| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with 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. |
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| E.1.1.1 | Medical condition in easily understood language |
| Patients with inherited anemias and anemias that have developed later in life that have received long-term blood transfusion therapy, leading to an overload of iron. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065974 |
| E.1.2 | Term | Chronic iron overload |
| E.1.2 | System Organ Class | 100000004861 |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Primary Objective #1 Safety and Tolerability
To evaluate the safety and tolerability based on clinical assessments of two doses of SSP-004184 when administered daily to patients with transfusional iron overload.
Primary Objective # 2 Pharmacodynamic
To identify a differential response between dose groups in liver iron content determined by magnetic resonance imaging (MRI).
Primary Objective # 3
To assess the safety and pharmacodynamic activity of FBS0701 when administered daily for up to 96 weeks. |
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| E.2.2 | Secondary objectives of the trial |
| Secondary Objective #1 To assess the steady state pharmacokinetics of SSP-004184 in a sub-set of patients. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Willing and able to sign the approved informed consent.
2. Age: 18-60 years old at Screening
3. 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:
a. Be transfusion-dependent (8 or more transfusions annually) and
b. Require chronic treatment with deferoxamine, deferasirox, and/or deferiprone.
4. Willing to discontinue all existing iron chelation therapies for a minimum period of one to five days prior to first dose of SSP-004184, the 24 week duration of the study and 1 week after last dose for a total of approximately 26 weeks.
5. Serum ferritin > 500 ng/mL at Screening.
6. Baseline (Day -14 to Day -7) liver iron concentration (LIC) between ≥3.5 and <30 mg iron per g (equivalent, dry weight, liver) determined by FerriScan® MRI.
7. Baseline (Day -14 to Day -7) cardiac MRI T2* ≥10 milliseconds.
8. Mean of the previous three pre-transfusion hemoglobin concentrations ≥ 7.5 g/dL.
9. Agrees to use an approved method of contraception from Screening and until 28 days after the last administration of the study drug. Agreed methods of contraception may include: condom; use of birth control pills, patches, implants or injections, diaphragm with vaginal spermicide, intrauterine device (IUD) and/or surgical sterilization (vasectomy or tubal ligation at least six months prior to dosing). Patients practicing abstinence must agree to use an approved method of contraception should they become sexually active during the study. A monthly pregnancy test will be performed on all female patients of child-bearing potential during the Screening and study period.
Requalification Inclusion Criteria (entry into 24 & 48 week extended dosing):
1.Willing to remain off all existing iron chelation therapies during FBS0701 dosing and 1 week after last dose for a total of approximately 50 - 98 weeks.
2. Have a serum ferritin above the upper limit of normal (>350 ng/mL) in the last assessment before Week 24/48.
3. Week 24/48 liver iron concentration (LIC) ≥2.0 mg iron per g (equivalent dry weight, liver) determined by FerriScan® MRI.
4. Week 24/48 cardiac MRI T2* ≥10 milliseconds.
5. Agree to continue to use an approved method of contraception until 28 days after the last administration of SSP-004184.
6. In the opinion of the Principal Investigator, sufficient compliance with study drug dosing to support continued use of SSP-004184.
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| E.4 | Principal exclusion criteria |
1. As a result of medical review, physical examination or Screening investigations, the Principal Investigator considers the patient unfit for the study.
2. 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.)
3. Evidence of clinically relevant oral, cardiovascular, gastrointestinal, hepatic, renal, endocrine, pulmonary, neurologic, psychiatric, immunologic, bone marrow or skin disorder as determined by the Investigator.
4. Evidence of significant renal insufficiency; e.g., 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.
5. Cardiac left ventricular ejection fraction:
a. Outside the locally determined normal range in the 12 months prior to Screening by echocardiography or MRI or
b. <50% at Baseline testing by MRI
6. Known sensitivity to magnesium stearate, croscarmellose sodium or FBS0701.
7. Platelet count below 100,000/µL or absolute neutrophil count less than 1500/mm3 at Screening
8. Liver Function Tests
a. ALT >5 times the local upper limit of normal on two occasions in the previous 12 months or
b. ALT > 200 IU at Screening
9. Use of any investigational agent within the 30 days prior to the Baseline testing.
Requalification Exclusion Criteria (entry into 24 & 48 week extended dosing):
1. Has restarted prior chelation therapy. (NOTE: Ideally, patients will move directly from the initial dosing phase to the extended dosing phase with no pause in study drug dosing. Should there be an administrative need to interrupt study treatment, the patient may be allowed to remain off all chelator therapy for a maximum of 3 weeks prior to starting the extended phase of the study, should the Medical Monitor and the patient’s Principal Investigator deem it safe and clinically reasonable to do so.)
2. Evidence of clinically relevant oral, cardiovascular, gastrointestinal, hepatic, renal, endocrine, pulmonary, neurologic, psychiatric, immunologic, bone marrow or skin disorder as determined by the Investigator which in the view of the Investigator and the Medical Monitor represents an unacceptable risk to the patient.
3. 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 less than 60 mL/min in the last assessment prior to the Week 24/48 visit.
4. Platelet count below 100,000/µL or absolute neutrophil count less than 1500/mm3 in the last assessment prior to the Week 24/48 visit.
5. Serum ALT >200 IU/L in the last assessment prior to the Week 24/48 visit
6. At Week 48 only: Left Ventricular Ejection Fraction <55% by MRI
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Endpoint #1 Safety and Tolerability:
Demographics will be tabulated and summarized. Medical and surgical history data at Screening will be listed, as will Physical Examination data including height and weight, vital signs (resting heart rate, semi-supine systolic/diastolic blood pressure, respiratory rate and temperature), and ECG parameters will be tabulated and summarized.
