Safety, Efficacy and Pharmacokinetics of an Oral Iron Chelator Given for a Year to Pediatric Patients With Iron Overload

• ClinicalTrials.gov Identifier: NCT01363908
• Recruitment Status: Terminated
• First Posted: June 2, 2011
• Results First Posted: May 27, 2015
• Last Update Posted: June 14, 2021
• Sponsor: Shire
• Information provided by (Responsible Party): Takeda ( Shire )

• Study Type: Interventional
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Conditions: Transfusional Iron Overload; Beta-Thalassemia
• Intervention: Drug: SPD602
• Enrollment: 30

Participant Flow

Recruitment Details
Pre-assignment Details	The study consisted a pharmacokinetic (PK) phase and a chronic dosing (CD) phase. A sufficient number of participants were screened to enroll 16 participants into the PK phase (8 participants per age cohort). These participants could consent to participate in the CD phase. Additional participants also participated in the CD phase.

Arm/Group Title	6 to <12 Year Old	12 to <18 Year Old
Arm/Group Description	During the pharmacokinetic phase, participants aged 6 to less than 12 years received a single oral dose of SPD602 16mg/kg. During the chronic dosing phase, participants commenced 48 weeks of treatment with an initial dose of SPD602 26mg/kg/day or 36mg/kg/day. Over the course of treatment, the dose could range from 8-60mg/kg/day depending on clinical response.	During the pharmacokinetic phase, participants aged 12 to less than 18 years received a single oral dose of SPD602 16mg/kg. During the chronic dosing phase, participants commenced 48 weeks of treatment with an initial dose of SPD602 26mg/kg/day or 36mg/kg/day. Over the course of treatment, the dose could range from 8-60mg/kg/day depending on clinical response.
Period Title: Screening/Enrollment
Started	14	16
Completed	13 [1]	16
Not Completed	1	0
[1] One participant did not receive investigational product.
Period Title: Pharmacokinetic (PK) Phase
Started	8 [1]	8 [1]
Completed	8	8
Not Completed	0	0
[1] Per study design, at least 8 participants in each age cohort participated in the PK phase.
Period Title: Chronic Dosing (CD) Phase
Started	13 [1]	16 [1]
Completed	3	10
Not Completed	10	6
Reason Not Completed
Adverse Event	1	1
Patient decision	0	1
Physician Decision	0	1
Early study termination	9	3
[1] The CD phase enrolled willing participants who completed the PK phase plus additional participants.

Baseline Characteristics

Arm/Group Title		6 to <12 Year Old	12 to <18 Year Old	Total
Arm/Group Description		During the pharmacokinetic phase, participants aged 6 to less than 12 years received a single oral dose of SPD602 16mg/kg. During the chronic dosing phase, participants commenced 48 weeks of treatment with an initial dose of SPD602 26mg/kg/day or 36mg/kg/day. Over the course of treatment, the dose could range from 8-60mg/kg/day depending on clinical response.	During the pharmacokinetic phase, participants aged 12 to less than 18 years received a single oral dose of SPD602 16mg/kg. During the chronic dosing phase, participants commenced 48 weeks of treatment with an initial dose of SPD602 26mg/kg/day or 36mg/kg/day. Over the course of treatment, the dose could range from 8-60mg/kg/day depending on clinical response.	Total of all reporting groups
Overall Number of Baseline Participants		13	16	29
Baseline Analysis Population Description		The Safety Analysis Set, defined as all participants who had taken at least 1 dose of investigational product.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	13 participants	16 participants	29 participants
		8.6 (1.85)	14.4 (1.78)	11.8 (3.42)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	13 participants	16 participants	29 participants
	Female	7 53.8%	8 50.0%	15 51.7%
	Male	6 46.2%	8 50.0%	14 48.3%

Outcome Measures

1. Primary Outcome

Title	Maximum Observed Plasma Concentration (Cmax) of SPD602 After a Single Oral Dose
Description	The pharmacokinetic (PK) parameters of SPD602 were measured in plasma of all patients following a single capsule dose of SPD602 at 16 mg/kg at start of treatment on Day 1 and at the clinic visit on Day 2. PK blood samples were collected as follows: Pre-dose on Day 1 (within 60 minutes prior to investigational product administration) and at 0.5, 1, 2, 3, 4, 8 hours (±3 minutes) and 24 hours (±30 minutes) post-dose. Plasma concentrations of SPD602 were determined using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The PK parameters were determined from plasma concentration-time data for SPD602 (total) by non-compartmental analysis.
Time Frame	Day 1 and up to 24 hours post-dose

Outcome Measure Data

Analysis Population Description

The Pharmacokinetic (PK) set, defined as all participants in the Safety Analysis Set for whom the primary PK data were considered sufficient and interpretable. The Safety Analysis Set was defined as all participants who had taken at least 1 dose of investigational product. Treatment assignment was based on the treatment actually received.

