Transfusion-dependent ß-thalassemia TDT
Conditions
Interventions
A minimum of 90 subjects with transfusion-dependent ß-thalassemia will be recruited, and they will be allocated to 1 the following treatment groups:
• Cohort 1a+b (N=30): SP-420 initially at 28 mg/kg
28 mg/kg, oral dosing 3 times per week, Monday, Wednesday, and Friday
56 mg/kg, oral dosing 3 times per week, Monday, Wednesday, and Friday
84 mg/kg, oral dosing 3 times per week, Monday, Wednesday, and Friday
Sponsors
Pharmacosmos A/S
Eligibility
Sex/Gender
All
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: 1. Women and men aged =18 years 2. Transfusion-dependent ß-thalassemia including HbE/ß-thalassemia requiring iron chelation therapy (ß-thalassemia with mutation and/or multiplication of a-globin is allowed) 3. On a stable dose of iron chelation for at least 4 weeks prior to screening 4. Weight =35 kg at screening 5. Willing to discontinue current iron chelation therapy 7 days (± 3 days) prior to the first dose of SP-420 and for the duration of the trial 6. Transfusion iron overload defined as LIC =5 and =20 mg/g dw on the R2-MRI obtained within 2 weeks prior to baseline 7. Subject has been treated and followed for at least the past 6 months in a specialised centre that maintained detailed medical records, including transfusion and iron chelation histories 8. Willingness to participate and signing the informed consent form
Exclusion criteria
Exclusion criteria: 1. ß-thalassemia with the structural Hb variants HbS and HbC 2. Cardiac MRI-T2* score 4000 ng/mL* 4. Current malignancy with the exceptions of localised basal cell or squamous cell skin cancer or localised prostate cancer or is receiving immunotherapy, chemotherapy, or radiation therapy for a malignancy 5. Current myelodysplastic syndrome 6. Current biliary disorder 7. ALAT >4 times the upper limit of normal, decompensated cirrhosis, or ascites at screening 8. Past or ongoing history of clinically significant kidney disease 9. Creatinine greater than the upper limit of normal at screening 10. Estimated glomerular filtration rate eGFR 0.5 mg/mg at screening 12. Heart failure grade II, III and IV by NYHA 13. LVEF on MRI 450 ms, 2nd or 3rd degree atrioventricular block, or incomplete left hemiblock, or the presence of clinically significant abnormalities as determined by the Investigator at screening 15. Hypertransfused defined as more than 6 units/month in average for the last 6 months prior to screening 16. Ongoing symptoms of neuropathy, including peripheral sensory neuropathy, peripheral motor neuropathy, or paresthesia at screening 17. Platelet count <100×109/L at screening 18. History of hypersensitivity to an iron chelator (investigational or marketed) or excipients 19. Documented history of non-compliance to chelation therapy within past 2 years 20. Received another investigational drug within 30 days or investigational antibody within 90 days before screening 21. Treatment with prohibited medication: iron, aluminium containing antacid therapies, systemic corticosteroids (topical and pulmonary corticosteroids are allowed), oral bisphosphonates, chronic use of high dose NSAIDs (as needed and low dose acetylsalicylic acid are allowed), drugs with known renal toxicity, drugs with known QTc prolongation, potent UGT inducers (e.g. rifampicin, phenytoin, phenobarbital, ritonavir) within 7 days prior to baseline 22. Initiation of treatment with luspatercept within 6 months prior to screening (luspatercept is allowed if initiated and dose is stable at least 6 months prior to screening) 23. Subject unable to undergo trial assessments including MRI, e.g. who are claustrophobic to MRI, have a cardiac pacemaker, ferromagnetic metal implants other than those approved as safe for use in MR scanners (e.g. some types of aneurysm clips, and shrapnel), and subjects who are obese (exceeding the equipment limits) 24. Pregnant or nursing women. In order to avoid pregnancy, women of childbearing potential (premenopausal and not surgically sterile) have to use highly efficient contraception (e.g. intrauterine devices, hormonal contraceptives (contraceptive pills, implants, transdermal patches, hormonal vaginal devices or injections with prolonged release)) during the whole trial period and 4 weeks post-dosing. A sterile sole partner or sexual abstinence is also considered acceptable provided it reflects the usual and preferred lifestyle of the participant 25. Men, even if surgically sterilised, (i.e. status post vasectomy), who do not agree to practice effective barrier contraception during the entire trial period, or agrees to completely abstain from heterosexual intercourse 26. Any other laboratory abnormality, medical condition, or
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Name: dose-response relationship of SP-420 for 24 weeks;Timepoints: from baseline to week 24;Measure: Total body iron removed by SP-420 | — |
Secondary
| Measure | Time frame |
|---|---|
| Name: clearing iron from the liver;Timepoints: from baseline to week 24;Measure: liver iron concentration (LIC)measured by R2-MRI;Name: clearing iron from the liver after 12 and 48 weeks;Timepoints: from baseline to week 12 and week 48;Measure: LIC measured by R2-MRI;Name: total body iron removal after 12 and 48 weeks;Timepoints: from baseline to week 12 and week 48, and from week 24 to week 48;Measure: Total body iron removed by SP-420;Name: serum (s-) ferritin;Timepoints: from baseline to weeks 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48;Measure: s-ferritin;Name: safety and tolerability;Timepoints: NA;Measure: adverse events (AEs)/physical examination (including auditory and ophthalmologic examinations), height, vital signs, ECG, and safety laboratory parameters (including urinalysis)/extensive ECG measurement will be performed in the 18 subjects in cohort 1a-3a | — |
Countries
Canada, Denmark, United Arab Emirates
Contacts
Public ContactAziz Zoghbi
Regional Manager
Outcome results
None listed