potassium or ciprofloxacin).
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Arm title
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Cefepime | |||||||||||||||
Arm description |
Cefepime 50 milligram per kilogram [mg/kg] per dose (up to 2 gram per dose [g/dose]) was administered every 8 hours as 30-minutes intravenous [IV] (at least 3 days of IV cefepime only or IV cefipime followed by oral amoxicillin/clavulanate potassium or ciprofloxacin). Total duration of treatment 10 to 14 days | |||||||||||||||
Arm type |
Active comparator | |||||||||||||||
Investigational medicinal product name |
Cefepime
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder and solvent for solution for injection/infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Cefepime 50 milligram per kilogram [mg/kg] per dose (up to 2 gram per dose [g/dose]) was administered every 8 hours as 30-minutes intravenous [IV] (at least 3 days of IV cefepime only or IV cefipime followed by oral amoxicillin/clavulanate potassium or ciprofloxacin).
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Baseline characteristics reporting groups
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Reporting group title |
Doripenem
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Reporting group description |
Doripenem 20 milligram per kilogram [mg/kg] per dose (up to 500 milligram per dose [mg/dose]) was administered every 8 hours as 60-minutes intravenous [IV] (at least 3 days of IV doripenem only or IV doripenem followed by oral amoxicillin/clavulanate potassium or ciprofloxacin). Total duration of treatment 10 to 14 days. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Cefepime
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Reporting group description |
Cefepime 50 milligram per kilogram [mg/kg] per dose (up to 2 gram per dose [g/dose]) was administered every 8 hours as 30-minutes intravenous [IV] (at least 3 days of IV cefepime only or IV cefipime followed by oral amoxicillin/clavulanate potassium or ciprofloxacin). Total duration of treatment 10 to 14 days | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Doripenem
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Reporting group description |
Doripenem 20 milligram per kilogram [mg/kg] per dose (up to 500 milligram per dose [mg/dose]) was administered every 8 hours as 60-minutes intravenous [IV] (at least 3 days of IV doripenem only or IV doripenem followed by oral amoxicillin/clavulanate potassium or ciprofloxacin). Total duration of treatment 10 to 14 days. | ||
Reporting group title |
Cefepime
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Reporting group description |
Cefepime 50 milligram per kilogram [mg/kg] per dose (up to 2 gram per dose [g/dose]) was administered every 8 hours as 30-minutes intravenous [IV] (at least 3 days of IV cefepime only or IV cefipime followed by oral amoxicillin/clavulanate potassium or ciprofloxacin). Total duration of treatment 10 to 14 days | ||
Subject analysis set title |
Clinical Intent-To-Treat (CITT)
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
All randomized participants who met the minimal disease definition of pneumonia regardless if a baseline pathogen was isolated from the baseline lower respiratory tract culture, pleural fluid or blood culture.
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Subject analysis set title |
Microbiological intent-to-treat(MITT)
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
Participants of CITT with at least one baseline pneumonia pathogen from pleural fluid, LRT, or blood culture susceptible to doripenem and cefepime. 3 and 2 participants from doripenem and cefepime, respectively had no susceptible pneumonia pathogens at baseline and were excluded from this set.
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End point title |
The Number of Participants With Clinical Cure Rate at Test Of Cure (TOC) Visit [1] | ||||||||||||
End point description |
The participants were classified as cure if they had resolution or clinical improvement of signs and symptoms of pneumonia, favorable response at End of treatment for IV study (EIV) visit; had no fever; improvement or no progression of radiographic findings of pneumonia on chest X ray; improvement in oxygenation or discontinued mechanical ventilation in intubated participants; and not received nonstudy systemic antibacterial therapy for pneumonia.
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End point type |
Primary
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End point timeframe |
TOC (7 to 14 days after the last dose of study medication therapy)
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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: Descriptive statistics were done, no inferential statistical analyses were performed |
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| Notes [2] - Clinical intent-to-treat [3] - Clinical intent-to-treat |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
The Number of Participants With Clinical Improvement Rate at End of IV (EIV) Visit | ||||||||||||
End point description |
Participants were considered as clinical improved if they had no fever, clinical improvement in signs and symptoms of pneumonia from baseline, decrease in WBC, improvement or lack of progression of radiographic findings in comparison with the screening chest X-ray, and not received any nonstudy systemic antibacterial therapy for the treatment of pneumonia after IV study drug therapy had begun.
