Pharmacokinetics of SSP-004184 in the Treatment of Chronic Iron Overload Requiring Chelation Therapy
Study Details
Study Description
Brief Summary
The purpose of this study is to evaluate SSP-004184AQ in patients with transfusional iron overload whose primary diagnosis is hereditary or congenital anemia.
SSP-004184AQ is an iron chelator under development for chronic daily oral administration to patients with transfusional iron overload.
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
Phase 2 |
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
Experimental: SPD602 50 mg/kg/day orally twice daily for 24 weeks |
Drug: SPD602
50 mg/kg/day orally twice daily for 24 weeks
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Change From Baseline in Liver Iron Concentration (LIC) as Assessed by FerriScan R2 Magnetic Resonance Imaging (MRI) [Baseline, 12 and 24 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. Early Termination was within the protocol defined visit date +/- 14 days window and was mapped to next scheduled MRI visit for 3 participants.
- Change From Baseline in LIC Adjusted by Transfusional Iron Intake And Assessed by FerriScan R2 MRI [Baseline, 12 and 24 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. 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 participants.
Secondary Outcome Measures
- Change From Baseline in LIC as Assessed by R2* MRI [Baseline, 12 and 24 weeks]
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 participants.
- Change From Baseline in LIC Adjusted by Transfusional Iron Intake And Assessed by R2* MRI [Baseline, 12 and 24 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 (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 participants.
- Change From Baseline in Cardiac T2* Relaxation Rate, an MRI Parameter Used to Estimate Cardiac Iron Load [Baseline, 12 and 24 weeks]
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 participants.
- Change From Baseline in Serum Ferritin [Baseline, 8 and 16 weeks]
Serum ferritin levels were determined from serum biochemistry analyses. A negative change from baseline indicates that serum ferritin decreased.
- Number of Participants Classified as a Responder by FerriScan R2 MRI Analysis of LIC [12 and 24 weeks]
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.
- Number of Participants Classified as a Responder by FerriScan R2 MRI Analysis of LIC Adjusted For Transfusional Iron Intake [12 and 24 weeks]
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.
- Number of Participants Classified as a Responder by R2* MRI Analysis of LIC [12 and 24 weeks]
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.
- Number of Participants Classified as a Responder by R2* MRI Analysis of LIC Adjusted For Transfusional Iron Intake [12 and 24 weeks]
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.
- Number of Participants Classified as a Responder by Serum Ferritin [8 and 16 weeks]
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.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Willing and able to sign the approved informed consent.
-
Age: 18-60 years old, inclusive, at Screening.
-
Subjects who have received more than 20 transfusions in their lifetime and who have transfusional iron overload requiring chronic treatment with an iron chelator. N.B.: Sickle Cell Disease subjects receiving regular exchange transfusions and iron overloaded subjects with thalassemia intermedia who are receiving regular transfusions (transfusion dependent thalassemia intermedia) are eligible.
-
Willing to discontinue all existing iron chelation therapies for a minimum period of one to five days prior to first dose of SSP-004184AQ, the 24 week duration of the study and 1 week after last dose for a total of approximately 26 weeks.
-
Willing to fast two hours prior to and one hour after each dose.
-
Serum ferritin >500ng/mL at Screening.
-
Baseline liver iron concentration is greater than or equal to 5mg iron per g (equivalent dry weight, liver)determined by FerriScan® R2 MRI.
-
Mean of the previous three pre-transfusion hemoglobin concentrations is greater than or equal to 7.5g/dL.
-
Adult female subjects should be:
-
Post-menopausal (12 consecutive months of spontaneous amenorrhea), or
-
Surgically sterile, or
-
Females of child-bearing potential must have a negative 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, or Screening investigations, the Principal Investigator (PI) considers the subject unfit for the study.
-
Non-elective hospitalization within the 30 days prior to Baseline testing.
-
Evidence of clinically relevant oral, cardiovascular, gastrointestinal, hepatic, biliary, renal, endocrine, pulmonary, neurologic, psychiatric, immunologic, bone marrow, or skin disorder that contraindicates dosing with SSP-004184AQ.
-
Iron overload from causes other than transfusional siderosis.
-
Evidence of severe renal insufficiency, eg, serum creatinine 1.5X above the upper limit of normal or proteinuria greater than 1 gm per day or a calculated glomerular filtration rate <60mL/min.