Arm/Group Title	6 to <12 Year Old	12 to <18 Year Old
Arm/Group Description:	During the pharmacokinetic phase, participants aged 6 to less than 12 years received a single oral dose of SPD602 16mg/kg. During the chronic dosing phase, participants commenced 48 weeks of treatment with an initial dose of SPD602 26mg/kg/day or 36mg/kg/day. Over the course of treatment, the dose could range from 8-60mg/kg/day depending on clinical response.	During the pharmacokinetic phase, participants aged 12 to less than 18 years received a single oral dose of SPD602 16mg/kg. During the chronic dosing phase, participants commenced 48 weeks of treatment with an initial dose of SPD602 26mg/kg/day or 36mg/kg/day. Over the course of treatment, the dose could range from 8-60mg/kg/day depending on clinical response.
Overall Number of Participants Analyzed	8	8
Mean (Standard Deviation); Unit of Measure: ng/mL
	31737.5 (10116.74)	28300.0 (7309.88)

2. Primary Outcome

Title	Time of Maximum Observed Plasma Concentration Sampled During a Dosing Interval (Tmax) of SPD602 After a Single Oral Dose
Description	The pharmacokinetic (PK) parameters of SPD602 were measured in plasma of all patients following a single capsule dose of SPD602 at 16 mg/kg at start of treatment on Day 1 and at the clinic visit on Day 2. PK blood samples were collected as follows: Pre-dose on Day 1 (within 60 minutes prior to investigational product administration) and at 0.5, 1, 2, 3, 4, 8 hours (±3 minutes) and 24 hours (±30 minutes) post-dose. Plasma concentrations of SPD602 were determined using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The PK parameters were determined from plasma concentration-time data for SPD602 (total) by non-compartmental analysis.
Time Frame	Day 1 and up to 24 hours post-dose

Outcome Measure Data

Analysis Population Description

The PK set, defined as all participants in the Safety Analysis Set for whom the primary PK data were considered sufficient and interpretable.

Arm/Group Title	6 to <12 Year Old	12 to <18 Year Old
Arm/Group Description:	During the pharmacokinetic phase, participants aged 6 to less than 12 years received a single oral dose of SPD602 16mg/kg. During the chronic dosing phase, participants commenced 48 weeks of treatment with an initial dose of SPD602 26mg/kg/day or 36mg/kg/day. Over the course of treatment, the dose could range from 8-60mg/kg/day depending on clinical response.	During the pharmacokinetic phase, participants aged 12 to less than 18 years received a single oral dose of SPD602 16mg/kg. During the chronic dosing phase, participants commenced 48 weeks of treatment with an initial dose of SPD602 26mg/kg/day or 36mg/kg/day. Over the course of treatment, the dose could range from 8-60mg/kg/day depending on clinical response.
Overall Number of Participants Analyzed	8	8
Median (Full Range); Unit of Measure: hours
	1.0; (0.5 to 1.0)	1.0; (0.6 to 2.0)

3. Primary Outcome

Title	Area Under The Plasma Concentration-Time Curve (AUC) From The Time of Dosing to The Last Measurable Concentration (AUClast) of SPD602 After a Single Oral Dose
Description	The pharmacokinetic (PK) parameters of SPD602 were measured in plasma of all patients following a single capsule dose of SPD602 at 16 mg/kg at start of treatment on Day 1 and at the clinic visit on Day 2. PK blood samples were collected as follows: Pre-dose on Day 1 (within 60 minutes prior to investigational product administration) and at 0.5, 1, 2, 3, 4, 8 hours (±3 minutes) and 24 hours (±30 minutes) post-dose. Plasma concentrations of SPD602 were determined using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The PK parameters were determined from plasma concentration-time data for SPD602 (total) by non-compartmental analysis.
Time Frame	Day 1 and up to 24 hours post-dose

Outcome Measure Data

Analysis Population Description

The PK set, defined as all participants in the Safety Analysis Set for whom the primary PK data were considered sufficient and interpretable.

Arm/Group Title	6 to <12 Year Old	12 to <18 Year Old
Arm/Group Description:	During the pharmacokinetic phase, participants aged 6 to less than 12 years received a single oral dose of SPD602 16mg/kg. During the chronic dosing phase, participants commenced 48 weeks of treatment with an initial dose of SPD602 26mg/kg/day or 36mg/kg/day. Over the course of treatment, the dose could range from 8-60mg/kg/day depending on clinical response.	During the pharmacokinetic phase, participants aged 12 to less than 18 years received a single oral dose of SPD602 16mg/kg. During the chronic dosing phase, participants commenced 48 weeks of treatment with an initial dose of SPD602 26mg/kg/day or 36mg/kg/day. Over the course of treatment, the dose could range from 8-60mg/kg/day depending on clinical response.
Overall Number of Participants Analyzed	8	8
Mean (Standard Deviation); Unit of Measure: h*mg/L
	69.4 (27.39)	71.6 (22.70)

4. Primary Outcome

Title	Terminal Half-life (t1/2) of SPD602 After a Single Oral Dose
Description	The pharmacokinetic (PK) parameters of SPD602 were measured in plasma of all patients following a single capsule dose of SPD602 at 16 mg/kg at start of treatment on Day 1 and at the clinic visit on Day 2. PK blood samples were collected as follows: Pre-dose on Day 1 (within 60 minutes prior to investigational product administration) and at 0.5, 1, 2, 3, 4, 8 hours (±3 minutes) and 24 hours (±30 minutes) post-dose. Plasma concentrations of SPD602 were determined using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The PK parameters were determined from plasma concentration-time data for SPD602 (total) by non-compartmental analysis.
Time Frame	Day 1 and up to 24 hours post-dose

Outcome Measure Data

Analysis Population Description

The PK set, defined as all participants in the Safety Analysis Set for whom the primary PK data were considered sufficient and interpretable.