Treatment-emergent adverse events will be listed and summarized per treatment. All adverse events reported in this study will be coded using MedDRA (Medical Dictionary for Regulatory Activities). Laboratory values outside the laboratory normal ranges will be listed separately with comments as to their clinical significance.
All patients who have taken at least one dose will be included in the safety analysis consistent with an intention to-treat analysis.
Medical History is taken at Screening and updated on Day 1 (pre-dose). Vitals signs, laboratory safety testing and adverse events are captured at each study visit. ECG’s are taken at Screening, Day 1 and then repeated 12 weekly to Wk 24. Physical Examinations are performed at Screening, Day1 and then repeated 4 weekly.
Primary Endpoint #2 Pharmacodynamic:
Changes in Liver Iron Concentration (LIC) as assessed by FerriScan® magnetic resonance imaging (MRI) from Baseline to Week 12 and Week 24 will be calculated and summarized by treatment arm.
Changes in LIC assessed by FerriScan® MRI normalized for initial LIC from Baseline to Week 12 and 24 will be calculated and summarized by treatment arm.
Changes in LIC assessed by FerriScan® MRI from Baseline to Week 12 and 24 normalized for iron intake by blood transfusion over the course of the study will be calculated and summarized by treatment arm.
Changes in serum ferritin levels from Screening through End-of-Study (Week 28)
Primary Endpoint #3
As above for Primary Endpoint #1 extended to End of Study (Week 100) for patients entering the up to 72 weeks extended dosing.
Vitals signs, laboratory safety testing and adverse events (recorded post first dose) continue to be captured at each study visit. ECG’s continue to be repeated 12 weekly (Week 36 and 48) during the extended dosing. Physical Examinations continue to be performed 4 weekly.
Changes in Liver Iron Concentration (LIC) as assessed by FerriScan® magnetic resonance imaging (MRI) from Baseline to Week 12, 24, 48, 72 and 96 will be calculated and summarized by dose.
Changes in LIC assessed by FerriScan® MRI normalized for initial LIC from Baseline to Week 12, 24, 48, 72 and 96 will be calculated and summarized by dose.
Changes in LIC assessed by FerriScan® MRI from Baseline to Week 12, 24, 48, 72 and 96 normalized for iron intake by blood transfusion over the course of the study, will be calculated and summarized by dose.
Changes in cardiac iron as assessed by T2* MRI from Baseline to Week 48, 72 and 96 will be calculated and summarized by dose.
Changes in serum ferritin levels from Screening through End-of-Study (Week 100).
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Endpoint # 1: most safety parameters are reviewed at each study visit (see above for details)
Primary Endpoint #2: MRI assessments are performed at baseline and Week 12 and 24. Serum Ferritin to be measured at each clinic visit to EoS (Wk 28).
Primary Endpoint #3: Vitals signs, laboratory safety testing and adverse events (recorded post first dose) continue to be captured at each study visit. ECG’s continue to be repeated 12 weekly (Wk 36 to Wk 96) during the extended dosing. Physical Examinations continue to be performed 4 weekly.
MRI examinations will continue to be performed at Wks 48, 72 and 96.
Serum Ferritin to be measured at each clinic visit to EoS (Wk 100).
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| E.5.2 | Secondary end point(s) |
Secondary Endpoint #1: Steady state pharmacokinetics (PK) will be evaluated at both Week 52 and Week 92 in a minimum of 6 patients.
The concentrations of SSP-004184 will be measured in plasma from all patients using a validated assay method. Pharmacokinetic parameters will be tabulated and summarized. The concentration-time profiles for each subject and the mean concentration-time profile will be plotted.
Pharmacokinetic parameters will be calculated for a minimum of 6 patients at both Week 52 and 92 using standard non-compartmental methods as described below.
The following pharmacokinetic parameters for SSP-004184 will be determined from the time and plasma concentration data:
AUC0–24: The area under the plasma concentration versus time curve will be calculated using the linear trapezoidal rule from the zero time point to the 24 hour time point plasma concentration.
Cmax: The maximum observed plasma concentration will be obtained directly from the plasma concentration time profile.
tmax: The time to maximum plasma concentration will be obtained by inspection. If the maximum plasma concentration occurs at more than one time point, the first is chosen.
kel: The terminal elimination rate constant will be obtained from the slope of the line, fitted by linear least squares regression, through the terminal points of the log (base e) concentration-time profiles.
t½: The half-life will be calculated by the equation t½ = 0.693/kel.
CL/F: Apparent total plasma clearance of drug after oral administration.
Vz/F: Apparent volume of distribution during terminal phase after oral administration.
Ue: Amount excreted into urine.
fe: Fraction of oral administered drug that is excreted unchanged in urine.
CLr: Renal Clearance
Descriptive statistics (mean, standard deviation and coefficient of variation) will be calculated for all pharmacokinetic parameters.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Sixteen blood samples for pharmacokinetics (3-4 mL per sample) will be collected in total. At both Week 52 and 92, the following samples will be collected: pre-dose and 0.5, 1.0, 2, 3, 4, 8 and 24 hours post dose.
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 5 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Italy |
| Thailand |
| Turkey |
| United Kingdom |
| United States |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| The end of trial is defined as the date of database lock. The justification is that we only end the trial when we are certain that all queries are answered and the database is cleaned. Until that point, sites and/or patients may be called upon for follow up information or clarification of data. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 30 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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