-
Severe iron overload including:
-
T2* MRI <10 ms
-
liver iron concentration by FerriScan R2 MRI >30mg/g liver (dw)
-
Known sensitivity to magnesium stearate, croscarmellose sodium or SSP-004184AQ.
-
Platelet count below 100,000/μL or absolute neutrophil count less than 1500/mm3 at Screening.
-
Insufficient venous access that precludes prescribed blood draws for safety laboratory assessments.
-
ALT at Screening >200 IU/L.
-
Use of any investigational agent within the 30 days prior to the Baseline testing.
-
Pregnant or lactating females.
-
Cardiac left ventricular ejection fraction
-
Below the locally determined normal range in the 12 months prior to Screening by echocardiograph or MRI or
-
<50% at Baseline testing by MRI (echocardiograph is acceptable for LVEF if MRI information is not available).
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | Children's Center for Cancer and Blood Diseases | Los Angeles | California | United States | 90027 |
2 | Ann & Robert H. Lurie Children's Hospital of Chicago | Chicago | Illinois | United States | 60611 |
3 | Weill Cornell Medical College | New York | New York | United States | 10065 |
4 | Children's Hospital of Philadelphia | Philadelphia | Pennsylvania | United States | 19104 |
5 | Toronto General Hospital | Toronto | Ontario | Canada | M5G 2C4 |
6 | Ain Shams University Pediatric Hospitals | Cairo | Egypt | ||
7 | Cairo University Pediatric Hospitals | Cairo | Egypt | ||
8 | Centro della Microcitemia e delle Anemie Congenite | Genova | Genoa | Italy | 16128 |
9 | San Luigi Hospital Thalassemia Centre | Orbassano | Torino | Italy | 10043 |
10 | Ospedale Regionale Microcitemie | Cagliari | Italy | 09121 | |
11 | Ospedale Maggiore Policlinico | Milan | Italy | 20122 | |
12 | American University of Beirut Medical Center | Beirut | Lebanon |
Sponsors and Collaborators
- Shire
Investigators
- Study Director: Study Director, Takeda
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- SPD602-203
- FBS0701-CTP-16
- 2011-005675-16
Study Results
Participant Flow
Recruitment Details | |
---|---|
Pre-assignment Detail | 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. |
Arm/Group Title | SPD602 50mg/mg/Day Twice Daily Dosing (BID) | SPD602 75mg/kg/Day Twice Daily Dosing (BID) | SPD602 50mg/kg/Day Once (QD) Then Twice Daily Dosing (BID) | SPD602 75mg/kg/Day Once (QD) Then Twice Daily Dosing (BID) | SPD602 50mg/kg/Day Once Daily Dosing (QD) | SPD602 75mg/kg/Day Once Daily Dosing (QD) |
---|---|---|---|---|---|---|
Arm/Group Description | Participants 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. | Participants 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. | Participants 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. | Participants 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. | Participants 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. | Participants 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. |
Period Title: Overall Study | ||||||
STARTED | 11 | 4 | 3 | 3 | 4 | 7 |
COMPLETED | 0 | 0 | 0 | 0 | 3 | 0 |
NOT COMPLETED | 11 | 4 | 3 | 3 | 1 | 7 |
Baseline Characteristics
Arm/Group Title | SPD602 50mg/kg/Day | SPD602 75mg/kg/Day | Total |
---|---|---|---|
Arm/Group Description | Participants received SPD602 50mg/kg/day oral dosing either twice daily (BID) or once daily (QD), then BID. | Participants received SPD602 75mg/kg/day oral dosing either twice daily (BID) or once daily (QD), then BID. | Total of all reporting groups |
Overall Participants | 12 | 7 | 19 |
Age (years) [Mean (Standard Deviation) ] | |||
Mean (Standard Deviation) [years] |
28.3
(5.79)
|
24.4
(5.80)
|
26.8
(5.94)
|
Sex: Female, Male (Count of Participants) | |||
Female |
8
66.7%
|
5
71.4%
|
13
68.4%
|
Male |
4
33.3%
|
2
28.6%
|
6
31.6%
|
Outcome Measures
Title | Change From Baseline in Liver Iron Concentration (LIC) as 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. Early Termination was within the protocol defined visit date +/- 14 days window and was mapped to next scheduled MRI visit for 3 participants. |