Arm/Group Title	6 to <12 Year Old	12 to <18 Year Old
Arm/Group Description:	During the pharmacokinetic phase, participants aged 6 to less than 12 years received a single oral dose of SPD602 16mg/kg. During the chronic dosing phase, participants commenced 48 weeks of treatment with an initial dose of SPD602 26mg/kg/day or 36mg/kg/day. Over the course of treatment, the dose could range from 8-60mg/kg/day depending on clinical response.	During the pharmacokinetic phase, participants aged 12 to less than 18 years received a single oral dose of SPD602 16mg/kg. During the chronic dosing phase, participants commenced 48 weeks of treatment with an initial dose of SPD602 26mg/kg/day or 36mg/kg/day. Over the course of treatment, the dose could range from 8-60mg/kg/day depending on clinical response.
Overall Number of Participants Analyzed	8	8
Mean (Standard Deviation); Unit of Measure: hours
	3.7 (0.93)	3.6 (0.97)

5. Primary Outcome

Title	Renal Clearance (CLr) of SPD602 After a Single Oral Dose
Description	The pharmacokinetic (PK) parameters of SPD602 were measured in urine of patients following a single capsule dose of SPD602 at 16 mg/kg at start of treatment on Day 1 and at the clinic visit on Day 2. Children who could cooperate provided urine samples for PK assessment on Day 1 over 3 time intervals: 0-4, 4-8, and 8-24 hours after the last dose (continued into Day 2). Urine concentrations of SPD602 were determined using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The PK parameters were determined from urine concentration-time data for SPD602 (total) by non-compartmental analysis.
Time Frame	Day 1 and up to 24 hours post-dose

Outcome Measure Data

Analysis Population Description

The PK set, defined as all participants in the Safety Analysis Set for whom the primary PK data were considered sufficient and interpretable.

Arm/Group Title	6 to <12 Year Old	12 to <18 Year Old
Arm/Group Description:	During the pharmacokinetic phase, participants aged 6 to less than 12 years received a single oral dose of SPD602 16mg/kg. During the chronic dosing phase, participants commenced 48 weeks of treatment with an initial dose of SPD602 26mg/kg/day or 36mg/kg/day. Over the course of treatment, the dose could range from 8-60mg/kg/day depending on clinical response.	During the pharmacokinetic phase, participants aged 12 to less than 18 years received a single oral dose of SPD602 16mg/kg. During the chronic dosing phase, participants commenced 48 weeks of treatment with an initial dose of SPD602 26mg/kg/day or 36mg/kg/day. Over the course of treatment, the dose could range from 8-60mg/kg/day depending on clinical response.
Overall Number of Participants Analyzed	8	8
Mean (Standard Deviation); Unit of Measure: L/h
	3.6 (2.06)	5.4 (2.38)

6. Primary Outcome

Title	Amount Excreted Into Urine (Ue) of SPD602 After a Single Oral Dose
Description	The pharmacokinetic (PK) parameters of SPD602 were measured in urine of patients following a single capsule dose of SPD602 at 16 mg/kg at start of treatment on Day 1 and at the clinic visit on Day 2. Children who could cooperate provided urine samples for PK assessment on Day 1 over 3 time intervals: 0-4, 4-8, and 8-24 hours after the last dose (continued into Day 2). Urine concentrations of SPD602 were determined using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The PK parameters were determined from urine concentration-time data for SPD602 (total) by non-compartmental analysis.
Time Frame	Day 1 and up to 24 hours post-dose

Outcome Measure Data

Analysis Population Description

The PK set, defined as all participants in the Safety Analysis Set for whom the primary PK data were considered sufficient and interpretable.

Arm/Group Title	6 to <12 Year Old	12 to <18 Year Old
Arm/Group Description:	During the pharmacokinetic phase, participants aged 6 to less than 12 years received a single oral dose of SPD602 16mg/kg. During the chronic dosing phase, participants commenced 48 weeks of treatment with an initial dose of SPD602 26mg/kg/day or 36mg/kg/day. Over the course of treatment, the dose could range from 8-60mg/kg/day depending on clinical response.	During the pharmacokinetic phase, participants aged 12 to less than 18 years received a single oral dose of SPD602 16mg/kg. During the chronic dosing phase, participants commenced 48 weeks of treatment with an initial dose of SPD602 26mg/kg/day or 36mg/kg/day. Over the course of treatment, the dose could range from 8-60mg/kg/day depending on clinical response.
Overall Number of Participants Analyzed	8	8
Mean (Standard Deviation); Unit of Measure: mg
	227.9 (107.44)	369.7 (140.17)

7. Primary Outcome

Title	Fraction Of Orally Administered Drug Excreted Unchanged In Urine (fe) of SPD602 After a Single Oral Dose
Description	The pharmacokinetic (PK) parameters of SPD602 were measured in urine of patients following a single capsule dose of SPD602 at 16 mg/kg at start of treatment on Day 1 and at the clinic visit on Day 2. Children who could cooperate provided urine samples for PK assessment on Day 1 over 3 time intervals: 0-4, 4-8, and 8-24 hours after the last dose (continued into Day 2). Urine concentrations of SPD602 were determined using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The PK parameters were determined from urine concentration-time data for SPD602 (total) by non-compartmental analysis.
Time Frame	Day 1 and up to 24 hours post-dose

Outcome Measure Data

Analysis Population Description

The PK set, defined as all participants in the Safety Analysis Set for whom the primary PK data were considered sufficient and interpretable.

