Clinical Trial Results:
Pharmacokinetics of penicillin, ampicillin and gentamicin in near- term and full-term neonates
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Summary
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EudraCT number |
2012-002836-97 |
Trial protocol |
EE |
Global end of trial date |
27 Aug 2014
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Results information
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Results version number |
v1(current) |
This version publication date |
29 Nov 2021
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First version publication date |
29 Nov 2021
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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 |
240193
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Tartu University Hospital
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Sponsor organisation address |
Puusepa 1A, Tartu, Estonia, 50406
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Public contact |
Children`s Clinic, Tartu University Hospital, +372 7319552, helgi.padari@kliinikum.ee
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Scientific contact |
Children`s Clinic, Tartu University Hospital, 5102696 7319552, helgi.padari@kliinikum.ee
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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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? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
12 Aug 2019
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
12 Aug 2014
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Global end of trial reached? |
Yes
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Global end of trial date |
27 Aug 2014
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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 describe the PK of ampicillin, penicillin G and gentamicin in neonates with suspected or proven neonatal sepsis or pneumonia and GA of ≥ 32 week in order to define optimal dosing regimen of the studied antibiotics.
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Protection of trial subjects |
Pharmacokinetics of penicillin, ampicillin and gentamicin was studied only in neonates to whom antibiotic treatment was clinically indicated.
Study included only neonates who had central venous or arterial catheter placed on clinical indication and no additional pain associated with pharmacokinetic samplings was caused.
Amount of blood drawn for pharmacokinetic samplings was restricted as guided by Committee for Medicinal Products for Human Use and Paediatric Committee of European Medicines Agency.
Epithelial lining fluid samples were taken only from patients who needed invasive ventilation (intubation) and tracheal aspiration was performed as part of the clinical routine.
Cerebrospinal fluid was taken for pharmacokinetic study only when lumbar puncture was clinically indicated.
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Background therapy |
in this study no background therapy was used | ||
Evidence for comparator |
In this study no comparator was used | ||
Actual start date of recruitment |
01 Oct 2012
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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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 |
Estonia: 32
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Worldwide total number of subjects |
32
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EEA total number of subjects |
32
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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) |
32
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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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 |
Eligible were neonates with following criteria: 1.GA ≥ 32 weeks 2. PNA < 28 days 3. Informed consent (IC) given by parents or guardian 4. Central venous or arterial catheter placed or will be placed on clinical indication 5. Treatment with intravenous ampicillin or penicillin G with or without gentamicin for suspected or proven neonatal sepsis. | |||||||||
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Pre-assignment
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Screening details |
All neonates with GA ≥ 32 weeks and PNA ˂ 28 days who were hospitalised to NICU of Tartu University Hospital or Tallinn Children’s Hospital with suspected or proven neonatal sepsis or pneumonia. | |||||||||
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Period 1
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Period 1 title |
overall trial (overall period)
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Is this the baseline period? |
Yes | |||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | |||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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ampicillin-gentamicin | |||||||||
Arm description |
Neonates with GA ≥ 32 weeks and PNA < 28 days, who had central venous or arterial catheter placed on clinical indication and who were treated with intavenous ampicillin due to congenital sepsis or pneumonia. Informed consent for participation had given by parents or guardian. | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
ampicillin
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder and solution for solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
Ampicillin was administered in a dose of 25 mg/kg based on current body weight of the neonate. The dosing interval was 12 h. No more than 10 minutes before administration to the patient 1 g of ampicillin (Sandoz GmbH) was reconstituted in 5 ml of 0.9% NaCl to a concentration of 200 mg/ml. Two ml (400 mg) of this solution was further diluted in 2 ml of 0.9% NaCl to a final concentration of 100 mg/ml.
Ampicillin was administered as a bolus injection over 3 minutes into a central or peripheral venous cannula.
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Arm title
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penicillin-gentamicin | |||||||||
Arm description |
Neonates with GA ≥ 32 weeks and PNA < 28 days, who had central venous or arterial catheter placed on clinical indication and who were treated with intravenous penicillin due to congenital sepsis or pneumonia. All participants had informed consent obtained from parents or guardian | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
penicillin
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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 in pre-filled syringe
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Routes of administration |
Intracavernous use
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Dosage and administration details |
Penicillin G was administered in a dose of 25 000 IU/kg based on current body weight of the neonate. The dosing interval was 12 h. No more than 10 minutes before administration to the patient 1000000 IU of penicillin G (Sandoz GmbH) was reconstituted in 5 ml of 0.9% NaCl to a concentration of 200000 IU/ml. Two ml (400000 IU) of this solution was further be diluted in 2 ml of 0.9% NaCl to a final concentration of 100000 IU/ml.
Penicillin was administered as a bolus injection over 3 minutes into a central or peripheral venous cannula.
