Pharmacokinetics of SSP-004184 in the Treatment of Chronic Iron Overload Requiring Chelation Therapy

Phase 2

Terminated

Conditions: Iron Overload Due to Repeated Red Blood Cell Transfusions

Interventions: Drug: SPD602

Registration Number: NCT01604941

Lead Sponsor: Shire

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 32

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:
1. Post-menopausal (12 consecutive months of spontaneous amenorrhea), or
2. Surgically sterile, or
3. 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:
1. T2* MRI <10 ms
2. 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
1. Below the locally determined normal range in the 12 months prior to Screening by echocardiograph or MRI or
2. <50% at Baseline testing by MRI (echocardiograph is acceptable for LVEF if MRI information is not available).

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
SPD602	SPD602	50 mg/kg/day orally twice daily for 24 weeks

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
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 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.
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.
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.
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.
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.

Trial Locations

Locations (12): San Luigi Hospital Thalassemia Centre
🇮🇹
Orbassano, Torino, Italy
Ospedale Regionale Microcitemie
🇮🇹
Cagliari, Italy
Ospedale Maggiore Policlinico
🇮🇹
Milan, Italy
Centro della Microcitemia e delle Anemie Congenite
🇮🇹
Genova, Genoa, Italy
Ain Shams University Pediatric Hospitals
🇪🇬
Cairo, Egypt
Children's Center for Cancer and Blood Diseases
🇺🇸
Los Angeles, California, United States
Toronto General Hospital
🇨🇦
Toronto, Ontario, Canada
Ann & Robert H. Lurie Children's Hospital of Chicago
🇺🇸
Chicago, Illinois, United States
Cairo University Pediatric Hospitals
🇪🇬
Cairo, Egypt
Children's Hospital of Philadelphia
🇺🇸
Philadelphia, Pennsylvania, United States
Weill Cornell Medical College
🇺🇸
New York, New York, United States
American University of Beirut Medical Center
🇱🇧
Beirut, Lebanon