Time Frame | Baseline, 12 and 24 weeks |
Outcome Measure Data
Analysis Population Description |
---|
The Full Analysis Set, defined as all participants in the Safety Set who had at least 1 post-baseline primary efficacy assessment. The Safety Set was defined as all participants who had taken at least 1 BID dose of investigational product. |
Arm/Group Title | SPD602 50 mg/kg/d | All Participants With BID Dosing |
---|---|---|
Arm/Group Description | Participants received SPD602 50mg/kg/day oral dosing either twice daily (BID) or once daily (QD), then BID. | Of the 21 participants 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. |
Measure Participants | 5 | 11 |
Week 12, n=5,10 |
-3.4
(6.4)
|
-3.8
(5.0)
|
Week 24, n=1,2 |
-5.3
(NA)
|
-2.1
(4.5)
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | SPD602 50 mg/kg/d |
---|---|---|
Comments | Analysis of Week 12 for 50 mg/kg/d dosing | |
Type of Statistical Test | Superiority or Other (legacy) | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.2960 |
Comments | The P-value is from analysis of paired t-test at post treatment timepoint vs. Baseline. | |
Method | paired t-test | |
Comments |
Statistical Analysis 2
Statistical Analysis Overview | Comparison Group Selection | All Participants With BID Dosing |
---|---|---|
Comments | Analysis of Week 12 for all participants with BID dosing | |
Type of Statistical Test | Superiority or Other (legacy) | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.0400 |
Comments | The P-value is from analysis of paired t-test at post treatment timepoint vs. Baseline. | |
Method | paired t-test | |
Comments |
Statistical Analysis 3
Statistical Analysis Overview | Comparison Group Selection | All Participants With BID Dosing |
---|---|---|
Comments | Analysis of Week 24 for all participants with BID dosing | |
Type of Statistical Test | Superiority or Other (legacy) | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.6303 |
Comments | The P-value is from analysis of paired t-test at post treatment timepoint vs. Baseline. | |
Method | paired t-test | |
Comments |
Title | Change From Baseline in LIC as Assessed by R2* MRI |
---|---|
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 participants. |
Time Frame | Baseline, 12 and 24 weeks |
Outcome Measure Data
Analysis Population Description |
---|
The Full Analysis Set, defined as all participants in the Safety Set who had at least 1 post-baseline primary efficacy assessment. The Safety Set was defined as all participants who had taken at least 1 BID dose of investigational product. |
Arm/Group Title | SPD602 50 mg/kg/d | All Participants With BID Dosing |
---|---|---|
Arm/Group Description | Participants received SPD602 50mg/kg/day oral dosing either twice daily (BID) or once daily (QD), then BID. | Of the 21 participants 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. |
Measure Participants | 5 | 11 |
Week 12, n=5,9 |
-3.2
(2.3)
|
-3.2
(2.1)
|
Week 24, n=1,2 |
-2.4
(NA)
|
-3.3
(1.3)
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | SPD602 50 mg/kg/d |
---|---|---|
Comments | Analysis of Week 12 for 50 mg/kg/d dosing | |
Type of Statistical Test | Superiority or Other (legacy) | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.0365 |
Comments | P-value is from analysis of paired t-test at post treatment timepoint vs. Baseline. | |
Method | paired t-test | |
Comments |
Statistical Analysis 2
Statistical Analysis Overview | Comparison Group Selection | All Participants With BID Dosing |
---|---|---|
Comments | Analysis of Week 12 for all participants with BID dosing | |
Type of Statistical Test | Superiority or Other (legacy) | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.0019 |
Comments | The P-value is from analysis of paired t-test at post treatment timepoint vs. Baseline. | |
Method | paired t-test | |
Comments |
Statistical Analysis 3
Statistical Analysis Overview | Comparison Group Selection | All Participants With BID Dosing |
