Clinical Trial Results:
A Phase 2, 24 Week, Open Label, Multi-Center Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of SSP-004184 (SPD602) in the Treatment of Chronic Iron Overload Requiring Chelation Therapy
Summary
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EudraCT number |
2011-005675-16 |
Trial protocol |
IT |
Global end of trial date |
18 Apr 2014
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Results information
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Results version number |
v1(current) |
This version publication date |
12 Oct 2019
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First version publication date |
25 Jul 2015
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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 |
SPD602-203
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01604941 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Shire Development LLC
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Sponsor organisation address |
300 Shire Way, Lexington, Massachusetts, United States, 02421
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Public contact |
Study Physician, Shire Development LLC, +1 866 842 5335,
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Scientific contact |
Study Physician, Shire Development LLC, +1 866 842 5335,
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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 |
18 Apr 2014
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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 |
18 Apr 2014
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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 |
To evaluate the steady-state pharmacokinetic parameters in subjects taking an SSP-004184AQ twice daily (BID) dose in the iron-overloaded population; to evaluate the changes in LIC after 12 and 24 weeks in subjects taking an SSP-004184AQ BID dose; and to assess the safety and tolerability of SSP-004184AQ when administered daily for 24 weeks in iron-overloaded subjects.
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Protection of trial subjects |
This study was conducted in accordance with the International Conference on Harmonisation (ICH) harmonised tripartite guideline E6(R1): Good Clinical Practice, the principles of the Declaration of Helsinki, as well as other applicable local ethical and legal requirements.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
14 Sep 2012
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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 |
Italy: 13
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Country: Number of subjects enrolled |
Canada: 4
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Country: Number of subjects enrolled |
Lebanon: 11
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Country: Number of subjects enrolled |
United States: 4
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Worldwide total number of subjects |
32
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EEA total number of subjects |
13
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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) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
32
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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 started as a double-arm study with once daily (QD) dosing but was amended first to a double-arm study with twice daily (BID) dosing and then to a single-arm study after removing the higher dose. Some participants were enrolled directly to BID dosing, some to QD dosing and then re-enrolled to BID dosing, some completed with QD dosing. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
Subjects were screened for enrollment over a period of 45 days | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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 |
Non-randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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SPD602 50mg/kg/day Twice Daily Dosing (BID) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Subjects were randomly assigned to 50 mg/kg/day oral BID dosing and continued BID dosing until the end of study (24 weeks) or early discontinuation. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
SPD602
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Investigational medicinal product code |
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Other name |
SSP-004184, FBS0701, deferitazole
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Pharmaceutical forms |
Capsule, hard
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects were administered a combination of 50, 100, 200, 250, or 375 mg capsules for a total dose of 50 mg/kg/day twice daily. Initial dosing was based on the subject’s weight at Day 1 or as close to Day 1 as possible (e.g., screening, baseline, a blood transfusion clinic visit prior to Day 1). If during the course of the study the subject’s weight differed from the weight used for Day 1 by more than 10%, the amount of SSP-004184AQ dispensed was to be corrected.
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Arm title
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SPD602 75mg/kg/day Twice Daily Dosing (BID) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Subjects were randomly assigned to 75 mg/kg/day oral BID dosing and continued BID dosing until the end of study (24 weeks) or early discontinuation. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
SPD602
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Investigational medicinal product code |
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Other name |
SSP-004184, FBS0701, deferitazole
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Pharmaceutical forms |
Capsule, hard
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects were administered a combination of 50, 100, 200, 250, or 375 mg capsules for a total dose of 75 mg/kg/day twice daily. Initial dosing was based on the subject’s weight at Day 1 or as close to Day 1 as possible (e.g., screening, baseline, a blood transfusion clinic visit prior to Day 1). If during the course of the study the subject’s weight differed from the weight used for Day 1 by more than 10%, the amount of SSP-004184AQ dispensed was to be corrected.
