Clinical Trial Results:
A Phase 1, Multicenter, Open-label Study to Determine the Safety and Pharmacokinetics of MMX Mesalamine Following Administration in Children and Adolescents With Ulcerative Colitis
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Summary
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EudraCT number |
2011-000164-10 |
Trial protocol |
GB SK |
Global end of trial date |
27 Jun 2013
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Results information
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Results version number |
v1(current) |
This version publication date |
04 Sep 2018
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First version publication date |
15 Feb 2015
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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 |
SPD476-112
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01130844 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Shire Development LLC
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Sponsor organisation address |
725 Chesterbrook Boulevard, Wayne, United States, 19087
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Public contact |
Medical Communications, Shire Pharmaceutical Development, +44 0800556614,
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Scientific contact |
Medical Communications, Shire Pharmaceutical Development, +44 0800556614,
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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 |
27 Jun 2013
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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 |
27 Jun 2013
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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 was to assess the pharmacokinetics (PK) of 5-aminosalicylic acid (5-ASA) and its major metabolite acetyl 5-aminosalicylic acid (Ac-5-ASA) after administration of Multi-Matrix System (MMX) mesalamine at 3 different doses (30mg/kg/day, 60mg/kg/day, or 100mg/kg/day) for 7 days in children and adolescents with a history of ulcerative colitis.
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Protection of trial subjects |
The study protocol, protocol amendments, the informed consent document, relevant supporting information, and all types of subject recruitment information were submitted and approved by the IEC/IRB and regulatory agency (if appropriate) prior to study initiation. This study was conducted in accordance with International Conference on Harmonisation Good Clinical Practice, the principles of the Declaration of Helsinki, as well as other applicable local ethical and legal requirements. The subject’s parent(s) or LAR-signed informed consent and documentation of assent by the subject (indicating the subject was aware of the investigational nature of the study, was able and willing to participate in the study, and was aware of the required restrictions and procedures) were mandatory conditions for taking part in the study. They were obtained in
writing prior to the performance of any study-specific procedures. The subject’s informed consent was documented (on an appropriate form approved by the IEC/IRB) by the signature of the subject's LAR/parents (and the subject) and investigator or investigator's delegate and dated.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
08 Oct 2010
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety, Efficacy | ||
Long term follow-up duration |
7 Months | ||
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 |
Poland: 41
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Country: Number of subjects enrolled |
Slovakia: 3
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Country: Number of subjects enrolled |
United States: 8
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Worldwide total number of subjects |
52
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EEA total number of subjects |
44
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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) |
11
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Adolescents (12-17 years) |
41
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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 |
This was a multicenter study conducted in 12 sites across 3 countries (United States, Poland, and Slovakia) | ||||||||||||
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Pre-assignment
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Screening details |
For subjects who were on a mesalamine product at the Screening Visit (Days -28 to -2), both they (and their LARs) and the investigator needed to feel confident that switching them from their current therapy was appropriate. Subjects who were on another product or not currently on any product for their UC had to have been on a regimen for 4 weeks. | ||||||||||||
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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 |
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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Multi-Matrix System (MMX) Mesalamine (30 mg/kg) | ||||||||||||
Arm description |
MMX Mesalamine: 30 mg/kg/day of MMX Mesalamine tablets, dosed once daily (QD) for 7 days. | ||||||||||||
Arm type |
Experimental | ||||||||||||
Investigational medicinal product name |
MMX Mesalamine
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Investigational medicinal product code |
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Other name |
Lialda, SPD476
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
MMX Mesalamine tablets, 30 mg/kg/day, QD for 7 days, as achievable by the nearest and most appropriate combination of the available dosage strengths (300, 600, and/or 1200mg)
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Arm title
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MMX Mesalamine (60 mg/kg) | ||||||||||||
Arm description |
MMX Mesalamine: 60 mg/kg/day of MMX Mesalamine tablets, QD for 7 days. | ||||||||||||
Arm type |
Experimental | ||||||||||||
Investigational medicinal product name |
MMX Mesalamine
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Investigational medicinal product code |
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Other name |
Lialda, SPD476
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
MMX Mesalamine tablets, 60 mg/kg/day, QD for 7 days, as achievable by the nearest and most appropriate combination of the available dosage strengths (300, 600, and/or 1200mg)
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Arm title
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MMX Mesalamine (100 mg/kg) | ||||||||||||
Arm description |
MMX Mesalamine: 100 mg/kg/day of MMX Mesalamine tablets, QD for 7 days. | ||||||||||||
