E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Non-transfusion Dependent Beta-thalassaemia. |
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E.1.1.1 | Medical condition in easily understood language |
Iron overload in the blood. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10074355 |
E.1.2 | Term | Non-transfusion dependent thalassaemia |
E.1.2 | System Organ Class | 100000004850 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To assess the safety and tolerability of VIT-2763 versus placebo in adult and adolescent NTDT subjects over a 12-week treatment period. |
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E.2.2 | Secondary objectives of the trial |
- To assess the preliminary efficacy of VIT-2763 versus placebo on iron markers in adult and adolescent NTDT subjects over a 12-week treatment period. - To evaluate the PK of VIT-2763 in adult and adolescent NTDT subjects over a 12-week treatment period (using a population PK approach). |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Documented diagnosis of NTDT, including a β-thalassaemia intermedia-phenotype. 2. NTDT is defined as subjects having received <5 units of red blood cells (RBCs) during the 24-week period prior to randomisation/first drug administration of VIT-2763 or placebo (Day 1; 1 unit is defined as 200 to 350 ml of transfused packedRBCs and last RBC transfusion must have been received ≥14 days prior to randomisation). Note: Subjects who are supposed to receive RBC transfusions after randomization in the Investigator’s opinion, and according to local practise, and having received at least 1 dose of VIT-2763, may be considered to stay on study treatment for safety reasons, and in case there are no tolerability concerns. Subjects will be censored for secondary efficacy. 3. Male and female adult NTDT subjects, 18-65 years of age inclusive (Cohort I only) at time of screening. 4. Male and female adolescent NTDT subjects, 12-17 years of age inclusive (Cohort II only) at time of screening. 5. Subjects must have a mean baseline Hb ≤11 g/dl, based on 2 consecutive measurements ≥1 week apart within 6 weeks prior to randomisation/baseline, and obtained Hb values show less than 10% relative difference (and equal or less than 1.0 g/dl absolute change between the highest and lowest value) between at least 2 measurements. Note: If there is 1 retrospective Hb value available for the subject at maximum of 2 weeks prior to screening (Day -28), the Hb value can be taken into consideration. A subject not meeting this criterion would be excluded but can be rescreened at maximum 2 times at a later time point. |
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E.4 | Principal exclusion criteria |
1. Documented diagnosis of TDT, including a beta-thalassaemia major phenotype (including β0/β0, β+/β+, β0/β+ genotype), and mixed compound heterozygous for sickling phenotype variants such as Hb S/β-thalassaemia, or transfusion dependent non-deletional Hb H disease (i.e., Hb constant spring) or Hb C disease. 2. Subjects on concomitant ICT or subjects on prior ICT when discontinued less than 4 weeks prior randomisation. If ICT was discontinued ≥4 weeks prior randomization the subject is eligible. 3. ICT naïve subjects with serum ferritin <150 ng/ml and/or documented LIC ≤1 mg/g liver dry weight assessed through MRI, or subjects on prior ICT with serum ferritin <300 ng/ml and/or documented LIC <3 mg/g liver dry weight assessed through MRI. Note: If documented LIC MRI scans retrieved within 24 months prior to randomization are not available per local practice, serum ferritin will be used only to document iron overload status. 4. Subjects with TSAT <30%. 5. Subjects with documented LIC >15 mg/g liver dry weight assessed through MRI, or a documented myocardial T2* <20 ms, if available per local practice and retrieved within 24 months prior to randomization. 6. Adult or adolescent subjects with body weight <40.0 kg or >100 kg at screening. 7. Chronic liver disease and/or ALT, AST or GGT above 3-fold the ULN range at screening. Note: A subject fulfilling this criterion will be excluded but can be rescreened at a later time point (in order to fulfil eligibility, ≥2 values within ≥1 week should be assessed and be within eligibility limits). 8. eGFR <30 ml/min/1.73 m2 (according to chronic kidney disease classification Stage 4 or higher), and/or significant albuminuria >30 mg/mmol. eGFR should be estimated according to Chronic Kidney Disease Epidemiology Collaboration formula (CKI-EPI) in adults, and Schwartz formula in adolescents. 9. Newly diagnosed folate deficiency anaemia and/or Vitamin B12 megaloblastic anaemia. Subjects with known folate deficiency anaemia and/or Vitamin B12 megaloblastic anaemia who are on ≥12 weeks stable replacement therapy are eligible. Note: A subject fulfilling this criterion will be excluded but can be rescreened at a later time point. 10. Any history or clinically important finding of cardiac disorders, such as clinically relevant cardiac arrhythmia, cardiomyopathy, coronary disease, valve disorder, or heart failure according to New York Heart Association classification 3-4. 11. Subjects with history of partial or total splenectomy within 6 months prior to screening. |
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E.5 End points |
E.5.1 | Primary end point(s) |
• Reported or observed AEs: by SOC and PT (MedDRA coded term), by severity and relation to study product in each treatment group. • Reported or observed SAEs: by SOC and PT (MedDRA coded term), by severity and relation to study product in each treatment group. • Changes in vital signs (blood pressure, pulse rate, and respiratory rate), clinical laboratory safety tests (haematology, serum biochemistry, coagulation, and urinalysis), 12-lead ECG, and physical examination findings. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
For AEs: The AE reporting period ends at the last study contact Visit 9/Week 16. For SAEs: The SAE reporting period lasts until 4 weeks (28+-4 days) following the last study drug administration. For Changes in vital signs: during the study and until Visit 8/Week 12 |
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E.5.2 | Secondary end point(s) |
• Assessment of iron parameters (total serum iron, serum ferritin, serum transferrin, unsaturated iron binding capacity, calculated TSAT, from baseline over a 12-week period (absolute and change from baseline)). • PK parameters: Individual estimates of Cmax, clearance, distribution volume, AUC will be obtained using a population PK approach in adult and adolescent subjects combined with suitable mathematical/statistical analysis, using nonlinear mixed-effects modelling. Sparse sampling for determination of VIT-2763 plasma concentration following multiple dosing will be obtained from pre-dose trough to 3 or 4 hours post-dose at selected study visits. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Iron parameters: prior to first administration and over a 12-week period • PK parameters: Blood samples for the determination of VIT-2763 plasma concentrations (sparse sampling) are collected on Visit 3 and Visit 7 at pre-dose trough and at approximately 1 hour and 4 hours post-dose, and on Visits 6 and 8 at pre-dose trough and approximately at 1 hour and 3 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 | No |
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 | No |
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 | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
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 | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 10 |
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 |
Greece |
Israel |
Italy |
Lebanon |
Thailand |
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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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 1 |
E.8.9.2 | In all countries concerned by the trial days | 0 |