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Arm title
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SPD602 50mg/kg/day Once (QD) Then Twice Daily Dosing (BID) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Subjects were randomly assigned to QD dosing then re-enrolled to 50 mg/kg/day oral BID dosing and continued BID dosing until the end of study (24 weeks) or early discontinuation. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
SPD602
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Investigational medicinal product code |
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Other name |
SSP-004184, FBS0701, deferitazole
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Pharmaceutical forms |
Capsule, hard
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects were administered a combination of 50, 100, 200, 250, or 375 mg capsules for a total dose of 50 mg/kg/day once then twice daily. Initial dosing was based on the subject’s weight at Day 1 or as close to Day 1 as possible (e.g., screening, baseline, a blood transfusion clinic visit prior to Day 1). If during the course of the study the subject’s weight differed from the weight used for Day 1 by more than 10%, the amount of SSP-004184AQ dispensed was to be corrected.
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Arm title
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SPD602 75mg/kg/day Once (QD) Then Twice Daily Dosing (BID) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Subjects were randomly assigned to QD dosing then re-enrolled to 75 mg/kg/day oral BID dosing and continued BID dosing until the end of study (24 weeks) or early discontinuation. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
SPD602
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Investigational medicinal product code |
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Other name |
SSP-004184, FBS0701, deferitazole
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Pharmaceutical forms |
Capsule, hard
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects were administered a combination of 50, 100, 200, 250, or 375 mg capsules for a total dose of 75 mg/kg/day once then twice daily. Initial dosing was based on the subject’s weight at Day 1 or as close to Day 1 as possible (e.g., screening, baseline, a blood transfusion clinic visit prior to Day 1). If during the course of the study the subject’s weight differed from the weight used for Day 1 by more than 10%, the amount of SSP-004184AQ dispensed was to be corrected.
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Arm title
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SPD602 50mg/kg/day Once Daily Dosing (QD) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Subjects were randomly assigned to 50 mg/kg/day oral QD dosing and continued QD dosing until the end of study (24 weeks) or early discontinuation. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
SPD602
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Investigational medicinal product code |
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Other name |
SSP-004184, FBS0701, deferitazole
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Pharmaceutical forms |
Capsule, hard
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects were administered a combination of 50, 100, 200, 250, or 375 mg capsules for a total dose of 50 mg/kg/day once daily. Initial dosing was based on the subject’s weight at Day 1 or as close to Day 1 as possible (e.g., screening, baseline, a blood transfusion clinic visit prior to Day 1). If during the course of the study the subject’s weight differed from the weight used for Day 1 by more than 10%, the amount of SSP-004184AQ dispensed was to be corrected.
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Arm title
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SPD602 75mg/kg/day Once Daily Dosing (QD) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Subjects were randomly assigned to 75 mg/kg/day oral QD dosing and continued QD dosing until the end of study (24 weeks) or early discontinuation. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
SPD602
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Investigational medicinal product code |
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Other name |
SSP-004184, FBS0701, deferitazole
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Pharmaceutical forms |
Capsule, hard
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects were administered a combination of 50, 100, 200, 250, or 375 mg capsules for a total dose of 75 mg/kg/day once daily. Initial dosing was based on the subject’s weight at Day 1 or as close to Day 1 as possible (e.g., screening, baseline, a blood transfusion clinic visit prior to Day 1). If during the course of the study the subject’s weight differed from the weight used for Day 1 by more than 10%, the amount of SSP-004184AQ dispensed was to be corrected.