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Baseline characteristics reporting groups
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Reporting group title |
ampicillin-gentamicin
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Reporting group description |
Neonates with GA ≥ 32 weeks and PNA < 28 days, who had central venous or arterial catheter placed on clinical indication and who were treated with intavenous ampicillin due to congenital sepsis or pneumonia. Informed consent for participation had given by parents or guardian. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
penicillin-gentamicin
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Reporting group description |
Neonates with GA ≥ 32 weeks and PNA < 28 days, who had central venous or arterial catheter placed on clinical indication and who were treated with intravenous penicillin due to congenital sepsis or pneumonia. All participants had informed consent obtained from parents or guardian | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
ampicillin-gentamicin
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Reporting group description |
Neonates with GA ≥ 32 weeks and PNA < 28 days, who had central venous or arterial catheter placed on clinical indication and who were treated with intavenous ampicillin due to congenital sepsis or pneumonia. Informed consent for participation had given by parents or guardian. | ||
Reporting group title |
penicillin-gentamicin
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Reporting group description |
Neonates with GA ≥ 32 weeks and PNA < 28 days, who had central venous or arterial catheter placed on clinical indication and who were treated with intravenous penicillin due to congenital sepsis or pneumonia. All participants had informed consent obtained from parents or guardian | ||
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End point title |
clearance [1] [2] | ||||||||
End point description |
penicillin
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End point type |
Primary
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End point timeframe |
steady state
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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: median and quartiles were calculated only [2] - 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: the end point was for one arm |
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| No statistical analyses for this end point | |||||||||
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End point title |
Volume of distribution [3] [4] | ||||||||
End point description |
penicillin
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End point type |
Primary
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End point timeframe |
steady state
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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: median and quartiles were calculated only [4] - 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: median and quartiles were calculated only |
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| No statistical analyses for this end point | |||||||||
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End point title |
half-life [5] [6] | ||||||||
End point description |
penicillin
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End point type |
Primary
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End point timeframe |
steady state
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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: median and quartiles were calculated only [6] - 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: the end point was for one arm |
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| No statistical analyses for this end point | |||||||||
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End point title |
maximum concentration in serum [7] [8] | ||||||||
End point description |
penicillin
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End point type |
Primary
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End point timeframe |
steady state
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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: median and quartiles were calculated only [8] - 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: the end point was for one arm |
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| No statistical analyses for this end point | |||||||||
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End point title |
minimum concentation in serum [9] [10] | ||||||||
End point description |
penicillin
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End point type |
Primary
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End point timeframe |
steady state
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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: median and quartiles were calculated only [10] - 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: the end point was for one arm |
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| No statistical analyses for this end point | |||||||||
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End point title |
area under the concentration-time curve [11] [12] | ||||||||
End point description |
penicillin
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End point type |
Primary
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End point timeframe |
steady state
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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: median and quartiles were calculated only [12] - 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: the end point was for one arm |
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| No statistical analyses for this end point | |||||||||
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End point title |
clearance 1 [13] [14] | ||||||||
End point description |
ampicillin
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End point type |
Primary
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End point timeframe |
steady state
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| 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: arithmetic mean and standard deviation were calculated only [14] - 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: the end point was for one arm |
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| No statistical analyses for this end point | |||||||||
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End point title |
half-life 1 [15] [16] | ||||||||
End point description |
ampicillin
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End point type |
Primary
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End point timeframe |
steady state
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| Notes [15] - 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: arithmetic mean and standard deviation were calculated only [16] - 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: the end point was for one arm |
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| No statistical analyses for this end point | |||||||||
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End point title |
Volume of distribution 1 [17] [18] | ||||||||
End point description |
ampicillin
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End point type |
Primary
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End point timeframe |
steady state
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| Notes [17] - 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: arithmetic mean and standard deviation were calculated only [18] - 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: arithmetic mean and standard deviation were calculated only |
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| No statistical analyses for this end point | |||||||||
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End point title |
area under the concentration-time curve 1 [19] [20] | ||||||||
End point description |
ampicillin
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End point type |
Primary
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End point timeframe |
steady state
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| Notes [19] - 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: arithmetic mean and standard deviation were calculated only [20] - 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: the end point was for one arm |
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| No statistical analyses for this end point | |||||||||
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Adverse events information [1]
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Timeframe for reporting adverse events |
Starting fom the day when study drug was administeed for pharmacokinetic studying. Finishing up to two days (+/-one day) after the end of treatment with all study dugs. Fom 22.12.2012 - 31.08.2014.
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Adverse event reporting additional description |
Daily physical examination; daily monitoing of uine output; weight monitoing at least evey other day; continuous monitoring of heart rate, transcutaneous oxygen satuation; laboatoy tests when clinicallly indicated
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Assessment type |
Systematic | |||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
Predefined | |||||||||||||||
Dictionary version |
2
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Reporting groups
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Reporting group title |
group I
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Reporting group description |
ampicillin-gentamicin group | |||||||||||||||
Reporting group title |
group II
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Reporting group description |
penicillin-gentamicin group | |||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 0.1% | ||||||||||||||||
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| Notes [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported. Justification: We did not obseve any advese events |
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? No | |||
Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
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. | |||
| Due to small number of patients covariate analysis for population pharmacokinetics was not possible Due to technical reasons we did not obtain enough samples of ELF and CSF for probability of target attainment simulations | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/33591074 http://www.ncbi.nlm.nih.gov/pubmed/29463540 |
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