Arm type |
Experimental | ||||||||||||
Investigational medicinal product name |
MMX Mesalamine
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Investigational medicinal product code |
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Other name |
Lialda, SPD476
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
MMX Mesalamine tablets, 100 mg/kg/day, QD for 7 days, as achievable by the nearest and most appropriate combination of the available dosage strengths (300, 600, and/or 1200mg)
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Baseline characteristics reporting groups
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Reporting group title |
Multi-Matrix System (MMX) Mesalamine (30 mg/kg)
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Reporting group description |
MMX Mesalamine: 30 mg/kg/day of MMX Mesalamine tablets, dosed once daily (QD) for 7 days. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
MMX Mesalamine (60 mg/kg)
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Reporting group description |
MMX Mesalamine: 60 mg/kg/day of MMX Mesalamine tablets, QD for 7 days. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
MMX Mesalamine (100 mg/kg)
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Reporting group description |
MMX Mesalamine: 100 mg/kg/day of MMX Mesalamine tablets, QD for 7 days. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Multi-Matrix System (MMX) Mesalamine (30 mg/kg)
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Reporting group description |
MMX Mesalamine: 30 mg/kg/day of MMX Mesalamine tablets, dosed once daily (QD) for 7 days. | ||
Reporting group title |
MMX Mesalamine (60 mg/kg)
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Reporting group description |
MMX Mesalamine: 60 mg/kg/day of MMX Mesalamine tablets, QD for 7 days. | ||
Reporting group title |
MMX Mesalamine (100 mg/kg)
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Reporting group description |
MMX Mesalamine: 100 mg/kg/day of MMX Mesalamine tablets, QD for 7 days. | ||
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End point title |
Area Under the Plasma Concentration Versus Time Curve (AUC) of Multi-Matrix System (MMX) Mesalamine (5-ASA) at Steady State [1] | ||||||||||||||||
End point description |
AUC can be used as a measure of drug exposure. It is derived from drug concentration and time so it gives a measure how much and how long a drug stays in a body.
This end point used the Pharmacokinetic Set (PKS), which consisted of all subjects in the Safety Analysis Set who generated sufficient plasma samples to allow reliable determination of Cmax and AUC. The Safety Analysis Set consisted of subjects who took at least 1 dose of investigational product and had at least 1 post-dose safety assessment.
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End point type |
Primary
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End point timeframe |
Over a 24-hour period starting on day 7
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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: There was no inferential statistical analysis of the pharmacokinetic data. Summary statistics (number of subjects, mean, SD, CV, medium, maximum, minimum, and geometric mean) were presented by treatment group and by treatment group within age group (5-12 years; 13-17 years) for all pharmacokinetic parameters. Plasma concentrations at each nominal sampling time were also summarized using descriptive statistics. |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Maximum Plasma Concentration (Cmax) of MMX Mesalamine (5-ASA) at Steady State [2] | ||||||||||||||||
End point description |
Cmax is a term that refers to the maximum (or peak) concentration that a drug achieves in the body after the drug has been administrated.
This end point used the Pharmacokinetic Set (PKS), which consisted of all subjects in the Safety Analysis Set who generated sufficient plasma samples to allow reliable determination of Cmax and AUC. The Safety Analysis Set consisted of subjects who took at least 1 dose of investigational product and had at least 1 post-dose safety assessment.
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End point type |
Primary
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End point timeframe |
Over a 24-hour period starting on day 7
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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: There was no inferential statistical analysis of the pharmacokinetic data. Summary statistics (number of subjects, mean, SD, CV, medium, maximum, minimum, and geometric mean) were presented by treatment group and by treatment group within age group (5-12 years; 13-17 years) for all pharmacokinetic parameters. Plasma concentrations at each nominal sampling time were also summarized using descriptive statistics. |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Time to Maximum Plasma Concentration (Tmax) of MMX Mesalamine (5-ASA) at Steady State [3] | ||||||||||||||||
End point description |
Tmax is the time after administration of a drug when the maximum plasma concentration in the body is reached.
This end point used the Pharmacokinetic Set (PKS), which consisted of all subjects in the Safety Analysis Set who generated sufficient plasma samples to allow reliable determination of Cmax and AUC. The Safety Analysis Set consisted of subjects who took at least 1 dose of investigational product and had at least 1 post-dose safety assessment.
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End point type |
Primary
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End point timeframe |
Over a 24-hour period starting on day 7
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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: There was no inferential statistical analysis of the pharmacokinetic data. Summary statistics (number of subjects, mean, SD, CV, medium, maximum, minimum, and geometric mean) were presented by treatment group and by treatment group within age group (5-12 years; 13-17 years) for all pharmacokinetic parameters. Plasma concentrations at each nominal sampling time were also summarized using descriptive statistics. |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Total Body Clearance (CL) of MMX Mesalamine (5-ASA) at Steady State [4] | ||||||||||||||||
End point description |
Clearance of a substance from the blood by the kidneys.
This end point used the Pharmacokinetic Set (PKS), which consisted of all subjects in the Safety Analysis Set who generated sufficient plasma samples to allow reliable determination of Cmax and AUC. The Safety Analysis Set consisted of subjects who took at least 1 dose of investigational product and had at least 1 post-dose safety assessment.