Arm/Group Title	6 to <12 Year Old	12 to <18 Year Old
Arm/Group Description:	During the pharmacokinetic phase, participants aged 6 to less than 12 years received a single oral dose of SPD602 16mg/kg. During the chronic dosing phase, participants commenced 48 weeks of treatment with an initial dose of SPD602 26mg/kg/day or 36mg/kg/day. Over the course of treatment, the dose could range from 8-60mg/kg/day depending on clinical response.	During the pharmacokinetic phase, participants aged 12 to less than 18 years received a single oral dose of SPD602 16mg/kg. During the chronic dosing phase, participants commenced 48 weeks of treatment with an initial dose of SPD602 26mg/kg/day or 36mg/kg/day. Over the course of treatment, the dose could range from 8-60mg/kg/day depending on clinical response.
Overall Number of Participants Analyzed	8	8
Mean (Standard Deviation); Unit of Measure: percentage of total dose
	42.1 (14.34)	52.5 (20.52)

8. Primary Outcome

Title	Change From Baseline in Liver Iron Concentration (LIC) Assessed by FerriScan R2 Magnetic Resonance Imaging (MRI)
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.
Time Frame	Baseline, 24 weeks, and 48 weeks

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS), defined as all participants in the Safety Analysis Set who had at least 1 post-baseline primary efficacy assessment, which was considered as the LICs assessed from FerriScan R2 MRI.

Arm/Group Title	6 to <12 Year Old	12 to <18 Year Old
Arm/Group Description:	During the pharmacokinetic phase, participants aged 6 to less than 12 years received a single oral dose of SPD602 16mg/kg. During the chronic dosing phase, participants commenced 48 weeks of treatment with an initial dose of SPD602 26mg/kg/day or 36mg/kg/day. Over the course of treatment, the dose could range from 8-60mg/kg/day depending on clinical response.	During the pharmacokinetic phase, participants aged 12 to less than 18 years received a single oral dose of SPD602 16mg/kg. During the chronic dosing phase, participants commenced 48 weeks of treatment with an initial dose of SPD602 26mg/kg/day or 36mg/kg/day. Over the course of treatment, the dose could range from 8-60mg/kg/day depending on clinical response.
Overall Number of Participants Analyzed	10	15
Mean (Standard Deviation); Unit of Measure: mg Fe/g*dw
Week 24, n=7,15	-1.8 (2.8)	0.8 (2.7)
Week 48, n=2,10	0.8 (0.4)	-0.2 (1.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	6 to <12 Year Old
	Comments	Analysis of 6 to <12 year olds at 24 weeks
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0781
	Comments	The P-value was from the analysis of Wilcoxon signed rank test at post-treatment time point vs baseline.
	Method	Wilcoxon signed rank test
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	6 to <12 Year Old
	Comments	Analysis of 6 to <12 year olds at 48 weeks
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.5000
	Comments	The P-value was from the analysis of Wilcoxon signed rank test at post-treatment time point vs baseline.
	Method	Wilcoxon signed rank test
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	12 to <18 Year Old
	Comments	Analysis of 12 to <18 year olds at 24 weeks
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2609
	Comments	The P-value was from the analysis of Wilcoxon signed rank test at post-treatment time point vs baseline.
	Method	Wilcoxon signed rank test
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	12 to <18 Year Old
	Comments	Analysis of 12 to <18 year olds at 48 weeks
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.9219
	Comments	The P-value was from the analysis of Wilcoxon signed rank test at post-treatment time point vs baseline.
	Method	Wilcoxon signed rank test
	Comments	[Not Specified]

9. Primary Outcome

Title	Change From Baseline in LIC Adjusted by Transfusional Iron Intake And Assessed by FerriScan R2 MRI
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.
Time Frame	Baseline, 24 weeks, and 48 weeks

Outcome Measure Data

Analysis Population Description

The FAS, defined as all participants in the Safety Analysis Set who had at least 1 post-baseline primary efficacy assessment, which was considered as the LICs assessed from FerriScan R2 MRI.