---|---|---|
Comments | Analysis of Week 24 for all participants with BID dosing | |
Type of Statistical Test | Superiority or Other (legacy) | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.1695 |
Comments | The P-value is from analysis of paired t-test at post treatment timepoint vs. Baseline. | |
Method | paired t-test | |
Comments |
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 (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 participants. |
Time Frame | Baseline, 12 and 24 weeks |
Outcome Measure Data
Analysis Population Description |
---|
The Full Analysis Set, defined as all participants in the Safety Set who had at least 1 post-baseline primary efficacy assessment. The Safety Set was defined as all participants who had taken at least 1 BID dose of investigational product. |
Arm/Group Title | SPD602 50 mg/kg/d | All Participants With BID Dosing |
---|---|---|
Arm/Group Description | Participants received SPD602 50mg/kg/day oral dosing either twice daily (BID) or once daily (QD), then BID. | Of the 21 participants 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. |
Measure Participants | 5 | 11 |
Week 12, n=5,9 |
-6.0
(4.5)
|
-6.2
(3.2)
|
Week 24, n=1,2 |
-9.9
(NA)
|
-10.5
(0.8)
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | SPD602 50 mg/kg/d |
---|---|---|
Comments | Analysis of Week 12 for 50 mg/kg/d dosing | |
Type of Statistical Test | Superiority or Other (legacy) | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.0394 |
Comments | The P-value is from analysis of paired t-test at post treatment timepoint vs. Baseline. | |
Method | paired t-test | |
Comments |
Statistical Analysis 2
Statistical Analysis Overview | Comparison Group Selection | All Participants With BID Dosing |
---|---|---|
Comments | Analysis of Week 12 for all participants with BID dosing | |
Type of Statistical Test | Superiority or Other (legacy) | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.0004 |
Comments | The P-value is from analysis of paired t-test at post treatment timepoint vs. Baseline. | |
Method | paired t-test | |
Comments |
Statistical Analysis 3
Statistical Analysis Overview | Comparison Group Selection | All Participants With BID Dosing |
---|---|---|
Comments | Analysis of Week 24 for all participants with BID dosing | |
Type of Statistical Test | Superiority or Other (legacy) | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.0332 |
Comments | The P-value is from analysis of paired t-test at post treatment timepoint vs. Baseline. | |
Method | paired t-test | |
Comments |
Title | Change From Baseline in Cardiac T2* Relaxation Rate, an MRI Parameter Used to Estimate Cardiac Iron Load |
---|---|
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 participants. |
Time Frame | Baseline, 12 and 24 weeks |
Outcome Measure Data
Analysis Population Description |
---|
The Full Analysis Set, defined as all participants in the Safety Set who had at least 1 post-baseline primary efficacy assessment. The Safety Set was defined as all participants who had taken at least 1 BID dose of investigational product. |
Arm/Group Title | SPD602 50 mg/kg/d | All Participants With BID Dosing |
---|---|---|
Arm/Group Description | Participants received SPD602 50mg/kg/day oral dosing either twice daily (BID) or once daily (QD), then BID. | Of the 21 participants 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. |
Measure Participants | 5 | 11 |
Week 12, n=5,7 |
-0.64
(3.080)
|
-0.24
(3.910)
|
Week 24, n=1,2 |
-4.10
(NA)
|
-2.60
(2.121)
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | SPD602 50 mg/kg/d |
---|---|---|
Comments | Analysis of Week 12 for 50 mg/kg/d dosing | |
Type of Statistical Test | Superiority or Other (legacy) | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.3202 |
Comments | The P-value is from Paired t-test for log-transformed data at post treatment timepoint vs. Baseline. | |
Method | paired t-test | |
Comments |
Statistical Analysis 2