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End point type |
Secondary
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End point timeframe |
EIV (within 24 hours after completion of the last dose of IV study medication therapy)
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| Notes [4] - Clinical intent-to-treat [5] - Clinical intent-to-treat |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
The Number of Participants With Clinical Cure Rate at Late Follow-Up (LFU) Visit | ||||||||||||
End point description |
The participants were classified as clinical cure if all pretreatment signs and symptoms showed no evidence of resurgence after administration of the last dose of study medication and no nonstudy systemic antibacterial therapy was given for the treatment of pneumonia.
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End point type |
Secondary
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End point timeframe |
LFU (28 to 42 days after the last dose of study medication therapy)
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| Notes [6] - Clinical intent-to-treat [7] - Clinical intent-to-treat |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
The Number of Participants With Favorable Per-participant Microbiological Response Rate | |||||||||||||||||||||
End point description |
Favorable per-participant microbiological response rate was evaluated at the at End of IV (EIV) visit, Test Of Cure (TOC) visit, and Late Follow-Up (LFU) visit. The favorable per-participant microbiological response was considered when all baseline pathogens were eradicated (absence) or presumed eradicated (absence of material to culture in a participant who has a positive clinical response to treatment). NOTE: No participants in the cefepime treatment group met criteria for inclusion in the Microbiological intent-to-treat analysis.
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End point type |
Secondary
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End point timeframe |
EIV (within 24 hours after completion of the last dose of IV study medication therapy), TOC (7 to 14 days after the last dose of study medication therapy), and LFU (28 to 42 days after the last dose of study medication therapy)
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| Notes [8] - MITT [9] - 1) MITT 2) Participants had no susceptible pneumonia pathogens at baseline and were excluded |
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| No statistical analyses for this end point | ||||||||||||||||||||||
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End point title |
Number of Participants With Favorable Per-pathogen Microbiological Outcome Rate at End of IV (EIV) Visit | |||||||||||||||||||||
End point description |
A total of 3 pathogens were isolated at baseline from lower respiratory tract (LRT) culture in 2 participants in the doripenem treatment group and were susceptible to the study drug received: 2 pathogens (Staphylococcus aureus Klebsiella pneumoniae) were isolated at baseline from 1 participant and a 3rd pathogen (Streptococcus pneumoniae) was isolated at baseline from the other participant (see listed in the table below; the number in parenthesis next to each pathogen represent the number of participants with the pathogen isolated at baseline in the doripenem treatment group). The favourable per-participant microbiological response was considered when all baseline pathogens were eradicated (absence) or presumed eradicated (absence of material to culture in a participant who has a positive clinical response to treatment). NOTE: No participants in the cefepime treatment group met criteria for inclusion in the Microbiological intent-to-treat analysis.
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End point type |
Secondary
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End point timeframe |
EIV (within 24 hours after completion of the last dose of IV study medication therapy)
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| Notes [10] - MITT [11] - 1) MITT 2) Participants had no susceptible pneumonia pathogens at baseline and were excluded. |
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| No statistical analyses for this end point | ||||||||||||||||||||||
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End point title |
Number of Participants With Favorable Per-pathogen Microbiological Outcome Rate at Test Of Cure (TOC) Visit | |||||||||||||||||||||
End point description |
A total of 3 pathogens were isolated at baseline from lower respiratory tract (LRT) culture in 2 participants in the doripenem treatment group and were susceptible to the study drug received: 2 pathogens (Staphylococcus aureus Klebsiella pneumoniae) were isolated at baseline from 1 participant and a 3rd pathogen (Streptococcus pneumoniae) was isolated at baseline from the other participant (see listed in the table below; the number in parenthesis next to each pathogen represent the number of participants with the pathogen isolated at baseline in the doripenem treatment group). The favourable per-participant microbiological response was considered when all baseline pathogens were eradicated (absence) or presumed eradicated (absence of material to culture in a participant who has a positive clinical response to treatment). NOTE: No participants in the cefepime treatment group met criteria for inclusion in the Microbiological intent-to-treat analysis.