Arm/Group Title	6 to <12 Year Old	12 to <18 Year Old
Arm/Group Description:	During the pharmacokinetic phase, participants aged 6 to less than 12 years received a single oral dose of SPD602 16mg/kg. During the chronic dosing phase, participants commenced 48 weeks of treatment with an initial dose of SPD602 26mg/kg/day or 36mg/kg/day. Over the course of treatment, the dose could range from 8-60mg/kg/day depending on clinical response.	During the pharmacokinetic phase, participants aged 12 to less than 18 years received a single oral dose of SPD602 16mg/kg. During the chronic dosing phase, participants commenced 48 weeks of treatment with an initial dose of SPD602 26mg/kg/day or 36mg/kg/day. Over the course of treatment, the dose could range from 8-60mg/kg/day depending on clinical response.
Overall Number of Participants Analyzed	10	15
Mean (Standard Deviation); Unit of Measure: mg Fe/g*dw
Week 24, n=7,15	-8.3 (3.7)	-4.0 (3.1)
Week 48, n=2,10	-13.7 (5.3)	-11.9 (5.4)

10. Secondary Outcome

Title	Change From Baseline in LIC Assessed by R2* MRI
Description	The efficacy of SPD602 was assessed by determining LIC. Abdominal MRI data were collected by using R2* standard procedures and used to determine LIC. A negative change from baseline indicates that LIC decreased.
Time Frame	Baseline, 24 weeks, and 48 weeks

Outcome Measure Data

Analysis Population Description

The FAS, defined as all participants in the Safety Analysis Set who had at least 1 post-baseline primary efficacy assessment, which was considered as the LICs assessed from FerriScan R2 MRI.

Arm/Group Title	6 to <12 Year Old	12 to <18 Year Old
Arm/Group Description:	During the pharmacokinetic phase, participants aged 6 to less than 12 years received a single oral dose of SPD602 16mg/kg. During the chronic dosing phase, participants commenced 48 weeks of treatment with an initial dose of SPD602 26mg/kg/day or 36mg/kg/day. Over the course of treatment, the dose could range from 8-60mg/kg/day depending on clinical response.	During the pharmacokinetic phase, participants aged 12 to less than 18 years received a single oral dose of SPD602 16mg/kg. During the chronic dosing phase, participants commenced 48 weeks of treatment with an initial dose of SPD602 26mg/kg/day or 36mg/kg/day. Over the course of treatment, the dose could range from 8-60mg/kg/day depending on clinical response.
Overall Number of Participants Analyzed	10	15
Mean (Standard Deviation); Unit of Measure: mg Fe/g*dw
Week 24, n=7,15	0.3 (1.7)	0.2 (1.4)
Week 48, n=3,10	0.6 (4.1)	0.3 (1.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	6 to <12 Year Old
	Comments	Analysis of 6 to <12 year olds at 24 weeks
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.6875
	Comments	The P-value was from analysis of Wilcoxon signed-rank test at post-treatment time point vs. baseline.
	Method	Wilcoxon signed-rank test
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	6 to <12 Year Old
	Comments	Analysis of 6 to <12 year olds at 48 weeks
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	1.0000
	Comments	The P-value was from analysis of Wilcoxon signed-rank test at post-treatment time point vs. baseline.
	Method	Wilcoxon signed-rank test
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	12 to <18 Year Old
	Comments	Analysis of 12 to <18 year olds at 24 weeks
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.8181
	Comments	The P-value was from analysis of Wilcoxon signed-rank test at post-treatment time point vs. baseline.
	Method	Wilcoxon signed-rank test
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	12 to <18 Year Old
	Comments	Analysis of 12 to <18 year olds at 48 weeks
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.5566
	Comments	P-value was from analysis of Wilcoxon signed-rank test at post-treatment time point vs. baseline.
	Method	Wilcoxon signed-rank
	Comments	[Not Specified]

11. Secondary Outcome

Title	Change From Baseline in LIC Adjusted by Transfusional Iron Intake And Assessed by R2* MRI
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 and used to determine LIC. A negative change from baseline indicates that LIC decreased.
Time Frame	Baseline, 24 weeks, and 48 weeks

Outcome Measure Data

Analysis Population Description

The FAS, defined as all participants in the Safety Analysis Set who had at least 1 post-baseline primary efficacy assessment, which was considered as the LICs assessed from FerriScan R2 MRI.

Arm/Group Title	6 to <12 Year Old	12 to <18 Year Old
Arm/Group Description:	During the pharmacokinetic phase, participants aged 6 to less than 12 years received a single oral dose of SPD602 16mg/kg. During the chronic dosing phase, participants commenced 48 weeks of treatment with an initial dose of SPD602 26mg/kg/day or 36mg/kg/day. Over the course of treatment, the dose could range from 8-60mg/kg/day depending on clinical response.	During the pharmacokinetic phase, participants aged 12 to less than 18 years received a single oral dose of SPD602 16mg/kg. During the chronic dosing phase, participants commenced 48 weeks of treatment with an initial dose of SPD602 26mg/kg/day or 36mg/kg/day. Over the course of treatment, the dose could range from 8-60mg/kg/day depending on clinical response.
Overall Number of Participants Analyzed	10	15
Mean (Standard Deviation); Unit of Measure: mg Fe/g*dw
Week 24, n=7,15	-6.2 (2.2)	-4.6 (3.4)
Week 48, n=3,10	-9.1 (5.6)	-11.4 (5.2)

12. Secondary Outcome

Title	Change From Baseline in Cardiac Iron Load Assessed by T2* MRI
Description	The efficacy of SPD602 was assessed by determining cardiac iron load. Cardiac MRI data were collected by using T2* standard procedures and used to determine iron load. A negative change from baseline indicates that iron load increased.
Time Frame	Baseline, 24 weeks, and 48 weeks

Outcome Measure Data

Analysis Population Description

The FAS, defined as all participants in the Safety Analysis Set who had at least 1 post-baseline primary efficacy assessment, which was considered as the LICs assessed from FerriScan R2 MRI.

