Clinical Trial Results:
Efficacy and safety of paracetamol in comparison to ibuprofen for patent ductus arteriosus treatment in preterm infants. A randomized, open label, comparator-controlled, prospective study.
Summary
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EudraCT number |
2013-003883-30 |
Trial protocol |
IT |
Global end of trial date |
17 Apr 2019
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Results information
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Results version number |
v1(current) |
This version publication date |
20 Nov 2019
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First version publication date |
20 Nov 2019
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Other versions |
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 |
044CF13273
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02422966 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.p.A
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Sponsor organisation address |
Piazzale della Stazione s.n.c. S.Palomba-Pomezia (Rome) Italy, Rome, Italy, 00071
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Public contact |
A.C.R.A.F. HQMD Clinical Operations, ACRAF S.p.A, +39 0691945349, paola.lipone@angelinipharma.com
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Scientific contact |
A.C.R.A.F. HQMD Clinical Operations, ACRAF S.p.A, +39 0691945349, paola.lipone@angelinipharma.com
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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 |
17 Apr 2019
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
17 Apr 2019
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Global end of trial reached? |
Yes
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Global end of trial date |
17 Apr 2019
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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 |
The study objective is to assess the efficacy and safety of paracetamol in comparison to ibuprofen in the treatment of patent ductus arteriosus in preterm infants.
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Protection of trial subjects |
The study was carried out according to ICH guidelines of Good Clinical Practices (CPMP/ICH/135/95) and Helsinki Declaration (Fortaleza - Brasil 2013)
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Background therapy |
Not applicable | ||
Evidence for comparator |
Pedea (ibuprofen) 5 mg/ml solution for injection has been selected as treatment comparator because it represents the only drug authorised in the EU since 29 July 2004 for the treatment of a hsPDA in preterm newborn infants less than 34 weeks of gestational age [EU/3/01/020]. Doses of ibuprofen to be administered to the patients are consistent with those reported in the relevant SPC. | ||
Actual start date of recruitment |
18 Dec 2015
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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 |
Italy: 109
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Worldwide total number of subjects |
109
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EEA total number of subjects |
109
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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 |
109
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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) |
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 |
Recruitment of 110 patients was planned. 110 patients were randomised to allocated intervention (52 in Ibuprofen group and 58 in Paracetamol) from 8 December 2015 to 22 January 2019.One patient was erroneously randomised to Ibuprofen group but did not receive medication. | ||||||||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
One patient was erroneously randomised to Ibuprofen group but did not receive medication. | ||||||||||||||||||||||||||||||||||||
Period 1
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Period 1 title |
PERIOD 1 (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||||||||||||||||||||
Blinding implementation details |
Not applicable
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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IBUPROFEN 5mg/ml | ||||||||||||||||||||||||||||||||||||
Arm description |
Ibuprofen intravenous solution administered at an initial dose of 10 mg/kg, followed by 5 mg/kg at 24 h and 5 mg/kg at 48 h. | ||||||||||||||||||||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Ibuprofen
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Investigational medicinal product code |
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Other name |
Pedea
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
Ibuprofen intravenous solution at an initial dose of 10 mg/kg, followed by 5 mg/kg at 24 h and 5 mg/kg at 48 h.
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Arm title
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PARACETAMOL 10 mg/ml | ||||||||||||||||||||||||||||||||||||
Arm description |
Paracetamol intravenous solution 15 mg/kg (corresponding to 1.5 ml/kg) per dose every 6 hours for 3 days, for a total amount of 12 doses. | ||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Paracetamol
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Investigational medicinal product code |
044
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Other name |
Tachipirina i.v.
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Pharmaceutical forms |
Solution for injection/infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Paracetamol intravenous solution 15 mg/kg (corresponding to 1.5 ml/kg) per dose every 6 hours for 3 days, for a total amount of 12 doses.
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Baseline characteristics reporting groups
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Reporting group title |
IBUPROFEN 5mg/ml
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Reporting group description |
Ibuprofen intravenous solution administered at an initial dose of 10 mg/kg, followed by 5 mg/kg at 24 h and 5 mg/kg at 48 h. | ||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
PARACETAMOL 10 mg/ml
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Reporting group description |
Paracetamol intravenous solution 15 mg/kg (corresponding to 1.5 ml/kg) per dose every 6 hours for 3 days, for a total amount of 12 doses. | ||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Safety population
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Subject analysis set type |
Safety analysis | ||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Safety population (SP) was defined as all randomised patients who took at least one dose of the study medication.
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Subject analysis set title |
Modified Intention to Treat (m-ITT) population
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Subject analysis set type |
Modified intention-to-treat | ||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The modified Intention-to-Treat (m-ITT) population: all randomized patients completing the first treatment course, and having the baseline and the day 3 echocardiographic assessments.
The Per Protocol (PP) population was defined as patients from the mITT population with no major protocol violations. Since no major protocol violations were detected the m-ITT and the PP population were the same.
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End points reporting groups
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Reporting group title |
IBUPROFEN 5mg/ml
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Reporting group description |
Ibuprofen intravenous solution administered at an initial dose of 10 mg/kg, followed by 5 mg/kg at 24 h and 5 mg/kg at 48 h. | ||
Reporting group title |
PARACETAMOL 10 mg/ml
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Reporting group description |
Paracetamol intravenous solution 15 mg/kg (corresponding to 1.5 ml/kg) per dose every 6 hours for 3 days, for a total amount of 12 doses. | ||
Subject analysis set title |
Safety population
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
Safety population (SP) was defined as all randomised patients who took at least one dose of the study medication.
