Beta-Thalassemia, Transfusional Iron Overload
Conditions
Keywords
Beta-Thalassemia, Sickle Cell Anemia, Transfusional iron overload, Iron Overload, Iron Chelation
Brief summary
This is an open-label study to assess the pharmacokinetics, safety, efficacy and tolerability of SSP-004184AQ. The study consists of two phases: the pharmacokinetic phase, using a single 16 mg/kg dose of SSP-004184AQ; and the chronic dosing phase, during which patients will receive an additional 48 weeks of SSP-004184AQ dosing. Two age groups will be studied: 6-\<12, and 12-\<18 years old. The study is designed to initially assess the pharmacokinetics and safety of SSP-004184AQ in older children (adolescents, 12-\<18 years old) and then if deemed safe, in younger children (6-\<12 years old).
Detailed description
Pharmacokinetic Phase: Patients will receive a single 16 mg/kg dose of SSP-004184AQ in capsule form. Chronic Dosing Phase: Patients will receive SSP-004184AQ capsules daily for 48 weeks. Doses may range from 8-60 mg/kg/d.
Interventions
DRUGSPD602
Sponsors
Shire
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Parents willing and able to sign the approved informed consent for their children and subjects between the ages of 6 and \<18 years willing and able to provide their assent (based on institutional guidelines). * Able to swallow whole capsules. * Age \>6 and \<18 years. * Transfusion-dependent subjects who have transfusional iron overload requiring chronic treatment with deferoxamine, deferasirox, or deferiprone. A transfusion dependent subject is defined in this study as one with a minimum transfusion history totaling more than 20 units of packed red blood cells OR a calculated iron load based on transfusion history of 200mg/kg AND a transfusion requirement of 7 or more transfusions per year; or, in subjects with sickle cell anemia, be iron overloaded but can be receiving transfusion exchange therapy in lieu of transfusions. * In the opinion of the Investigator (and in consultation with the subject's parents), the subject is able to discontinue all existing iron chelation therapies for a minimum period of 1-5 days prior first dose of SSP-004184AQ, for the initial pharmacokinetic period of 8 days (if applicable), and for up to 49 weeks if continuing into the chronic dosing phase. * Subjects able to have an MRI must have: 1. liver iron concentration \>2 and \<30mg/g (dry weight, liver) by FerriScan® R2 2. cardiac MRI T2\* \>10ms (Note: Subjects not able to have an MRI will be considered iron overloaded on the basis of serum ferritin only.) * Serum ferritin \>500ng/mL at Screening. * Mean of the previous 3 pre-transfusion hemoglobin concentrations greater than or equal to 7.5g/dL. * If appropriate, depending on age, female subjects of child-bearing potential need to use a medically acceptable method for birth control from screening until 30 days after the last dose of the study drug. Females of child-bearing potential must have a negative serum beta-HCG pregnancy test at the Screening Visit and a negative urine pregnancy test at the Baseline Visit. Females of child-bearing potential must agree to abstain from sexual activity that could result in pregnancy or agree to use acceptable methods of contraception.
Exclusion criteria
* As a result of medical review, physical examination (including height and weight) or Screening investigations, the Principal Investigator considers the subject unfit for the study. * Iron overload from causes other than transfusional hemosiderosis. * Severe cardiac dysfunction. * Non-elective hospitalization within the 30 days prior to Baseline testing. * Evidence of clinically significant oral, cardiovascular, gastrointestinal, hepatic, biliary, renal, endocrine, pulmonary, neurologic, psychiatric, or skin disorder that contra-indicates dosing with SSP-004184AQ. * Evidence of significant renal insufficiency, eg, serum creatinine above the upper limit of normal or proteinuria greater than 1 gm per day. * Known sensitivity to any ingredient in the SSP-004184AQ formulation. * Platelet count below 100,000/µL or absolute neutrophil count less than 1500/mm3 at Screening. * ALT \>180 IU/L at Screening. * Use of any investigational agent within the 30 days prior to Baseline testing. * Pregnant or lactating females. * Cardiac left ventricular ejection fraction a) Below the locally determined normal range in the 12 months prior to screening by echocardiography or MRI or \<50% at Baseline testing by MRI (echocardiograph is acceptable for LVEF if MRI information is not available).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in LIC Adjusted by Transfusional Iron Intake And Assessed by FerriScan R2 MRI | Baseline, 24 weeks, and 48 weeks | 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. |