Statistical Analysis Overview | Comparison Group Selection | All Participants With BID Dosing |
---|---|---|
Comments | Analysis of Week 12 for all participants with BID dosing | |
Type of Statistical Test | Superiority or Other (legacy) | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.4549 |
Comments | The P-value is from Paired t-test for log-transformed data at post treatment timepoint vs. Baseline. | |
Method | paired t-test | |
Comments |
Statistical Analysis 3
Statistical Analysis Overview | Comparison Group Selection | All Participants With BID Dosing |
---|---|---|
Comments | Analysis of Week 24 for all participants with BID dosing | |
Type of Statistical Test | Superiority or Other (legacy) | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.3291 |
Comments | The P-value is from Paired t-test for log-transformed data at post treatment timepoint vs. Baseline. | |
Method | paired t-test | |
Comments |
Title | Change From Baseline in Serum Ferritin |
---|---|
Description | Serum ferritin levels were determined from serum biochemistry analyses. A negative change from baseline indicates that serum ferritin decreased. |
Time Frame | Baseline, 8 and 16 weeks |
Outcome Measure Data
Analysis Population Description |
---|
The Full Analysis Set, defined as all participants in the Safety Set who had at least 1 post-baseline primary efficacy assessment. The Safety Set was defined as all participants who had taken at least 1 BID dose of investigational product. |
Arm/Group Title | SPD602 50 mg/kg/d | All Participants With BID Dosing |
---|---|---|
Arm/Group Description | Participants received SPD602 50mg/kg/day oral dosing either twice daily (BID) or once daily (QD), then BID. | Of the 21 participants 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. |
Measure Participants | 5 | 11 |
Week 8, n=5,11 |
-762.63
(2100.683)
|
-568.08
(1426.687)
|
Week 16, n=1,4 |
586.47
(NA)
|
137.63
(972.970)
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | SPD602 50 mg/kg/d |
---|---|---|
Comments | Analysis of Week 8 for 50 mg/kg/d dosing | |
Type of Statistical Test | Superiority or Other (legacy) | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.6703 |
Comments | The P-value is from Paired t-test for log-transformed data at post treatment timepoint vs. Baseline. | |
Method | paired t-test | |
Comments |
Statistical Analysis 2
Statistical Analysis Overview | Comparison Group Selection | All Participants With BID Dosing |
---|---|---|
Comments | Analysis of Week 8 for all participants with BID dosing | |
Type of Statistical Test | Superiority or Other (legacy) | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.2618 |
Comments | The P-value is from Paired t-test for log-transformed data at post treatment timepoint vs. Baseline. | |
Method | paired t-test | |
Comments |
Statistical Analysis 3
Statistical Analysis Overview | Comparison Group Selection | All Participants With BID Dosing |
---|---|---|
Comments | Analysis of Week 16 for all participants with BID dosing | |
Type of Statistical Test | Superiority or Other (legacy) | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.7679 |
Comments | The P-value is from Paired t-test for log-transformed data at post treatment timepoint vs. Baseline. | |
Method | paired t-test | |
Comments |
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. 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 participants. |
Time Frame | Baseline, 12 and 24 weeks |
Outcome Measure Data
Analysis Population Description |
---|
The Full Analysis Set, defined as all participants in the Safety Set who had at least 1 post-baseline primary efficacy assessment. The Safety Set was defined as all participants who had taken at least 1 BID dose of investigational product. |
Arm/Group Title | SPD602 50 mg/kg/d | All Participants With BID Dosing |
---|---|---|
Arm/Group Description | Participants received SPD602 50mg/kg/day oral dosing either twice daily (BID) or once daily (QD), then BID. | Of the 21 participants 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. |