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Baseline characteristics reporting groups
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Reporting group title |
Overall Study
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Reporting group description |
All randomized subjects | |||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
SPD602 50mg/kg/day Twice Daily Dosing (BID)
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Reporting group description |
Subjects were randomly assigned to 50 mg/kg/day oral BID dosing and continued BID dosing until the end of study (24 weeks) or early discontinuation. | ||
Reporting group title |
SPD602 75mg/kg/day Twice Daily Dosing (BID)
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Reporting group description |
Subjects were randomly assigned to 75 mg/kg/day oral BID dosing and continued BID dosing until the end of study (24 weeks) or early discontinuation. | ||
Reporting group title |
SPD602 50mg/kg/day Once (QD) Then Twice Daily Dosing (BID)
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Reporting group description |
Subjects were randomly assigned to QD dosing then re-enrolled to 50 mg/kg/day oral BID dosing and continued BID dosing until the end of study (24 weeks) or early discontinuation. | ||
Reporting group title |
SPD602 75mg/kg/day Once (QD) Then Twice Daily Dosing (BID)
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Reporting group description |
Subjects were randomly assigned to QD dosing then re-enrolled to 75 mg/kg/day oral BID dosing and continued BID dosing until the end of study (24 weeks) or early discontinuation. | ||
Reporting group title |
SPD602 50mg/kg/day Once Daily Dosing (QD)
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Reporting group description |
Subjects were randomly assigned to 50 mg/kg/day oral QD dosing and continued QD dosing until the end of study (24 weeks) or early discontinuation. | ||
Reporting group title |
SPD602 75mg/kg/day Once Daily Dosing (QD)
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Reporting group description |
Subjects were randomly assigned to 75 mg/kg/day oral QD dosing and continued QD dosing until the end of study (24 weeks) or early discontinuation. | ||
Subject analysis set title |
SPD602 50mg/kg/Day
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Participants received SPD602 50mg/kg/day oral dosing either twice daily (BID) or once daily (QD), then BID.
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Subject analysis set title |
All participants with BID dosing
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Of the 21 subjects randomly assigned to BID dosing (including re-enrolled participants), 10 were excluded from the Full Analysis Set. Data for this arm were analyzed to verify that the protocol, as finally amended, was not impacted by using only the lower dose.
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End point title |
Change From Baseline in Liver Iron Concentration (LIC) as Assessed by FerriScan R2 Magnetic Resonance Imaging (MRI) [1] | ||||||||||||||||||
End point description |
The efficacy of SPD602 was assessed by determining LIC. Abdominal MRI data were collected by using FerriScan R2 standard procedures and used to determine LIC. A negative change from baseline indicates that LIC decreased. Early Termination was within the protocol defined visit date +/- 14 days window and was mapped to next scheduled MRI visit for 3 subjects.
This endpoint analyzed the Full Analysis Set (FAS), defined as all subjects in the Safety Set who had at least 1 post-baseline primary efficacy assessment. The Safety Set was defined as all subjects who had taken at least 1 BID dose of investigational product.
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End point type |
Primary
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End point timeframe |
Baseline, 12 and 24 weeks
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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: Differences for LIC were compared between baseline and post-baseline visits. No between-group comparisons were made as part of this study. |
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No statistical analyses for this end point |
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End point title |
Change From Baseline in LIC Adjusted by Transfusional Iron Intake And Assessed by FerriScan R2 MRI [2] | ||||||||||||||||||
End point description |
The efficacy of SPD602 was assessed by determining LIC and adjusting for transfusional iron intake. Abdominal MRI data were collected by using FerriScan R2 standard procedures and used to determine LIC. A negative change from baseline indicates that LIC decreased. For participants who had a blood transfusion on the MRI exam date, the blood transfusion done immediately prior to the MRI exam date was included in the calculation of daily transfusion intake. Early Termination was within the protocol defined visit date +/- 14 days window and was mapped to next scheduled MRI visit for 3 subjects.
This endpoint analyzed the FAS, defined as all subjects in the Safety Set who had at least 1 post-baseline primary efficacy assessment. The Safety Set was defined as all subjects who had taken at least 1 BID dose of investigational product.
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End point type |
Primary
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End point timeframe |
Baseline, 12 and 24 weeks
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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: Differences for LIC were compared between baseline and post-baseline visits. No between-group comparisons were made as part of this study. |
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No statistical analyses for this end point |
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End point title |
Change From Baseline in LIC as Assessed by R2* MRI | ||||||||||||||||||
End point description |
The efficacy of SPD602 was assessed by determining LIC. Abdominal MRI data were collected by using R2* standard procedures (liver and pancreas) and used to determine LIC. A negative change from baseline indicates that LIC decreased. Early Termination was within the protocol defined visit date +/- 14 days window and was mapped to next scheduled MRI visit for 3 subjects.
