Beta-thalassemia, Transfusional Iron Overload
Conditions
Keywords
Beta-thalassemia, Sickle cell anemia, Transfusional iron overload, Iron overload, Iron chelation
Brief summary
The purpose of this research study is to evaluate the safety of two doses of FBS0701, a new oral iron chelator, and its effectiveness in clearing iron from the liver. FBS0701 is a medication taken by mouth that causes the body to get rid of iron. Iron chelators are used in patients with β-thalassemia and other forms of anemia who experience iron overload - iron increases in the body as a result of regularly required blood transfusions. Patients who qualify will be randomized to receive one of two doses of FBS0701 for up to 24 weeks (6 months) with a total study duration of up to 33 weeks. These patients will be eligible to participate in a dosing extension for up to 72 weeks. The maximum duration of dosing will be up to 96 weeks. The safety of patients will be monitored frequently during the study by physical exams, ECGs, and blood tests. To assess the amount of iron in the liver and heart, each patient must undergo 6 MRI scans during the study. Patients will not need to stay in the hospital for this study but will need to visit the outpatient clinic up to 28 times over the 96 week period. Patients currently taking an iron chelator will be required to stop for a total of up to 26 weeks. The results of this study will help to determine if FBS0701 may be effective as an iron chelator.
Interventions
DRUGSPD602 (FBS0701, SSP-004184)
Oral FBS0701 taken one time daily for up to 96 weeks.
Sponsors
Shire
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
* Transfusional iron overload due to: hereditary anemias such as sickle cell disease, β-thalassemia and Diamond-Blackfan anemia; acquired anemias such as Myelodysplastic Syndrome and other forms of bone marrow failure. Patients must also be transfusion-dependent and require chronic treatment with deferoxamine, deferasirox, and/or deferiprone. * Willing to discontinue all existing iron chelation therapies throughout study period. * Serum ferritin greater than 500 ng/mL at Screening. * Baseline liver iron concentration and cardiac MRI T2\* per protocol requirements. * Mean of the previous three pre-transfusion hemoglobin concentrations greater than or equal to 7.5 g/dL. * Agrees to use an approved method of contraception throughout study period.
Exclusion criteria
* As a result of medical review, physical examination or Screening investigations, the Principal Investigator considers the patient unfit for the study. * Non-elective hospitalization within the 30 days prior to Baseline testing. (Patients with sickle cell anemia who are admitted to the hospital for management of sickle crisis pain whose uncomplicated hospital course was four days or less and who, 14 days prior to Baseline testing, have returned to their previous health status are acceptable.) * Evidence of clinically relevant oral, cardiovascular, gastrointestinal, hepatic, renal, endocrine, pulmonary, neurologic, psychiatric, immunologic, bone marrow or skin disorder as determined by the Investigator. * Evidence of significant renal insufficiency; possible examples include: serum creatinine above the upper limit of normal, proteinuria greater than 2 gm per day or calculated creatinine clearance of less than 60 mL/minute. * Cardiac left ventricular ejection fraction outside of protocol requirements. * Known sensitivity to magnesium stearate, croscarmellose sodium or FBS0701. * Platelet count below 100,000/µL and/or absolute neutrophil count less than 1500/mm3 at Screening and \<50% at Baseline testing by MRI * Alkaline phosphatase, AST or ALT outside of protocol requirements. * Liver Function Tests: ALT \>5 times the local upper limit of normal on two occasions in the previous 12 months or ALT at Screening \>200 IU/L * Use of any investigational agent within the 30 days prior to the Baseline testing.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Liver Iron Concentration (LIC) at 96 Weeks | Baseline and 96 weeks | LIC was determined by R2 Magnetic Resonance Imaging (MRI). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Plasma Concentration (Cmax) of SPD602 | 92 weeks | Cmax is a term that refers to the maximum (or peak) concentration that a drug achieves in the body after the drug has been administered. |