Measure Participants | 5 | 11 |
Week 12, n=5,10 |
-6.3
(8.4)
|
-6.6
(6.7)
|
Week 24, n=1,2 |
-12.8
(NA)
|
-9.3
(5.0)
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | SPD602 50 mg/kg/d |
---|---|---|
Comments | Analysis of Week 12 for 50 mg/kg/d dosing | |
Type of Statistical Test | Superiority or Other (legacy) | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.1683 |
Comments | The P-value is from analysis of paired t-test at post treatment timepoint vs. Baseline. | |
Method | paired t-test | |
Comments |
Statistical Analysis 2
Statistical Analysis Overview | Comparison Group Selection | All Participants With BID Dosing |
---|---|---|
Comments | Analysis of Week 12 for all participants with BID dosing | |
Type of Statistical Test | Superiority or Other (legacy) | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.0123 |
Comments | The P-value is from analysis of paired t-test at post treatment timepoint vs. Baseline. | |
Method | paired t-test | |
Comments |
Statistical Analysis 3
Statistical Analysis Overview | Comparison Group Selection | All Participants With BID Dosing |
---|---|---|
Comments | Analysis of Week 24 for all participants with BID dosing | |
Type of Statistical Test | Superiority or Other (legacy) | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.2334 |
Comments | The P-value is from analysis of paired t-test at post treatment timepoint vs. Baseline. | |
Method | paired t-test | |
Comments |
Title | Number of Participants Classified as a Responder by FerriScan R2 MRI Analysis of LIC |
---|---|
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. |
Time Frame | 12 and 24 weeks |
Outcome Measure Data
Analysis Population Description |
---|
The Full Analysis Set, defined as all participants in the Safety Set who had at least 1 post-baseline primary efficacy assessment. The Safety Set was defined as all participants who had taken at least 1 BID dose of investigational product. |
Arm/Group Title | SPD602 50 mg/kg/d | All Participants With BID Dosing |
---|---|---|
Arm/Group Description | Participants received SPD602 50mg/kg/day oral dosing either twice daily (BID) or once daily (QD), then BID. | Of the 21 participants 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. |
Measure Participants | 5 | 11 |
Week 12, n=5,10 |
4
33.3%
|
8
114.3%
|
Week 24, n=1,2 |
1
8.3%
|
1
14.3%
|
Title | Number of Participants Classified as a Responder by FerriScan R2 MRI Analysis of LIC Adjusted For Transfusional Iron Intake |
---|---|
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. |
Time Frame | 12 and 24 weeks |
Outcome Measure Data
Analysis Population Description |
---|
The Full Analysis Set, defined as all participants in the Safety Set who had at least 1 post-baseline primary efficacy assessment. The Safety Set was defined as all participants who had taken at least 1 BID dose of investigational product. |
Arm/Group Title | SPD602 50 mg/kg/d | All Participants With BID Dosing |
---|---|---|
Arm/Group Description | Participants received SPD602 50mg/kg/day oral dosing either twice daily (BID) or once daily (QD), then BID. | Of the 21 participants 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. |
Measure Participants | 5 | 11 |
Week 12, n=5,10 |
4
33.3%
|
8
114.3%
|
Week 24, n=1,2 |
1
8.3%
|
1
14.3%
|
Title | Number of Participants Classified as a Responder by R2* MRI Analysis of LIC |
---|---|
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. |
Time Frame | 12 and 24 weeks |
Outcome Measure Data
Analysis Population Description |
---|
The Full Analysis Set, defined as all participants in the Safety Set who had at least 1 post-baseline primary efficacy assessment. The Safety Set was defined as all participants who had taken at least 1 BID dose of investigational product. |
Arm/Group Title | SPD602 50 mg/kg/d | All Participants With BID Dosing |
---|---|---|