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End point type |
Primary
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End point timeframe |
Over a 24-hour period starting on day 7
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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: There was no inferential statistical analysis of the pharmacokinetic data. Summary statistics (number of subjects, mean, SD, CV, medium, maximum, minimum, and geometric mean) were presented by treatment group and by treatment group within age group (5-12 years; 13-17 years) for all pharmacokinetic parameters. Plasma concentrations at each nominal sampling time were also summarized using descriptive statistics. |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
AUC of MMX Mesalamine Major Metabolite (Ac-5-ASA) at Steady State [5] | ||||||||||||||||
End point description |
This end point used the Pharmacokinetic Set (PKS), which consisted of all subjects in the Safety Analysis Set who generated sufficient plasma samples to allow reliable determination of Cmax and AUC. The Safety Analysis Set consisted of subjects who took at least 1 dose of investigational product and had at least 1 post-dose safety assessment.
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End point type |
Primary
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End point timeframe |
Over a 24-hour period starting on day 7
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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: There was no inferential statistical analysis of the pharmacokinetic data. Summary statistics (number of subjects, mean, SD, CV, medium, maximum, minimum, and geometric mean) were presented by treatment group and by treatment group within age group (5-12 years; 13-17 years) for all pharmacokinetic parameters. Plasma concentrations at each nominal sampling time were also summarized using descriptive statistics. |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Cmax of MMX Mesalamine Major Metabolite (Ac-5-ASA) at Steady State [6] | ||||||||||||||||
End point description |
This end point used the Pharmacokinetic Set (PKS), which consisted of all subjects in the Safety Analysis Set who generated sufficient plasma samples to allow reliable determination of Cmax and AUC. The Safety Analysis Set consisted of subjects who took at least 1 dose of investigational product and had at least 1 post-dose safety assessment.
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End point type |
Primary
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End point timeframe |
Over a 24-hour period starting on day 7
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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: There was no inferential statistical analysis of the pharmacokinetic data. Summary statistics (number of subjects, mean, SD, CV, medium, maximum, minimum, and geometric mean) were presented by treatment group and by treatment group within age group (5-12 years; 13-17 years) for all pharmacokinetic parameters. Plasma concentrations at each nominal sampling time were also summarized using descriptive statistics. |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Tmax of MMX Mesalamine Major Metabolite (Ac-5-ASA) at Steady State [7] | ||||||||||||||||
End point description |
This end point used the Pharmacokinetic Set (PKS), which consisted of all subjects in the Safety Analysis Set who generated sufficient plasma samples to allow reliable determination of Cmax and AUC. The Safety Analysis Set consisted of subjects who took at least 1 dose of investigational product and had at least 1 post-dose safety assessment.
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End point type |
Primary
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End point timeframe |
Over a 24-hour period starting on day 7
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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: There was no inferential statistical analysis of the pharmacokinetic data. Summary statistics (number of subjects, mean, SD, CV, medium, maximum, minimum, and geometric mean) were presented by treatment group and by treatment group within age group (5-12 years; 13-17 years) for all pharmacokinetic parameters. Plasma concentrations at each nominal sampling time were also summarized using descriptive statistics. |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
CL of MMX Mesalamine Major Metabolite (Ac-5-ASA) at Steady State [8] | ||||||||||||||||
End point description |
This end point used the Pharmacokinetic Set (PKS), which consisted of all subjects in the Safety Analysis Set who generated sufficient plasma samples to allow reliable determination of Cmax and AUC. The Safety Analysis Set consisted of subjects who took at least 1 dose of investigational product and had at least 1 post-dose safety assessment.
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End point type |
Primary
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End point timeframe |
Over a 24-hour period starting on day 7
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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: There was no inferential statistical analysis of the pharmacokinetic data. Summary statistics (number of subjects, mean, SD, CV, medium, maximum, minimum, and geometric mean) were presented by treatment group and by treatment group within age group (5-12 years; 13-17 years) for all pharmacokinetic parameters. Plasma concentrations at each nominal sampling time were also summarized using descriptive statistics. |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Percent Absorption of MMX Mesalamine (5-ASA) in Urine at Steady State | ||||||||||||||||
End point description |
This end point used the Pharmacokinetic Set (PKS), which consisted of all subjects in the Safety Analysis Set who generated sufficient plasma samples to allow reliable determination of Cmax and AUC. The Safety Analysis Set consisted of subjects who took at least 1 dose of investigational product and had at least 1 post-dose safety assessment.
