Safety, Tolerability, Pharmacokinetics (PK), Pharmacodynamics (PD) and Preliminary Efficacy of VIT-2763 in β-thalassaemia

Study Overview
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Brief Summary
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This is a randomised, double-blind, placebo-controlled parallel group trial to investigate the safety, tolerability and efficacy of multiple doses of VIT-2763 versus placebo in participants with non-transfusion-dependent Beta-thalassemia (NTDT).

Detailed Description
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The study includes a 12-week treatment period and a safety follow-up period of 4 weeks. About 36 participants (adults and adolescents) are expected to take part in this study at a number of different institutions internationally. Adult Participants (Cohort I) will be randomized to receive either VIT-2763 once daily (QD) or twice daily (BID) or placebo, at a dose of 120 mg or 60mg depending on their body weight. Following cohort I review, adolescent participants (Cohort II) will be randomized to the same study arms with the same interventions. The study medication will be given as oral capsules, containing 60 mg of VIT-2763 or placebo.

Official Title
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A Phase 2a, Double-blind, Randomised, Placebo-controlled, Parallel Group, Multicentre Study on Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Preliminary Efficacy of Multiple Doses of VIT-2763 in Subjects With Non-transfusion Dependent β-thalassaemia

Conditions
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Beta-Thalassemia, Non-transfusion-dependent Thalassemia

Intervention / Treatment
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* Drug: VIT-2763 once a day (QD)
* Drug: VIT-2763 twice a day (BID)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented diagnosis of NTDT, including a β-thalassemia intermedia-phenotype. NTDT is defined as subjects having received less than 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 packed RBCs and last RBC transfusion must have been received at east 14 days prior to randomisation). Male and female adult NTDT subjects, 18-65 years of age inclusive (Cohort I only) at time of screening. Male and female adolescent NTDT subjects, 12-17 years of age inclusive (Cohort II only) at time of screening. Subjects must have a mean baseline hemoglobin (Hb) equal to or lower than 11 g/dl, based on at least 2 consecutive measurements with at least 1 week apart within 6 weeks prior to randomisation/baseline. Exclusion Criteria: Documented diagnosis of transfusion dependent thalassemia (TDT), including a beta-thalassemia major phenotype (including β0/β0, β+/β+, β0/β+ genotype), and mixed compound heterozygous for sickling phenotype variants such as Hb S/β- thalassemia, or transfusion dependent non-deletional Hb H disease (i.e., Hb constant spring) or Hb C disease. Subjects on concomitant iron chelation therapy (ICT) or subjects on prior ICT when discontinued less than 4 weeks prior randomisation. If ICT was discontinued at least 4 weeks prior randomization the subject is eligible. ICT naïve subjects or subjects who discontinued ICT therapy at least 6 months before the screening visit with serum ferritin lower than 150 ng/ml and/or documented liver iron concentration (LIC) equal to or lower than 1 mg/g liver dry weight assessed through magnetic resonance imaging (MRI), or subjects on prior ICT with serum ferritin lower than 300 ng/ml and/or documented LIC lower than 3 mg/g liver dry weight assessed through MRI. Subjects with transferrin saturation (TSAT) less than 30%. Subjects with documented LIC greater than 15 mg/g liver dry weight assessed through MRI, or a documented myocardial T2* less than 20 ms, if available per local practice and retrieved within 24 months prior to randomization. Adult or adolescent subjects with body weight lower than 40.0 kg or greater than 100 kg at screening. Chronic liver disease and/or alanine transaminase (ALT), aspartate transaminase (AST) or gamma-glutamyl transpeptidase (GGT) above 3-fold the upper limit of normal (ULN) range at screening. Estimated glomerular filtration rate (eGFR) less than 30 ml/min/1.73 m2 (according to chronic kidney disease classification Stage 4 or higher), and/or significant albuminuria greater than 30 mg/mmol. eGFR should be estimated according to Chronic Kidney Disease Epidemiology Collaboration formula (CKI-EPI) in adults, and Schwartz formula in adolescents. Newly diagnosed folate deficiency anemia and/or Vitamin B12 megaloblastic anemia. Subjects with known folate deficiency anemia and/or Vitamin B12 megaloblastic anemia who are on at least 12 weeks stable replacement therapy are eligible. 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. Subjects with history of partial or total splenectomy within 6 months prior to screening.