Arm/Group Title	6 to <12 Year Old	12 to <18 Year Old
Arm/Group Description:	During the pharmacokinetic phase, participants aged 6 to less than 12 years received a single oral dose of SPD602 16mg/kg. During the chronic dosing phase, participants commenced 48 weeks of treatment with an initial dose of SPD602 26mg/kg/day or 36mg/kg/day. Over the course of treatment, the dose could range from 8-60mg/kg/day depending on clinical response.	During the pharmacokinetic phase, participants aged 12 to less than 18 years received a single oral dose of SPD602 16mg/kg. During the chronic dosing phase, participants commenced 48 weeks of treatment with an initial dose of SPD602 26mg/kg/day or 36mg/kg/day. Over the course of treatment, the dose could range from 8-60mg/kg/day depending on clinical response.
Overall Number of Participants Analyzed	10	15
Mean (Standard Deviation); Unit of Measure: milliseconds
Week 24, n=7,15	-9.63 (10.766)	-6.27 (13.731)
Week 48, n=3,10	-10.60 (20.893)	-9.40 (14.693)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	6 to <12 Year Old
	Comments	Analysis of 6 to <12 year olds at 24 weeks
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0475
	Comments	The P-value was from paired t test for log-transformed data at post-treatment time point vs. baseline.
	Method	paired t test
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	6 to <12 Year Old
	Comments	Analysis of 6 to <12 year olds at 48 weeks
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.4410
	Comments	The P-value was from paired t test for log-transformed data at post-treatment time point vs. baseline.
	Method	paired t test
	Comments	The P-value was from paired t test for log-transformed data at post-treatment time point vs. baseline.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	12 to <18 Year Old
	Comments	Analysis of 12 to <18 year olds at 24 weeks
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0417
	Comments	The P-value was from paired t test for log-transformed data at post-treatment time point vs. baseline.
	Method	paired t test
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	12 to <18 Year Old
	Comments	Analysis of 12 to <18 year olds at 48 weeks
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0409
	Comments	The P-value was from paired t test for log-transformed data at post-treatment time point vs. baseline.
	Method	paired t test
	Comments	[Not Specified]

13. Secondary Outcome

Title	Change From Baseline in Serum Ferritin
Description	Serum ferritin levels were assessed to determine if a participant was a successful responder and were determined from serum biochemistry analyses conducted at the central laboratories. A negative change from baseline indicates that serum ferritin decreased.
Time Frame	Baseline, 24 weeks, and 48 weeks

Outcome Measure Data

Analysis Population Description

The FAS, defined as all participants in the Safety Analysis Set who had at least 1 post-baseline primary efficacy assessment, which was considered as the LICs assessed from FerriScan R2 MRI.

Arm/Group Title	6 to <12 Year Old	12 to <18 Year Old
Arm/Group Description:	During the pharmacokinetic phase, participants aged 6 to less than 12 years received a single oral dose of SPD602 16mg/kg. During the chronic dosing phase, participants commenced 48 weeks of treatment with an initial dose of SPD602 26mg/kg/day or 36mg/kg/day. Over the course of treatment, the dose could range from 8-60mg/kg/day depending on clinical response.	During the pharmacokinetic phase, participants aged 12 to less than 18 years received a single oral dose of SPD602 16mg/kg. During the chronic dosing phase, participants commenced 48 weeks of treatment with an initial dose of SPD602 26mg/kg/day or 36mg/kg/day. Over the course of treatment, the dose could range from 8-60mg/kg/day depending on clinical response.
Overall Number of Participants Analyzed	10	15
Mean (Standard Deviation); Unit of Measure: ng/mL
Week 24, n=7,15	73.19 (706.423)	-981.49 (1694.314)
Week 48, n=3,10	-590.21 (843.249)	-1119.90 (1503.732)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	6 to <12 Year Old
	Comments	Analysis of 6 to <12 year olds at 24 weeks
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.9901
	Comments	The P-value was from paired t test for log-transformed data at post-treatment time point vs. baseline.
	Method	paired t test
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	6 to <12 Year Old
	Comments	Analysis of 6 to <12 year olds at 48 weeks
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.3039
	Comments	The P-value was from paired t test for log-transformed data at post-treatment time point vs. baseline.
	Method	paired t test
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	12 to <18 Year Old
	Comments	Analysis of 12 to <18 year olds at 24 weeks
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0044
	Comments	The P-value was from paired t test for log-transformed data at post-treatment time point vs. baseline.
	Method	paired t test
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	12 to <18 Year Old
	Comments	Analysis of 12 to <18 year olds at 48 weeks
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0395
	Comments	The P-value was from paired t test for log-transformed data at post-treatment time point vs. baseline.
	Method	paired t test
	Comments	[Not Specified]