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End point type |
Secondary
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End point timeframe |
Over a 24-hour period starting on day 7
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Cumulative Amount of MMX Mesalamine (5-ASA) Recovered in Urine at Steady State | ||||||||||||||||
End point description |
This end point used the Pharmacokinetic Set (PKS), which consisted of all subjects in the Safety Analysis Set who generated sufficient plasma samples to allow reliable determination of Cmax and AUC. The Safety Analysis Set consisted of subjects who took at least 1 dose of investigational product and had at least 1 post-dose safety assessment.
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End point type |
Secondary
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End point timeframe |
Over a 24-hour period starting on day 7
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Cumulative Amount of MMX Mesalamine Major Metabolite (Ac-5-ASA) Recovered in Urine at Steady State | ||||||||||||||||
End point description |
This end point used the Pharmacokinetic Set (PKS), which consisted of all subjects in the Safety Analysis Set who generated sufficient plasma samples to allow reliable determination of Cmax and AUC. The Safety Analysis Set consisted of subjects who took at least 1 dose of investigational product and had at least 1 post-dose safety assessment.
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End point type |
Secondary
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End point timeframe |
Over a 24-hour period starting on day 7
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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 |
12 to 14 days
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Assessment type |
Systematic | ||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||
Dictionary version |
15.0
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Reporting groups
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Reporting group title |
Multi-Matrix System (MMX) Mesalamine (30 mg/kg)
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Reporting group description |
MMX Mesalamine: 30 mg/kg/day of MMX Mesalamine tablets, QD for 7 days. | ||||||||||||||||||||
Reporting group title |
MMX Mesalamine (60 mg/kg)
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Reporting group description |
MMX Mesalamine: 60 mg/kg/day of MMX Mesalamine tablets, QD for 7 days. | ||||||||||||||||||||
Reporting group title |
MMX Mesalamine (100 mg/kg)
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Reporting group description |
MMX Mesalamine: 100 mg/kg/day of MMX Mesalamine tablets, QD for 7 days. | ||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||
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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: None occurred at a frequency that was equal to or greater than the threshold for reporting non-serious adverse events. |
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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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20 May 2010 |
*The maximum daily dose of investigational product (4800 mg) was specified.
*The adverse drug reaction “nausea” was added to the safety background section.
*The word “visit” was added to the footnote of the schedule of assessments: “A
follow-up telephone call or visit is to be made/conducted 5 to 7 days after the last dose of investigational product.”
*The word “screening” was added to clarify that the subject screening number was
combined with the site number to form the unique subject identifier.
*Language was added to clarify the investigational product had to be swallowed whole and can not be chewed, broken, or crushed.
*Text that required subjects to fast overnight (for at least 8 hours) prior to blood
collection for biochemistry analysis was removed. For children and adolescents, aged 5-17 years, fasting was not required in this situation. |
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04 Aug 2010 |
*Efficacy data were updated to include protocol SPD476-304 and SPD476-404 study
results and SPD476-409 study start date.
*Safety data were updated to include the most frequently reported adverse drug reactions. |
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09 Feb 2011 |
*Text was added to reflect the addition of Eastern European countries.
*Text was added to concomitant medication section to allow for the administration of the influenza vaccine.
*Text was added to refer the reader to the current investigator’s brochure.
*Prescribing information was removed. |
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18 Aug 2011 |
*The selection of a primary investigator was added.
*An ECG assessment was added at screening and on Day 7 to meet European Regulatory Agency request.
*Text was revised to reflect a change in the participating Eastern European countries, and increase in the enrollment (and thus total study) period.
*The biochemistry and hematology blood sample collection was revised: the Day 7
pre-dose samples were removed and it was specified that if the baseline (Day -1)
assessment was within 21 days of screening, samples were not required. This lowered the total blood volume collected to approximately 43mL-51mL depending on subject visit scheduling. At no point during any 4-week period more than 43mL of blood was collected from a subject. The change was made to meet the European Union guidance that not more than 3% of total blood volume can be collected in a 4-week period.
*The need to record abnormal physical examination findings in the eCRF, unless they are clinically significant, was removed.
*Vital signs were revised such that they were only collected after being in a supine
position for 5 minutes, instead of sitting, to match ECG collection.
*Text was revised to clarify that only clinically significant changes in physical
examination and ECGs were captured (as AEs) and analyzed.
*The physical examination section was removed, as physical examination findings were not being captured in the eCRF unless they were reported as an AE or SAE. |
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04 Sep 2012 |
*The rationale text was updated to include reference to the Phase 3 efficacy and safety study.
*An error in exclusion criterion 4 was corrected (from L.73 to 1.73).
*Text in the dose group reference was corrected (from children
older than 6 years to older than 5 years).
*Labeling and packaging information was updated to include information for sites in Australia and the Russian Federation.
*Text was revised to better define the expectation for collection of AEs that may be related to the subject’s chronic disease.
*Text was revised to include an interim analysis.
*Name and contact details of the principal investigator were added. |
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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. | |||||||
| None reported | |||||||