| Area Under The Steady-state Plasma Concentration-time Curve (AUC) of SPD602 | 92 weeks | AUC can be used as a measure of drug exposure. It is derived from drug concentration and time so it gives a measure of how much and how long a drug stays in a body. |
Countries
Italy, Thailand, Turkey (Türkiye), United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| SPD602 16 mg/kg/Day Participants received SPD602 orally once daily for up to 96 weeks. At Week 24, the iron clearing activity of SPD602 was assessed for each participant and the dose may have been adjusted to a higher or lower dose if the clinical response was deemed insufficient or too robust, respectively (maximum dose=60mg/kg/day; minimum dose=8mg/kg/day). Participants not dose adjusted at Week 24 may also have had later dose adjustments to a higher or lower dose. | 24 |
| SPD602 32 mg/kg/Day Participants received SPD602 orally once daily for up to 96 weeks. At Week 24, the iron clearing activity of SPD602 was assessed for each participant and the dose may have been adjusted to a higher or lower dose if the clinical response was deemed insufficient or too robust, respectively (maximum dose=60mg/kg/day; minimum dose=8mg/kg/day). Participants not dose adjusted at Week 24 may also have had later dose adjustments to a higher or lower dose. | 27 |
| Total | 51 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 2 |
| Overall Study | Other | 1 | 1 |
| Overall Study | Physician Decision | 0 | 3 |
| Overall Study | Withdrawal by Subject | 5 | 3 |
Baseline characteristics
| Characteristic | SPD602 32 mg/kg/Day | Total | SPD602 16 mg/kg/Day |
|---|---|---|---|
| Age, Categorical <=18 years | 1 Participants | 1 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 26 Participants | 50 Participants | 24 Participants |
| Age, Continuous | 28.4 years STANDARD_DEVIATION 7.11 | 28.5 years STANDARD_DEVIATION 7.77 | 28.7 years STANDARD_DEVIATION 8.6 |
| Sex: Female, Male Female | 14 Participants | 26 Participants | 12 Participants |
| Sex: Female, Male Male | 13 Participants | 25 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 24 / 24 | 26 / 27 |
| serious Total, serious adverse events | 3 / 24 | 2 / 27 |
Outcome results
Primary
Change From Baseline in Liver Iron Concentration (LIC) at 96 Weeks
LIC was determined by R2 Magnetic Resonance Imaging (MRI).
Time frame: Baseline and 96 weeks
Population: Full Analysis Set, defined as all subjects in the Safety Set who had at least 1 post-baseline primary efficacy assessment. The Safety Set was defined as all subjects who received any amount of investigational product.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SPD602 | Change From Baseline in Liver Iron Concentration (LIC) at 96 Weeks | -1.75 mg/g | Standard Deviation 4.839 |
p-value: 0.0765t-test, 2 sided
Secondary
Area Under The Steady-state Plasma Concentration-time Curve (AUC) of SPD602
AUC can be used as a measure of drug exposure. It is derived from drug concentration and time so it gives a measure of how much and how long a drug stays in a body.
Time frame: 92 weeks
Population: PK Analysis Set, defined as all subjects in the Safety Set for whom the primary PK data were considered sufficient and interpretable. The Safety Set was defined as all subjects who received any amount of investigational product.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SPD602 | Area Under The Steady-state Plasma Concentration-time Curve (AUC) of SPD602 | 62998.6 ng*hr/ml | Standard Deviation 23094.72 |
Secondary
Maximum Plasma Concentration (Cmax) of SPD602
Cmax is a term that refers to the maximum (or peak) concentration that a drug achieves in the body after the drug has been administered.
Time frame: 92 weeks
Population: Pharmacokinetic (PK) Analysis Set, defined as all subjects in the Safety Set for whom the primary PK data were considered sufficient and interpretable. The Safety Set was defined as all subjects who received any amount of investigational product.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SPD602 | Maximum Plasma Concentration (Cmax) of SPD602 | 25702.7 ng/ml | Standard Deviation 4448.06 |