| Renal Clearance (CLr) of SPD602 After a Single Oral Dose | Day 1 and up to 24 hours post-dose | 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. |
| Amount Excreted Into Urine (Ue) of SPD602 After a Single Oral Dose | Day 1 and up to 24 hours post-dose | 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. |
| Fraction Of Orally Administered Drug Excreted Unchanged In Urine (fe) of SPD602 After a Single Oral Dose | Day 1 and up to 24 hours post-dose | 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. |
| Change From Baseline in Liver Iron Concentration (LIC) Assessed by FerriScan R2 Magnetic Resonance Imaging (MRI) | Baseline, 24 weeks, and 48 weeks | 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. |
| Maximum Observed Plasma Concentration (Cmax) of SPD602 After a Single Oral Dose | Day 1 and up to 24 hours post-dose | 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 of Maximum Observed Plasma Concentration Sampled During a Dosing Interval (Tmax) of SPD602 After a Single Oral Dose | Day 1 and up to 24 hours post-dose | 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. |
| 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 | Day 1 and up to 24 hours post-dose | 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. |
| Terminal Half-life (t1/2) of SPD602 After a Single Oral Dose | Day 1 and up to 24 hours post-dose | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in LIC Adjusted by Transfusional Iron Intake And Assessed by R2* MRI | Baseline, 24 weeks, and 48 weeks | 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. |
| Change From Baseline in Cardiac Iron Load Assessed by T2* MRI | Baseline, 24 weeks, and 48 weeks | 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. |
| Change From Baseline in Serum Ferritin | Baseline, 24 weeks, and 48 weeks | 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. |
| Change From Baseline in LIC Assessed by R2* MRI | Baseline, 24 weeks, and 48 weeks | 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. |
Countries
Canada, Italy, Lebanon, Turkey (Türkiye), United States
Participant flow
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.
Participants by arm
| Arm | Count |
|---|---|
| 6 to <12 Year Old 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. | 13 |
| 12 to <18 Year Old 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. | 16 |
| Total | 29 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Chronic Dosing (CD) Phase | Adverse Event | 1 | 1 |
| Chronic Dosing (CD) Phase | Early study termination | 9 | 3 |
| Chronic Dosing (CD) Phase | Patient decision | 0 | 1 |
| Chronic Dosing (CD) Phase | Physician Decision | 0 | 1 |
Baseline characteristics
| Characteristic | 6 to <12 Year Old | 12 to <18 Year Old | Total |
|---|---|---|---|
| Age, Continuous | 8.6 years STANDARD_DEVIATION 1.85 | 14.4 years STANDARD_DEVIATION 1.78 | 11.8 years STANDARD_DEVIATION 3.42 |
| Sex: Female, Male Female | 7 Participants | 8 Participants | 15 Participants |
| Sex: Female, Male Male | 6 Participants | 8 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 13 / 13 | 15 / 16 |
| serious Total, serious adverse events | 0 / 13 | 0 / 16 |
Outcome results
Primary
Amount Excreted Into Urine (Ue) of SPD602 After a Single Oral Dose
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
Population: The PK set, defined as all participants in the Safety Analysis Set for whom the primary PK data were considered sufficient and interpretable.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 6 to <12 Year Old | Amount Excreted Into Urine (Ue) of SPD602 After a Single Oral Dose | 227.9 mg | Standard Deviation 107.44 |
| 12 to <18 Year Old | Amount Excreted Into Urine (Ue) of SPD602 After a Single Oral Dose | 369.7 mg | Standard Deviation 140.17 |
Primary
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
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
Population: The PK set, defined as all participants in the Safety Analysis Set for whom the primary PK data were considered sufficient and interpretable.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 6 to <12 Year Old | 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 | 69.4 h*mg/L | Standard Deviation 27.39 |
| 12 to <18 Year Old | 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 | 71.6 h*mg/L | Standard Deviation 22.7 |
Primary
Change From Baseline in LIC Adjusted by Transfusional Iron Intake And Assessed by FerriScan R2 MRI
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