Adverse Events

Time Frame	[Not Specified]
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	6 to <12 Year Old		12 to <18 Year Old
Arm/Group Description	During the pharmacokinetic phase, participants aged 6 to less than 12 years received a single oral dose of SPD602 16mg/kg. During the chronic dosing phase, participants commenced 48 weeks of treatment with an initial dose of SPD602 26mg/kg/day or 36mg/kg/day. Over the course of treatment, the dose could range from 8-60mg/kg/day depending on clinical response.		During the pharmacokinetic phase, participants aged 12 to less than 18 years received a single oral dose of SPD602 16mg/kg. During the chronic dosing phase, participants commenced 48 weeks of treatment with an initial dose of SPD602 26mg/kg/day or 36mg/kg/day. Over the course of treatment, the dose could range from 8-60mg/kg/day depending on clinical response.
All-Cause Mortality
	6 to <12 Year Old		12 to <18 Year Old
	Affected / at Risk (%)		Affected / at Risk (%)
Total	--/--		--/--
Serious Adverse Events
	6 to <12 Year Old		12 to <18 Year Old
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0.00%)		0/16 (0.00%)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	6 to <12 Year Old		12 to <18 Year Old
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/13 (100.00%)		15/16 (93.75%)
Blood and lymphatic system disorders
Anaemia † 1	1/13 (7.69%)	2	1/16 (6.25%)	4
Lymphadenopathy † 1	0/13 (0.00%)	0	1/16 (6.25%)	1
Neutropenia † 1	0/13 (0.00%)	0	3/16 (18.75%)	3
Ear and labyrinth disorders
Ear pain † 1	0/13 (0.00%)	0	1/16 (6.25%)	1
Hearing impaired † 1	1/13 (7.69%)	1	0/16 (0.00%)	0
Tinnitus † 1	0/13 (0.00%)	0	2/16 (12.50%)	5
Gastrointestinal disorders
Abdominal discomfort † 1	1/13 (7.69%)	1	0/16 (0.00%)	0
Abdominal pain † 1	4/13 (30.77%)	6	3/16 (18.75%)	7
Abdominal pain upper † 1	1/13 (7.69%)	1	0/16 (0.00%)	0
Constipation † 1	0/13 (0.00%)	0	2/16 (12.50%)	5
Diarrhoea † 1	2/13 (15.38%)	2	3/16 (18.75%)	3
Flatulence † 1	0/13 (0.00%)	0	1/16 (6.25%)	1
Nausea † 1	5/13 (38.46%)	6	2/16 (12.50%)	7
Vomiting † 1	4/13 (30.77%)	6	5/16 (31.25%)	5
General disorders
Asthenia † 1	1/13 (7.69%)	1	2/16 (12.50%)	2
Chest discomfort † 1	0/13 (0.00%)	0	1/16 (6.25%)	1
Chest pain † 1	1/13 (7.69%)	1	0/16 (0.00%)	0
Influenza like illness † 1	1/13 (7.69%)	2	2/16 (12.50%)	3
Pyrexia † 1	2/13 (15.38%)	2	5/16 (31.25%)	8
Infections and infestations
Bronchitis † 1	1/13 (7.69%)	1	0/16 (0.00%)	0
Gastroenteritis † 1	0/13 (0.00%)	0	2/16 (12.50%)	2
Hordeolum † 1	1/13 (7.69%)	1	0/16 (0.00%)	0
Influenza † 1	2/13 (15.38%)	2	1/16 (6.25%)	2
Molluscum contagiosum † 1	0/13 (0.00%)	0	1/16 (6.25%)	1
Nasopharyngitis † 1	1/13 (7.69%)	1	2/16 (12.50%)	2
Otitis externa † 1	0/13 (0.00%)	0	1/16 (6.25%)	1
Pharyngitis † 1	1/13 (7.69%)	1	2/16 (12.50%)	5
Pharyngitis streptococcal † 1	0/13 (0.00%)	0	1/16 (6.25%)	1
Rhinitis † 1	2/13 (15.38%)	3	1/16 (6.25%)	1
Sinusitis † 1	0/13 (0.00%)	0	1/16 (6.25%)	2
Tonsillitis † 1	1/13 (7.69%)	1	1/16 (6.25%)	1
Upper respiratory tract infection † 1	2/13 (15.38%)	2	1/16 (6.25%)	1
Urinary tract infection † 1	0/13 (0.00%)	0	1/16 (6.25%)	1
Injury, poisoning and procedural complications
Fall † 1	2/13 (15.38%)	2	0/16 (0.00%)	0
Foot fracture † 1	0/13 (0.00%)	0	1/16 (6.25%)	1
Head injury † 1	1/13 (7.69%)	1	0/16 (0.00%)	0
Joint injury † 1	1/13 (7.69%)	1	0/16 (0.00%)	0
Joint sprain † 1	1/13 (7.69%)	1	0/16 (0.00%)	0
Limb injury † 1	0/13 (0.00%)	0	1/16 (6.25%)	1
Skin laceration † 1	1/13 (7.69%)	1	0/16 (0.00%)	0
Investigations
Alanine aminotransferase increased † 1	1/13 (7.69%)	1	0/16 (0.00%)	0