Arm/Group Description | Participants received SPD602 50mg/kg/day oral dosing either twice daily (BID) or once daily (QD), then BID. | Of the 21 participants 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. |
Measure Participants | 5 | 11 |
Week 12, n=5,9 |
5
41.7%
|
9
128.6%
|
Week 24, n=1,2 |
1
8.3%
|
2
28.6%
|
Title | Number of Participants Classified as a Responder by R2* MRI Analysis of LIC Adjusted For Transfusional Iron Intake |
---|---|
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. |
Time Frame | 12 and 24 weeks |
Outcome Measure Data
Analysis Population Description |
---|
The Full Analysis Set, defined as all participants in the Safety Set who had at least 1 post-baseline primary efficacy assessment. The Safety Set was defined as all participants who had taken at least 1 BID dose of investigational product. |
Arm/Group Title | SPD602 50 mg/kg/d | All Participants With BID Dosing |
---|---|---|
Arm/Group Description | Participants received SPD602 50mg/kg/day oral dosing either twice daily (BID) or once daily (QD), then BID. | Of the 21 participants 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. |
Measure Participants | 5 | 11 |
Week 12, n=5,9 |
5
41.7%
|
9
128.6%
|
Week 24, n=1,2 |
1
8.3%
|
2
28.6%
|
Title | Number of Participants Classified as a Responder by Serum Ferritin |
---|---|
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. |
Time Frame | 8 and 16 weeks |
Outcome Measure Data
Analysis Population Description |
---|
The Full Analysis Set, defined as all participants in the Safety Set who had at least 1 post-baseline primary efficacy assessment. The Safety Set was defined as all participants who had taken at least 1 BID dose of investigational product. |
Arm/Group Title | SPD602 50 mg/kg/d | All Participants With BID Dosing |
---|---|---|
Arm/Group Description | Participants received SPD602 50mg/kg/day oral dosing either twice daily (BID) or once daily (QD), then BID. | Of the 21 participants 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. |
Measure Participants | 5 | 11 |
Week 8, n=5,11 |
3
25%
|
8
114.3%
|
Week 16, n=1,4 |
0
0%
|
1
14.3%
|
Adverse Events
Time Frame | ||||
---|---|---|---|---|
Adverse Event Reporting Description | All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set. | |||
Arm/Group Title | SPD602 50mg/kg/Day | SPD602 75mg/kg/Day | ||
Arm/Group Description | Participants received SPD602 50mg/kg/day oral dosing BID either as originally randomized or as a re-enrolled participant. | Participants received SPD602 75mg/kg/day oral dosing BID either as originally randomized or as a re-enrolled participant. | ||
All Cause Mortality |
||||
SPD602 50mg/kg/Day | SPD602 75mg/kg/Day | |||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | / (NaN) | / (NaN) | ||
Serious Adverse Events |
||||
SPD602 50mg/kg/Day | SPD602 75mg/kg/Day | |||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 2/12 (16.7%) | 2/7 (28.6%) | ||
Congenital, familial and genetic disorders | ||||
Sickle cell anaemia with crisis | 0/12 (0%) | 0 | 1/7 (14.3%) | 1 |
General disorders | ||||
Chest pain | 1/12 (8.3%) | 1 | 0/7 (0%) | 0 |
Pain | 0/12 (0%) | 0 | 1/7 (14.3%) | 1 |
Hepatobiliary disorders | ||||
Cholelithiasis | 1/12 (8.3%) | 1 | 0/7 (0%) | 0 |
Musculoskeletal and connective tissue disorders | ||||
Flank pain | 1/12 (8.3%) | 1 | 0/7 (0%) | 0 |
Nervous system disorders | ||||
Neuropathy peripheral | 1/12 (8.3%) | 1 | 0/7 (0%) | 0 |
Other (Not Including Serious) Adverse Events |
||||
SPD602 50mg/kg/Day | SPD602 75mg/kg/Day | |||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 9/12 (75%) | 7/7 (100%) | ||
Congenital, familial and genetic disorders | ||||
Sickle cell anaemia with crisis | 0/12 (0%) | 0 | 1/7 (14.3%) | 5 |
Gastrointestinal disorders | ||||
Constipation | 1/12 (8.3%) | 1 | 3/7 (42.9%) | 4 |
Vomiting | 3/12 (25%) | 4 | 1/7 (14.3%) | 1 |
Abdominal pain | 1/12 (8.3%) | 1 | 1/7 (14.3%) | 1 |
Faeces discoloured | 1/12 (8.3%) | 1 | 1/7 (14.3%) | 1 |
Nausea | 1/12 (8.3%) | 1 | 1/7 (14.3%) | 2 |
Diarrhoea | 1/12 (8.3%) | 1 | 0/7 (0%) | 0 |
Eructation | 1/12 (8.3%) | 1 | 0/7 (0%) | 0 |