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 6 to <12 Year Old | Change From Baseline in LIC Adjusted by Transfusional Iron Intake And Assessed by FerriScan R2 MRI | Week 24, n=7,15 | -8.3 mg Fe/g*dw | Standard Deviation 3.7 |
| 6 to <12 Year Old | Change From Baseline in LIC Adjusted by Transfusional Iron Intake And Assessed by FerriScan R2 MRI | Week 48, n=2,10 | -13.7 mg Fe/g*dw | Standard Deviation 5.3 |
| 12 to <18 Year Old | Change From Baseline in LIC Adjusted by Transfusional Iron Intake And Assessed by FerriScan R2 MRI | Week 24, n=7,15 | -4.0 mg Fe/g*dw | Standard Deviation 3.1 |
| 12 to <18 Year Old | Change From Baseline in LIC Adjusted by Transfusional Iron Intake And Assessed by FerriScan R2 MRI | Week 48, n=2,10 | -11.9 mg Fe/g*dw | Standard Deviation 5.4 |
Primary
Change From Baseline in Liver Iron Concentration (LIC) Assessed by FerriScan R2 Magnetic Resonance Imaging (MRI)
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
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 6 to <12 Year Old | Change From Baseline in Liver Iron Concentration (LIC) Assessed by FerriScan R2 Magnetic Resonance Imaging (MRI) | Week 24, n=7,15 | -1.8 mg Fe/g*dw | Standard Deviation 2.8 |
| 6 to <12 Year Old | Change From Baseline in Liver Iron Concentration (LIC) Assessed by FerriScan R2 Magnetic Resonance Imaging (MRI) | Week 48, n=2,10 | 0.8 mg Fe/g*dw | Standard Deviation 0.4 |
| 12 to <18 Year Old | Change From Baseline in Liver Iron Concentration (LIC) Assessed by FerriScan R2 Magnetic Resonance Imaging (MRI) | Week 24, n=7,15 | 0.8 mg Fe/g*dw | Standard Deviation 2.7 |
| 12 to <18 Year Old | Change From Baseline in Liver Iron Concentration (LIC) Assessed by FerriScan R2 Magnetic Resonance Imaging (MRI) | Week 48, n=2,10 | -0.2 mg Fe/g*dw | Standard Deviation 1.8 |
Comparison: Analysis of 6 to \<12 year olds at 24 weeksp-value: 0.0781Wilcoxon signed rank test
Comparison: Analysis of 6 to \<12 year olds at 48 weeksp-value: 0.5Wilcoxon signed rank test
Comparison: Analysis of 12 to \<18 year olds at 24 weeksp-value: 0.2609Wilcoxon signed rank test
Comparison: Analysis of 12 to \<18 year olds at 48 weeksp-value: 0.9219Wilcoxon signed rank test
Primary
Fraction Of Orally Administered Drug Excreted Unchanged In Urine (fe) of SPD602 After a Single Oral Dose
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
Population: The PK set, defined as all participants in the Safety Analysis Set for whom the primary PK data were considered sufficient and interpretable.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 6 to <12 Year Old | Fraction Of Orally Administered Drug Excreted Unchanged In Urine (fe) of SPD602 After a Single Oral Dose | 42.1 percentage of total dose | Standard Deviation 14.34 |
| 12 to <18 Year Old | Fraction Of Orally Administered Drug Excreted Unchanged In Urine (fe) of SPD602 After a Single Oral Dose | 52.5 percentage of total dose | Standard Deviation 20.52 |
Primary
Maximum Observed Plasma Concentration (Cmax) of SPD602 After a Single Oral Dose
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 6 to <12 Year Old | Maximum Observed Plasma Concentration (Cmax) of SPD602 After a Single Oral Dose | 31737.5 ng/mL | Standard Deviation 10116.74 |
| 12 to <18 Year Old | Maximum Observed Plasma Concentration (Cmax) of SPD602 After a Single Oral Dose | 28300.0 ng/mL | Standard Deviation 7309.88 |
Primary
Renal Clearance (CLr) of SPD602 After a Single Oral Dose
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
Population: The PK set, defined as all participants in the Safety Analysis Set for whom the primary PK data were considered sufficient and interpretable.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 6 to <12 Year Old | Renal Clearance (CLr) of SPD602 After a Single Oral Dose | 3.6 L/h | Standard Deviation 2.06 |
| 12 to <18 Year Old | Renal Clearance (CLr) of SPD602 After a Single Oral Dose | 5.4 L/h | Standard Deviation 2.38 |
Primary
Terminal Half-life (t1/2) of SPD602 After a Single Oral Dose
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
Population: The PK set, defined as all participants in the Safety Analysis Set for whom the primary PK data were considered sufficient and interpretable.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 6 to <12 Year Old | Terminal Half-life (t1/2) of SPD602 After a Single Oral Dose | 3.7 hours | Standard Deviation 0.93 |
| 12 to <18 Year Old | Terminal Half-life (t1/2) of SPD602 After a Single Oral Dose | 3.6 hours | Standard Deviation 0.97 |
Primary
Time of Maximum Observed Plasma Concentration Sampled During a Dosing Interval (Tmax) of SPD602 After a Single Oral Dose