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Multiple dose, multicenter, double-blind, placebo-controlled parallel group study in adult and adolescent male and female subjects with non-transfusion dependent thalassemia (NTDT)
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: VIT-2763 Once a day (QD)<br>Participants will be assigned to receive VIT-2763 once a day (QD) in a total daily dose of 60 mg or 120 mg depending on their body weight. The study medication (VIT-2763 and/or matching placebo) will be administered for all participants twice a day to maintain the blind. | Drug: VIT-2763 once a day (QD)<br>* Participants will receive VIT-2763 QD at a dose of 60 mg if their body weight is between 40 kg to 59 kg or at a dose of 120 mg if their body weight is between 60 kg and 100 kg, during 12 weeks.<br>|
| Experimental: VIT-2763 Twice a day (BID)<br>Participants will be assigned to receive VIT-2763 Twice a day (BID) in a total daily dose of 60 mg or 120 mg depending on their body weight. | Drug: VIT-2763 twice a day (BID)<br>* Participants will receive VIT-2763 BID at a dose of 60 mg if their body weight is between 40 kg to 59 kg or at a dose of 120 mg if their body weight is between 60 kg and 100 kg, during 12 weeks.<br>|
| Placebo Comparator: Placebo<br>Participants will be assigned to receive Placebo, Twice a day. | Drug: Placebo<br>* Participants will receive hard capsules of Placebo, twice a day.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Please note that in this section we are presenting just the overview of the adverse events experienced by the trial participants, in particular, the number of participants with at least one TEAE. Please refer to the detailed tables included on the Adverse Event Module for specifics. | From baseline to Week 16 | 
| Changes in the Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | Summary of the values by visit from baseline and changes from baseline by post-baseline visit. | From baseline to Week 12 | 
| Changes in the Heart Rate | Summary of the values by visit from baseline and changes from baseline by post-baseline visit. | From baseline to Week 12 | 
| Changes in 12-lead Electrocardiogram (ECG) Parameters | Values by visit from baseline and changes from baseline by post-baseline visit. The following ECG parameters were recorded: PR interval, QRS duration, QT interval, RR interval and QTcF interval. PR interval represents the time from the onset of the P wave to the start of the QRS complex. QRS duration represents the time required for a stimulus to spread through the ventricles (ventricular depolarization). QT interval represents the time from the start of the Q wave to the end of the T wave. RR interval represents the time from the onset of one R wave to the onset of the next one, one complete cardiac cycle. QT corrected for heart rate (QTc) interval reflects ventricular repolarization. | From baseline to Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Total Serum Iron | Assessment of total serum Iron from baseline over a 12-week period (absolute and change from baseline). For the serum iron parameter, the 'Baseline' was collected during the screening period within the biochemistry sample. | From baseline to Week 12 | 
| Change From Baseline in Serum Ferritin | Assessment of serum ferritin from baseline over a 12-week period (absolute and change from baseline). For the serum ferritin parameter, the 'Baseline' was collected during the screening period within the biochemistry sample. | From baseline to Week 12 | 
| Change From Baseline in Serum Transferrin | Assessment of serum transferrin from baseline over a 12-week period (absolute and change from baseline). For the serum transferrin parameter, the Baseline 2h post-dose was defined as the value at Visit 3 2h post-dose. | From baseline to Week 12 | 
| Change From Baseline in Calculated Transferrin Saturation (TSAT) ) | Assessment of TSAT from baseline over a 12-week period (absolute and change from baseline). For the calculated transferrin saturation parameter, the 'Baseline' was collected during the screening period within the biochemistry sample. Transferrin Saturation (TSAT) was calculated as Total Iron /Total Iron Binding Capacity (TIBC) X 100. | From baseline to Week 12 | 
| Pharmacokinetics Parameters - VIT-2763 Plasma Concentration Over Time | Sparse sampling for determination of VIT-2763 plasma concentration following multiple dosing was obtained from pre-dose trough to 3 hours or 4 hours post-dose at selected study visits. Pharmacokinetics parameters (Cmax, clearance, distribution volume, area under the curve (AUC) were not calculated for the study. | Baseline, Week 4, Week 8 and Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Beta-Thalassemia