Safety, Tolerability, Pharmacokinetics (PK), Pharmacodynamics (PD) and Preliminary Efficacy of VIT-2763 in β-thalassaemia
Condition: Beta-Thalassemia; Non-transfusion-dependent Thalassemia
MeSH terms: Thalassemia; beta-Thalassemia
Intervention: VIT-2763 once a day (QD); VIT-2763 twice a day (BID); Placebo
Intervention description: 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.; 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.; Participants will receive hard capsules of Placebo, twice a day.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention 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 (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking description: Participants will receive a randomisation number using a validated centralised procedure (IWRS) that automates the random assignment of treatment groups to randomisation numbers. The randomisation plan will be kept strictly confidential, accessible only to authorised persons, until the time of unblinding.
The study drugs (VIT-2763 or placebo) are provided in identical white opaque hard capsules in packaging of identical appearance.
Enrollment: 35.0
Sex: All
Minimum age: 12 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: Beta-Thalassemia

Summary:

      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).
    

Eligibility criteria:

        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.