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
Population: The PK set, defined as all participants in the Safety Analysis Set for whom the primary PK data were considered sufficient and interpretable.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 6 to <12 Year Old | Time of Maximum Observed Plasma Concentration Sampled During a Dosing Interval (Tmax) of SPD602 After a Single Oral Dose | 1.0 hours |
| 12 to <18 Year Old | Time of Maximum Observed Plasma Concentration Sampled During a Dosing Interval (Tmax) of SPD602 After a Single Oral Dose | 1.0 hours |
Secondary
Change From Baseline in Cardiac Iron Load Assessed by T2* MRI
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
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 6 to <12 Year Old | Change From Baseline in Cardiac Iron Load Assessed by T2* MRI | Week 24, n=7,15 | -9.63 milliseconds | Standard Deviation 10.766 |
| 6 to <12 Year Old | Change From Baseline in Cardiac Iron Load Assessed by T2* MRI | Week 48, n=3,10 | -10.60 milliseconds | Standard Deviation 20.893 |
| 12 to <18 Year Old | Change From Baseline in Cardiac Iron Load Assessed by T2* MRI | Week 24, n=7,15 | -6.27 milliseconds | Standard Deviation 13.731 |
| 12 to <18 Year Old | Change From Baseline in Cardiac Iron Load Assessed by T2* MRI | Week 48, n=3,10 | -9.40 milliseconds | Standard Deviation 14.693 |
Comparison: Analysis of 6 to \<12 year olds at 24 weeksp-value: 0.0475paired t test
Comparison: Analysis of 6 to \<12 year olds at 48 weeksp-value: 0.441paired t test
Comparison: Analysis of 12 to \<18 year olds at 24 weeksp-value: 0.0417paired t test
Comparison: Analysis of 12 to \<18 year olds at 48 weeksp-value: 0.0409paired t test
Secondary
Change From Baseline in LIC Adjusted by Transfusional Iron Intake And Assessed by R2* MRI
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
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 6 to <12 Year Old | Change From Baseline in LIC Adjusted by Transfusional Iron Intake And Assessed by R2* MRI | Week 24, n=7,15 | -6.2 mg Fe/g*dw | Standard Deviation 2.2 |
| 6 to <12 Year Old | Change From Baseline in LIC Adjusted by Transfusional Iron Intake And Assessed by R2* MRI | Week 48, n=3,10 | -9.1 mg Fe/g*dw | Standard Deviation 5.6 |
| 12 to <18 Year Old | Change From Baseline in LIC Adjusted by Transfusional Iron Intake And Assessed by R2* MRI | Week 24, n=7,15 | -4.6 mg Fe/g*dw | Standard Deviation 3.4 |
| 12 to <18 Year Old | Change From Baseline in LIC Adjusted by Transfusional Iron Intake And Assessed by R2* MRI | Week 48, n=3,10 | -11.4 mg Fe/g*dw | Standard Deviation 5.2 |
Secondary
Change From Baseline in LIC Assessed by R2* MRI
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
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 6 to <12 Year Old | Change From Baseline in LIC Assessed by R2* MRI | Week 24, n=7,15 | 0.3 mg Fe/g*dw | Standard Deviation 1.7 |
| 6 to <12 Year Old | Change From Baseline in LIC Assessed by R2* MRI | Week 48, n=3,10 | 0.6 mg Fe/g*dw | Standard Deviation 4.1 |
| 12 to <18 Year Old | Change From Baseline in LIC Assessed by R2* MRI | Week 24, n=7,15 | 0.2 mg Fe/g*dw | Standard Deviation 1.4 |
| 12 to <18 Year Old | Change From Baseline in LIC Assessed by R2* MRI | Week 48, n=3,10 | 0.3 mg Fe/g*dw | Standard Deviation 1.9 |
Comparison: Analysis of 6 to \<12 year olds at 24 weeksp-value: 0.6875Wilcoxon signed-rank test
Comparison: Analysis of 6 to \<12 year olds at 48 weeksp-value: 1Wilcoxon signed-rank test
Comparison: Analysis of 12 to \<18 year olds at 24 weeksp-value: 0.8181Wilcoxon signed-rank test
Comparison: Analysis of 12 to \<18 year olds at 48 weeksp-value: 0.5566Wilcoxon signed-rank
Secondary
Change From Baseline in Serum Ferritin
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
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 6 to <12 Year Old | Change From Baseline in Serum Ferritin | Week 24, n=7,15 | 73.19 ng/mL | Standard Deviation 706.423 |
| 6 to <12 Year Old | Change From Baseline in Serum Ferritin | Week 48, n=3,10 | -590.21 ng/mL | Standard Deviation 843.249 |
| 12 to <18 Year Old | Change From Baseline in Serum Ferritin | Week 24, n=7,15 | -981.49 ng/mL | Standard Deviation 1694.314 |
| 12 to <18 Year Old | Change From Baseline in Serum Ferritin | Week 48, n=3,10 | -1119.90 ng/mL | Standard Deviation 1503.732 |
Comparison: Analysis of 6 to \<12 year olds at 24 weeksp-value: 0.9901paired t test
Comparison: Analysis of 6 to \<12 year olds at 48 weeksp-value: 0.3039paired t test
Comparison: Analysis of 12 to \<18 year olds at 24 weeksp-value: 0.0044paired t test
Comparison: Analysis of 12 to \<18 year olds at 48 weeksp-value: 0.0395paired t test