This endpoint analyzed the FAS, defined as all subjects in the Safety Set who had at least 1 post-baseline primary efficacy assessment. The Safety Set was defined as all subjects who had taken at least 1 BID dose of investigational product.
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End point type |
Secondary
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End point timeframe |
Baseline, 12 and 24 weeks
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No statistical analyses for this end point |
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End point title |
Change From Baseline in LIC Adjusted by Transfusional Iron Intake And Assessed by R2* MRI | ||||||||||||||||||
End point description |
The efficacy of SPD602 was assessed by determining LIC and adjusting for transfusional iron intake. Abdominal MRI data were collected by using R2* standard procedures (liver and pancreas) and used to determine LIC. A negative change from baseline indicates that LIC decreased. For participants who had a blood transfusion on the MRI exam date, the blood transfusion done immediately prior to the MRI exam date was included in the calculation of daily transfusion intake. Early Termination was within the protocol defined visit date +/- 14 days window and was mapped to next scheduled MRI visit for 3 subjects.
This endpoint analyzed the FAS, defined as all subjects in the Safety Set who had at least 1 post-baseline primary efficacy assessment. The Safety Set was defined as all subjects who had taken at least 1 BID dose of investigational product.
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End point type |
Secondary
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End point timeframe |
Baseline, 12 and 24 weeks
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No statistical analyses for this end point |
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End point title |
Change From Baseline in Cardiac T2* Relaxation Rate, an MRI Parameter Used to Estimate Cardiac Iron Load | ||||||||||||||||||
End point description |
The efficacy of SPD602 was assessed by estimating cardiac iron load. T2* data from cardiac MRI were collected by using standard procedures and used as an estimate of cardiac iron load. T2* is an MR relaxation parameter that is reported in milliseconds. Iron within a tissue decreases homogeneity of the magnetic field and shortens the T2* relaxation rate (Anderson, 2001). Low cardiac T2* values are associated with increased risk of heart failure (Kirk, 2009). A negative change from baseline in the T2* relaxation rate indicates that iron load increased. Early Termination was within the protocol defined visit date +/ 14 days window and was mapped to next scheduled MRI visit for 3 subjects.
This endpoint analyzed the FAS, defined as all subjects in the Safety Set who had at least 1 post-baseline primary efficacy assessment. The Safety Set was defined as all subjects who had taken at least 1 BID dose of investigational product.
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End point type |
Secondary
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End point timeframe |
Baseline, 12 and 24 weeks
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No statistical analyses for this end point |
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End point title |
Change From Baseline in Serum Ferritin | ||||||||||||||||||
End point description |
Serum ferritin levels were determined from serum biochemistry analyses. A negative change from baseline indicates that serum ferritin decreased.
This endpoint analyzed the FAS, defined as all subjects in the Safety Set who had at least 1 post-baseline primary efficacy assessment. The Safety Set was defined as all subjects who had taken at least 1 BID dose of investigational product.
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End point type |
Secondary
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End point timeframe |
Baseline, 8 and 16 weeks
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No statistical analyses for this end point |
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End point title |
Number of Participants Classified as a Responder by FerriScan R2 MRI Analysis of LIC | |||||||||||||||
End point description |
A responder was defined as a participant whose observed liver iron concentration (LIC) at the measured time point was less than the baseline value. LIC was assessed by abdominal MRI with the FerriScan R2 according to standard procedures. Early Termination was within the protocol defined visit date +/- 14 days window and was mapped to next scheduled MRI visit for 3 participants.
This endpoint analyzed the FAS, defined as all subjects in the Safety Set who had at least 1 post-baseline primary efficacy assessment. The Safety Set was defined as all subjects who had taken at least 1 BID dose of investigational product.
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End point type |
Secondary
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End point timeframe |
12 and 24 weeks
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No statistical analyses for this end point |
|
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End point title |
Number of Participants Classified as a Responder by FerriScan R2 MRI Analysis of LIC Adjusted For Transfusional Iron Intake | |||||||||||||||
End point description |
A responder was defined as a participant whose observed liver iron concentration (LIC) at the measured time point was less than the baseline value. LIC was assessed by abdominal MRI with the FerriScan R2 according to standard procedures, and the results were adjusted for transfusional iron intake. Early Termination was within the protocol defined visit date +/- 14 days window and was mapped to next scheduled MRI visit for 3 participants. For participants who had a blood transfusion on the MRI exam date, the blood transfusion done immediately prior to the MRI exam date was included in the calculation of daily transfusion intake.