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Subject analysis set title |
Modified Intention to Treat (m-ITT) population
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Subject analysis set type |
Modified intention-to-treat | ||
Subject analysis set description |
The modified Intention-to-Treat (m-ITT) population: all randomized patients completing the first treatment course, and having the baseline and the day 3 echocardiographic assessments.
The Per Protocol (PP) population was defined as patients from the mITT population with no major protocol violations. Since no major protocol violations were detected the m-ITT and the PP population were the same.
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End point title |
Rate closure of PDA | |||||||||||||||
End point description |
The primary endpoint of the study was the evaluation of the success rate in closing PDA using
paracetamol in comparison to ibuprofen after the first 3 days of treatment.
Success was defined as the closing PDA after 3 days of treatment with paracetamol or ibuprofen
assessed echocardiographically at Visit 3.
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End point type |
Primary
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End point timeframe |
Day 3
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Statistical analysis title |
Group comparison | |||||||||||||||
Statistical analysis description |
Comparisons between groups was performed by χ2 test. Tests were performed at an alpha level of 5% two-sided
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Comparison groups |
PARACETAMOL 10 mg/ml v IBUPROFEN 5mg/ml
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Number of subjects included in analysis |
100
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||||||||
P-value |
≤ 0.05 | |||||||||||||||
Method |
Chi-squared | |||||||||||||||
Parameter type |
success percent | |||||||||||||||
Confidence interval |
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End point title |
Rate in closing PDA after the second treatment course of ibuprofen as rescue medication; | |||||||||||||||
End point description |
Success rate in closing PDA after the second treatment course of ibuprofen as rescue medication.
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End point type |
Secondary
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End point timeframe |
Day 6
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Notes [1] - The group refers to subjects with hsPDA at Visit 3 [2] - The group refers to subjects with hsPDA at Visit 3 |
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Statistical analysis title |
Group comparison | |||||||||||||||
Comparison groups |
IBUPROFEN 5mg/ml v PARACETAMOL 10 mg/ml
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Number of subjects included in analysis |
14
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||||||||
P-value |
≤ 0.05 | |||||||||||||||
Method |
Chi-squared | |||||||||||||||
Parameter type |
success percent | |||||||||||||||
Confidence interval |
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End point title |
Number of re-openings at 30 days | |||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
From Day 0 to Day 30
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Statistical analysis title |
Group comparison | |||||||||||||||
Statistical analysis description |
Comparisons between groups was performed by χ2 test. Tests were performed at an alpha level of 5% two-sided
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Comparison groups |
IBUPROFEN 5mg/ml v PARACETAMOL 10 mg/ml
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Number of subjects included in analysis |
82
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||||||||
P-value |
≤ 0.05 | |||||||||||||||
Method |
Chi-squared | |||||||||||||||
Parameter type |
Success percent | |||||||||||||||
Confidence interval |
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End point title |
Incidence of surgical ligations at 30 days | |||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
From Day 0 to Day 30
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Statistical analysis title |
Group comparison | |||||||||||||||
Statistical analysis description |
Comparisons between groups was performed by χ2 test. Tests were performed at an alpha level of 5% two-sided
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Comparison groups |
IBUPROFEN 5mg/ml v PARACETAMOL 10 mg/ml
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Number of subjects included in analysis |
96
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||||||||
P-value |
≤ 0.05 | |||||||||||||||
Method |
Chi-squared | |||||||||||||||
Parameter type |
Success percent | |||||||||||||||
Confidence interval |
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Adverse events information
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Timeframe for reporting adverse events |
Adverse Events (AE) were recorded from the signature of the Informed Consent up to the last visit scheduled in the study protocol (40 weeks post conception).
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Adverse event reporting additional description |
Safety was assessed by monitoring the frequency of adverse events in each treatment group. Changes from baseline in physical examination, vital signs and urine output were also assessed. Laboratory analyses were evaluated on the basis of the normal range, the Investigator’s judgment, and mean changes from screening.
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
18.0
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Reporting groups
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Reporting group title |
IBUPROFEN 5mg/ml
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Reporting group description |
51 subjects treated with Ibuprofen intravenous solution 5mg/ml. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
PARACETAMOL 10 mg/ml
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Reporting group description |
58 subjects treated with paracetamol 10 mg/ml | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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04 Mar 2015 |
• The substantial Amendment no. 1 (March 04th, 2015) was carried out to be fully compliant with the Italian Guideline for the treatment of personal data in clinical trials (Deliberazione n° 52 del 24 Luglio 2008 del Garante per la Protezione dei Dati Personali – “Linee Guida per i Trattamenti di Dati Personali nell’ambito delle Sperimentazioni Cliniche dei Medicinali”). In addition, changes regarding Sponsor Personnel involved in the study and contact details of a vendor were also proposed in the study protocol. Some minor changes were performed to correct typing errors and provide more detailed instructions for the adverse events recording/reporting. An updated version of the Investigator’s Brochure (IB) (version no. 3 of March 04th, 2015) including new Sponsor personnel, new available clinical and post-marketing data was also provided with this Study Amendment. The changes proposed were applied to all sites where the study was submitted/approved.
The Study Amendment no. 1 was approved by the National applicable Ethics Committees and the Italian Competent Authority, when applicable.
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05 Oct 2016 |
• The substantial Study Amendment no. 3 (October 5th, 2016) proposed the replacement of the Principal Investigator of the investigational site IT5 – UOC Neonatologia e Terapia Intensiva Neonatale, Fondazione Policlinico Agostino Gemelli (Roma) due to his retirement, starting from the 1st of November 2016. The proposed Study Amendment was applied only to the investigational site IT5 of the present clinical trial.
The Study Amendment no.3 was approved notified to the applicable by National Ethics Committee and Competent Authority, when applicableonly
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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. | |||
Not applicable |