Gastrooesophageal reflux disease | 1/12 (8.3%) | 1 | 0/7 (0%) | 0 |
Hiatus hernia | 1/12 (8.3%) | 1 | 0/7 (0%) | 0 |
Regurgitation | 1/12 (8.3%) | 1 | 0/7 (0%) | 0 |
Dyspepsia | 0/12 (0%) | 0 | 1/7 (14.3%) | 1 |
Frequent bowel movements | 0/12 (0%) | 0 | 1/7 (14.3%) | 1 |
General disorders | ||||
Pyrexia | 3/12 (25%) | 7 | 1/7 (14.3%) | 1 |
Oedema peripheral | 1/12 (8.3%) | 1 | 1/7 (14.3%) | 1 |
Asthenia | 1/12 (8.3%) | 1 | 0/7 (0%) | 0 |
Influenza like illness | 1/12 (8.3%) | 1 | 0/7 (0%) | 0 |
Axillary pain | 0/12 (0%) | 0 | 1/7 (14.3%) | 1 |
Fatigue | 0/12 (0%) | 0 | 1/7 (14.3%) | 1 |
Immune system disorders | ||||
Hypersensitivity | 1/12 (8.3%) | 2 | 0/7 (0%) | 0 |
Infections and infestations | ||||
Influenza | 1/12 (8.3%) | 1 | 1/7 (14.3%) | 1 |
Tonsillitis | 1/12 (8.3%) | 1 | 1/7 (14.3%) | 1 |
Nasopharyngitis | 1/12 (8.3%) | 2 | 0/7 (0%) | 0 |
Rhinitis | 1/12 (8.3%) | 1 | 0/7 (0%) | 0 |
Upper respiratory tract infection | 1/12 (8.3%) | 1 | 0/7 (0%) | 0 |
Bacteriuria | 0/12 (0%) | 0 | 1/7 (14.3%) | 1 |
Gastroenteritis | 0/12 (0%) | 0 | 1/7 (14.3%) | 1 |
Injury, poisoning and procedural complications | ||||
Allergic transfusion reaction | 1/12 (8.3%) | 1 | 0/7 (0%) | 0 |
Investigations | ||||
Blood urea increased | 1/12 (8.3%) | 1 | 1/7 (14.3%) | 1 |
International normalised ratio increased | 1/12 (8.3%) | 1 | 1/7 (14.3%) | 1 |
Activated partial thromboplastin time prolonged | 1/12 (8.3%) | 1 | 0/7 (0%) | 0 |
Anion gap increased | 1/12 (8.3%) | 1 | 0/7 (0%) | 0 |
Blood bicarbonate decreased | 1/12 (8.3%) | 1 | 0/7 (0%) | 0 |
Blood creatinine increased | 1/12 (8.3%) | 1 | 0/7 (0%) | 0 |
Nitrite urine present | 1/12 (8.3%) | 1 | 0/7 (0%) | 0 |
Red blood cells urine positive | 1/12 (8.3%) | 1 | 0/7 (0%) | 0 |
Urine protein/creatinine ratio increased | 1/12 (8.3%) | 1 | 0/7 (0%) | 0 |
Electrocardiogram T wave abnormal | 0/12 (0%) | 0 | 1/7 (14.3%) | 1 |
pH urine increased | 0/12 (0%) | 0 | 1/7 (14.3%) | 1 |
Metabolism and nutrition disorders | ||||
Folate deficiency | 1/12 (8.3%) | 1 | 0/7 (0%) | 0 |
Musculoskeletal and connective tissue disorders | ||||
Back pain | 2/12 (16.7%) | 8 | 1/7 (14.3%) | 1 |
Pain in extremity | 1/12 (8.3%) | 1 | 2/7 (28.6%) | 4 |
Arthralgia | 2/12 (16.7%) | 2 | 0/7 (0%) | 0 |
Limb discomfort | 1/12 (8.3%) | 1 | 1/7 (14.3%) | 1 |
Sensation of heaviness | 2/12 (16.7%) | 2 | 0/7 (0%) | 0 |
Myalgia | 1/12 (8.3%) | 1 | 0/7 (0%) | 0 |
Neck pain | 1/12 (8.3%) | 1 | 0/7 (0%) | 0 |
Muscle spasms | 0/12 (0%) | 0 | 1/7 (14.3%) | 2 |
Flank pain | 1/12 (8.3%) | 1 | 0/7 (0%) | 0 |
Nervous system disorders | ||||
Paraesthesia | 2/12 (16.7%) | 3 | 4/7 (57.1%) | 5 |
Headache | 2/12 (16.7%) | 4 | 2/7 (28.6%) | 2 |
Hypoaesthesia | 2/12 (16.7%) | 4 | 2/7 (28.6%) | 3 |
Dizziness | 0/12 (0%) | 0 | 1/7 (14.3%) | 1 |
Neuropathy peripheral | 0/12 (0%) | 0 | 1/7 (14.3%) | 1 |
Psychiatric disorders | ||||
Insomnia | 0/12 (0%) | 0 | 1/7 (14.3%) | 1 |
Renal and urinary disorders | ||||
Chromaturia | 2/12 (16.7%) | 2 | 2/7 (28.6%) | 2 |
Leukocyturia | 1/12 (8.3%) | 1 | 1/7 (14.3%) | 1 |
Glycosuria | 1/12 (8.3%) | 1 | 0/7 (0%) | 0 |
Polyuria | 1/12 (8.3%) | 1 | 0/7 (0%) | 0 |
Proteinuria | 1/12 (8.3%) | 1 | 0/7 (0%) | 0 |
Respiratory, thoracic and mediastinal disorders | ||||
Oropharyngeal pain | 2/12 (16.7%) | 3 | 1/7 (14.3%) | 1 |
Nasal congestion | 1/12 (8.3%) | 1 | 0/7 (0%) | 0 |
Dyspnoea | 0/12 (0%) | 0 | 1/7 (14.3%) | 1 |
Dyspnoea exertional | 0/12 (0%) | 0 | 1/7 (14.3%) | 1 |
Throat irritation | 0/12 (0%) | 0 | 1/7 (14.3%) | 1 |
Wheezing | 0/12 (0%) | 0 | 1/7 (14.3%) | 1 |
Skin and subcutaneous tissue disorders | ||||
Erythema | 0/12 (0%) | 0 | 1/7 (14.3%) | 1 |
Pruritus allergic | 0/12 (0%) | 0 | 1/7 (14.3%) | 1 |
Vascular disorders | ||||
Hypotension | 0/12 (0%) | 0 | 1/7 (14.3%) | 1 |
Pallor | 0/12 (0%) | 0 | 1/7 (14.3%) | 1 |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
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 |
ClinicalTransparency@shire.com |
- SPD602-203
- FBS0701-CTP-16
- 2011-005675-16