This endpoint analyzed the FAS, defined as all subjects in the Safety Set who had at least 1 post-baseline primary efficacy assessment. The Safety Set was defined as all subjects who had taken at least 1 BID dose of investigational product.
|
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End point type |
Secondary
|
|||||||||||||||
End point timeframe |
12 and 24 weeks
|
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No statistical analyses for this end point |
|
||||||||||||||||
End point title |
Number of Participants Classified as a Responder by R2* MRI Analysis of LIC | |||||||||||||||
End point description |
A responder was defined as a participant whose observed liver iron concentration (LIC) at the measured time point was less than the baseline value. LIC was assessed by abdominal MRI with the R2* according to standard procedures (liver and pancreas). Early Termination was within the protocol defined visit date +/- 14 days window and was mapped to next scheduled MRI visit for 3 participants.
This endpoint analyzed the FAS, defined as all subjects in the Safety Set who had at least 1 post-baseline primary efficacy assessment. The Safety Set was defined as all subjects who had taken at least 1 BID dose of investigational product.
|
|||||||||||||||
End point type |
Secondary
|
|||||||||||||||
End point timeframe |
12 and 24 weeks
|
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|
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No statistical analyses for this end point |
|
||||||||||||||||
End point title |
Number of Participants Classified as a Responder by R2* MRI Analysis of LIC Adjusted For Transfusional Iron Intake | |||||||||||||||
End point description |
A responder was defined as a participant whose observed liver iron concentration (LIC) at the measured time point was less than the baseline value. LIC was assessed by abdominal MRI with the R2* according to standard procedures (liver and pancreas), and the results were adjusted for transfusional iron intake. Early Termination was within the protocol defined visit date +/- 14 days window and was mapped to next scheduled MRI visit for 3 participants. For participants who had a blood transfusion on the MRI exam date, the blood transfusion done immediately prior to the MRI exam date was included in the calculation of daily transfusion intake.
This endpoint analyzed the FAS, defined as all subjects in the Safety Set who had at least 1 post-baseline primary efficacy assessment. The Safety Set was defined as all subjects who had taken at least 1 BID dose of investigational product.
|
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End point type |
Secondary
|
|||||||||||||||
End point timeframe |
12 and 24 weeks
|
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No statistical analyses for this end point |
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End point title |
Number of Participants Classified as a Responder by Serum Ferritin | |||||||||||||||
End point description |
A responder was defined as a participant whose observed serum ferritin level at the measured time point was less than the baseline value. Serum ferritin levels were determined from serum biochemistry analyses.
This endpoint analyzed the FAS, defined as all subjects in the Safety Set who had at least 1 post-baseline primary efficacy assessment. The Safety Set was defined as all subjects who had taken at least 1 BID dose of investigational product.