Aspartate aminotransferase increased † 1	1/13 (7.69%)	1	0/16 (0.00%)	0
Glucose tolerance test abnormal † 1	0/13 (0.00%)	0	1/16 (6.25%)	1
Neutrophil count decreased † 1	0/13 (0.00%)	0	1/16 (6.25%)	3
Spleen palpable † 1	0/13 (0.00%)	0	1/16 (6.25%)	1
Transaminases increased † 1	0/13 (0.00%)	0	1/16 (6.25%)	1
White blood cell count decreased † 1	0/13 (0.00%)	0	1/16 (6.25%)	1
Metabolism and nutrition disorders
Folate deficiency † 1	0/13 (0.00%)	0	1/16 (6.25%)	1
Musculoskeletal and connective tissue disorders
Arthralgia † 1	3/13 (23.08%)	4	1/16 (6.25%)	1
Back pain † 1	1/13 (7.69%)	1	0/16 (0.00%)	0
Myalgia † 1	1/13 (7.69%)	1	0/16 (0.00%)	0
Osteochondrosis † 1	1/13 (7.69%)	1	0/16 (0.00%)	0
Pain in extremity † 1	0/13 (0.00%)	0	1/16 (6.25%)	1
Sensation of heaviness † 1	1/13 (7.69%)	1	0/16 (0.00%)	0
Nervous system disorders
Dizziness † 1	0/13 (0.00%)	0	1/16 (6.25%)	1
Head discomfort † 1	0/13 (0.00%)	0	1/16 (6.25%)	1
Headache † 1	4/13 (30.77%)	10	8/16 (50.00%)	13
Hypoaesthesia † 1	0/13 (0.00%)	0	1/16 (6.25%)	2
Hyporeflexia † 1	0/13 (0.00%)	0	1/16 (6.25%)	1
Muscle contractions involuntary † 1	0/13 (0.00%)	0	2/16 (12.50%)	3
Neuropathy peripheral † 1	0/13 (0.00%)	0	1/16 (6.25%)	1
Paraesthesia † 1	2/13 (15.38%)	3	1/16 (6.25%)	2
Peripheral sensory neuropathy † 1	1/13 (7.69%)	1	0/16 (0.00%)	0
Presyncope † 1	0/13 (0.00%)	0	1/16 (6.25%)	1
Sinus headache † 1	0/13 (0.00%)	0	1/16 (6.25%)	1
Psychiatric disorders
Insomnia † 1	0/13 (0.00%)	0	1/16 (6.25%)	1
Renal and urinary disorders
Chromaturia † 1	0/13 (0.00%)	0	1/16 (6.25%)	1
Reproductive system and breast disorders
Amenorrhoea † 1	0/13 (0.00%)	0	1/16 (6.25%)	1
Respiratory, thoracic and mediastinal disorders
Cough † 1	4/13 (30.77%)	7	0/16 (0.00%)	0
Nasal congestion † 1	1/13 (7.69%)	1	0/16 (0.00%)	0
Oropharyngeal pain † 1	5/13 (38.46%)	5	2/16 (12.50%)	3
Pharyngeal erythema † 1	1/13 (7.69%)	1	0/16 (0.00%)	0
Pharyngeal haemorrhage † 1	0/13 (0.00%)	0	1/16 (6.25%)	1
Productive cough † 1	0/13 (0.00%)	0	1/16 (6.25%)	1
Upper airway obstruction † 1	0/13 (0.00%)	0	1/16 (6.25%)	1
Wheezing † 1	1/13 (7.69%)	1	0/16 (0.00%)	0
Skin and subcutaneous tissue disorders
Blister † 1	0/13 (0.00%)	0	1/16 (6.25%)	1
Dry skin † 1	1/13 (7.69%)	1	0/16 (0.00%)	0
Rash † 1	1/13 (7.69%)	1	0/16 (0.00%)	0
Rash macular † 1	1/13 (7.69%)	2	0/16 (0.00%)	0
Skin haemorrhage † 1	0/13 (0.00%)	0	1/16 (6.25%)	1
Urticaria † 1	0/13 (0.00%)	0	1/16 (6.25%)	1
Vascular disorders
Haematoma † 1	0/13 (0.00%)	0	1/16 (6.25%)	1
Hyperaemia † 1	1/13 (7.69%)	1	1/16 (6.25%)	1
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA (12.1)

Limitations and Caveats

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.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

If a multicenter publication is not submitted within twelve (12) months after conclusion, abandonment or termination of the Study at all sites, or after Sponsor confirms there shall be no multicenter Study publication, the Institution and/or such Principal Investigator may publish the results from the Institution site individually.

Results Point of Contact

• Name/Title: Study Director
• Organization: Shire
• Phone: +1 866 842 5335
• EMail: ClinicalTransparency@shire.com

• Responsible Party: Takeda ( Shire )
• ClinicalTrials.gov Identifier: NCT01363908
• Other Study ID Numbers: SPD602-202; SSP-004184AQ ( Other Identifier: Shire )
• First Submitted: May 30, 2011
• First Posted: June 2, 2011
• Results First Submitted: May 6, 2015
• Results First Posted: May 27, 2015
• Last Update Posted: June 14, 2021