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End point type |
Secondary
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End point timeframe |
TOC (7 to 14 days after the last dose of study medication therapy)
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| Notes [12] - MITT [13] - 1) MITT 2) Participants had no susceptible pneumonia pathogens at baseline and were excluded. |
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| No statistical analyses for this end point | ||||||||||||||||||||||
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End point title |
Number of Participants With Sustained Favorable Per-pathogen Microbiological Outcome Rate at Late Follow-Up (LFU) Visit | |||||||||||||||||||||
End point description |
A total of 3 pathogens were isolated at baseline from lower respiratory tract (LRT) culture in 2 participants in the doripenem treatment group and were susceptible to the study drug received: 2 pathogens (Staphylococcus aureus Klebsiella pneumoniae) were isolated at baseline from 1 participant and a 3rd pathogen (Streptococcus pneumoniae) was isolated at baseline from the other participant (see listed in the table below; the number in parenthesis next to each pathogen represent the number of participants with the pathogen isolated at baseline in the doripenem treatment group). The favorable per-participant microbiological response was considered when all baseline pathogens were eradicated (absence) or presumed eradicated (absence of material to culture in a participant who has a positive clinical response to treatment). NOTE: No participants in the cefepime treatment group met criteria for inclusion in the Microbiological intent-to-treat analysis.
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End point type |
Secondary
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End point timeframe |
LFU (28 to 42 days after the last dose of study medication therapy)
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| Notes [14] - MITT [15] - 1) MITT 2) Participants had no susceptible pneumonia pathogens at baseline and were excluded. |
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| No statistical analyses for this end point | ||||||||||||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Timeframe for AE
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Assessment type |
Non-systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
15.1
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Reporting groups
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Reporting group title |
Doripenem
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Reporting group description |
Doripenem 20 milligram per kilogram [mg/kg] per dose (up to 500 milligram per dose [mg/dose]) was administered every 8 hours as 60-minutes intravenous [IV] (at least 3 days of IV doripenem only or IV doripenem followed by oral amoxicillin/clavulanate potassium or ciprofloxacin). Total duration of treatment 10 to 14 days. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Cefepime
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Reporting group description |
Cefepime 50 milligram per kilogram [mg/kg] per dose (up to 2 gram per dose [g/dose]) was administered every 8 hours as 30-minutes intravenous [IV] (at least 3 days of IV cefepime only or IV cefipime followed by oral amoxicillin/clavulanate potassium or ciprofloxacin). Total duration of treatment 10 to 14 days | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||||||
Date |
Amendment |
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02 Apr 2011 |
The overall reason for the amendment is to incorporate comments from regulatory authorities and investigators from around the world and update the dosing of amoxicillin/clavulanate potassium to every 12 hours every 12 hours [q12h] (7:1 amoxicillin/clavulanate ratio). It includes the clarifications for the doripenem phase 3 program also to clarify that subjects should not receive non study systemic antibacterial therapy for more than 24 hours before the first dose of study drug and to remove CPIS from the study since it has not been validated as a criterion of improvement for children on mechanical ventilation.The amendment also includes the requirement that urinalysis with microscopy and creatinine clearance be calculated at baseline as well as to specify time points for the collection of safety laboratory test. The amendment incorporate to allow subjects to continue adjunctive therapy when switched to oral medication and to update the dosing of amoxicillin/clavulanate potassium. It also includes to align the protocol with the EU pediatric investigational plan (PIP) and to remove details of the IDMC that will be specified in the IDMC charter. The amended protocol includes to revise the pharmacokinetic sample collection and handling methods. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? Yes | |||||||
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Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||||||
| The major limitation of the study was limited enrollment which precludes a meaningful conclusion about the efficacy and safety of doripenem compared with cefepime. | |||||||