|
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End point type |
Secondary
|
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End point timeframe |
8 and 16 weeks
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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 |
25 weeks
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Adverse event reporting additional description |
All safety analyses, including analyses of AEs, were based on the Safety Set, which included subjects in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Subjects in the QD only dosing groups were not included in the Safety Set.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
12.1
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Reporting groups
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Reporting group title |
SPD602 50mg/kg/day
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Reporting group description |
Participants received SPD602 50mg/kg/day oral dosing BID either as originally randomized or as a re-enrolled subject. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
SPD602 75mg/kg/Day
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Reporting group description |
Participants received SPD602 75mg/kg/day oral dosing BID either as originally randomized or as a re-enrolled subject. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
|||||||
Were there any global substantial amendments to the protocol? Yes | |||||||
Date |
Amendment |
||||||
29 Apr 2013 |
Summary of key changes:
- Increased the number of potential sites
- Revised the timeframe for non-directive questions to query subjects regarding AEs and the withdrawal criteria for subjects with protocol deviations/violations or related serious AEs
- Removed PK serum iron assessment
- Clarified the following: number of subjects for BID dosing; Endpoint 3; study population; use of liver and pancreas in R2* MRI; time and nature of end-of-treatment visit; start of screening procedures; subjects who have already consented and provided a DNA sample while under QD dosing were not asked for another; eligibility for another SPD602 study
- Changed the following: dosing regimen-QD to BID; Inclusion criteria 3, 7, and 9 and exclusion criterion 3; pre-visit timing of MRIs; baseline period
- Updated the following: MRI windows; study design; PK parameters; AE collection window; potential study duration; blood samples for plasma PK assessment; follow-up period for reporting pregnancies
-Added the following: cardiac (T2*) iron and left ventricular ejection fraction (LVEF) assessment, neurological examination; Exclusion Criterion 13; LVEF <50% to withdrawal criteria and subjects who are re-randomly assigned from QD to BID dosing will not be re-screened; subsections to explain modified baseline procedures for subjects’ re-randomly assigned to BID dosing; subjects who received QD dosing then BID dosing only needed to be re-assessed for Exclusion Criterion 13 and downward dose titration under QD dosing; to footnote b that MRI R2* was to be collected wherever possible; times of serum ferritin measurements; subsections on how to transition subjects on QD to BID dosing
- Specified the following: calculation and summary of LVEF and change from baseline to Weeks 12 and 24 by dose group; pancreatic iron concentrations from R2* MRI were to be listed and used as a safety signal; Safety Analysis Set; when subjects should be randomly assigned; time of LVEF |
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02 Oct 2013 |
Summary of key changes:
- Updated Exclusion Criterion 3 with removal of “chronic cholecystitis” to reflect Investigator’s Brochure Version 7.0.
- Updated Exclusion Criterion 5 with preliminary data from the completed SPD602-104 study that suggested a reduction in elimination of SPD602
in subjects with impaired renal function (estimated glomerular filtration rate <60mL/min, previously <40mL/min).
- Clarified that Exclusion Criterion 13 only applied to LVEF below (not outside) the locally determined normal range or in subjects with LVEF <50%.
- Clarified that echocardiograph was acceptable to assess LVEF if MRI information was not available.
- Added information regarding preliminary data indicating that SPD602 was an inducer of cytochrome P450 2B6 isozyme (CYP2B6) and
CYP3A4 in vitro and may have had potential drug interactions with these substrates in vivo.
- Amended Primary Endpoint 3 to include LVEF as an example parameter.
- Clarified that if a subject did not roll over to BID from QD he or she should have proceeded to the End-of-Treatment/Early Discontinuation Visit. |
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31 Jan 2014 |
Summary of key changes:
- Changed title to reflect single treatment-arm analysis.
- Specified sample size to enroll approximately 50 subjects to reach approximately 25 evaluable subjects enrolled at 50mg/kg/day administered BID dosing.
- Adjusted objectives to reflect single treatment-arm analysis.
- Removed the 75mg/kg/day treatment-arm to reflect single treatment-arm study and adjusted objectives, statistical endpoints, and analysis accordingly.
- Changed the maximum dosage allowed from 75 to 50mg/kg/day.
- Confirmed that subjects who were randomly assigned to 75mg/kg/day under the prior protocol version should immediately have their doses titrated downward to a total daily dose of 50mg/kg.
- Added safety laboratory tests to screen for any underlying metabolic abnormalities that could have contributed to the development of suspected PN-related events.
- Added guidance for evaluation of suspected PN-related events (including paresthesia and/or hypoesthesia) by investigators. Updated statistical endpoints and analysis to reflect single treatment-arm study design.
- Added PN to AEs for management of study toxicities.
- Clarified wording for AEs of potential interest in the event that subjects reported suspected PN-related events (including paresthesia or hypoesthesia).
- Allowed pharmacokinetic assessment to be conducted starting at Week 4. |
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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. | |||||||
This study was terminated early because of non-clinical safety results. As such, not all subjects completed the study. The available efficacy data were summarized and analyzed as specified in the SAP; however, no efficacy conclusions could be drawn. |