Efficacy and Safety Evaluation of Oral Decitabine-Tetrahydrouridine in Hydroxyurea-Non-Eligible Sickle Cell Disease Patients

The primary objective of this multicentre trial is to investigate the **efficacy** of two dosing regimens of oral decitabine-tetrahydrouridine (NDec) combination, as measured by improvement in **haemoglobin** levels, compared to placebo in hydroxyurea (HU)-non-eligible patients with **sickle cell disease** (SCD). This is clinically relevant as it aims to provide an alternative treatment option for patients who cannot use HU, potentially improving their quality of life and disease management.

Secondary objectives include:

• Investigating the **safety** and tolerability of NDec in HU-non-eligible patients with SCD compared to placebo.
• Evaluating clinical **efficacy** measures of NDec in HU-non-eligible patients with SCD compared to placebo.
• Further describing the **pharmacokinetics** and **pharmacodynamics** of NDec in HU-non-eligible patients with SCD.

The clinical trial involves a total of **72 participants** diagnosed with **sickle cell disease**. The study population includes both male and female subjects, aged 18 years and older, who are not eligible for hydroxyurea treatment. Participants were selected based on specific criteria, including a confirmed diagnosis of sickle cell disease variants such as HbSS, HbSC, HbSβ0 thalassemia, and HbSβ+ thalassemia. The health status of participants is characterized by having experienced 2 to 10 episodes of documented vaso-occlusive crises within the last 12 months prior to the screening visit. Additionally, participants have a hemoglobin level between 5.0 g/dL and 10.5 g/dL and an absolute reticulocyte count above the upper limit of normal at the initial visit. The body weight of participants ranges from 40 to 125 kg. The trial does not include a vulnerable population, and no specific lifestyle considerations such as diet or physical activity are highlighted in the selection process.

The clinical trial is designed to evaluate the efficacy and safety of oral **decitabine-tetrahydrouridine** in patients with **sickle cell disease**. This is a phase II, randomized, double-blind, placebo-controlled study. The trial will involve a total duration of 52 weeks, with the primary endpoint assessed at week 24 and secondary endpoints extending to week 52. Participants will be randomly assigned to receive either the investigational product, a comparator, or a placebo. The study will include multiple visits to ensure comprehensive data collection and participant safety.

The sequence of study visits begins with an inclusion (screening) visit, where eligibility criteria are confirmed, including age, diagnosis of sickle cell disease, and specific hematological parameters. Following successful screening, participants will be enrolled and randomized. Subsequent visits will occur at regular intervals to monitor safety, efficacy, and pharmacokinetic parameters. The primary endpoint, change in total hemoglobin, will be evaluated from baseline to week 24. Secondary endpoints include pharmacokinetic assessments and changes in various hematological and clinical parameters.

The end-of-study visit will occur at week 52, marking the conclusion of participant involvement. Participants are expected to be involved for the entire duration of the trial unless early termination is warranted. Conditions for early termination include the occurrence of adverse events of grade 3 or higher, withdrawal of consent, or any other medical reasons deemed necessary by the investigator. The trial aims to provide valuable insights into the treatment of sickle cell disease, with a focus on improving hemoglobin levels and reducing disease-related complications.

The clinical trial involves the administration of **Decitabine/Tetrahydrouridine A 5/250 mg**, which is an experimental medication formulated as a hard capsule. This pharmaceutical product contains two active chemical substances: **decitabine** and **tetrahydrouridine**. The capsules are administered orally. The dosing regimen is designed to evaluate the efficacy and safety of this combination in patients with sickle cell disease over a maximum treatment period of 48 weeks. The specific dosage and frequency of administration are not detailed in the provided data. Participant compliance with the dosing schedule will be monitored throughout the trial.

In addition to the experimental treatment, the study includes the use of **Siklos 1 000 mg film-coated tablet** as a comparator treatment. This medication contains the active substance **hydroxycarbamide** and is also administered orally. The role of Siklos in the trial is to serve as a standard-of-care therapy for comparison against the experimental treatment. The maximum treatment period for this comparator is also 48 weeks, with the dosage expressed in milligrams per kilogram, although specific dosing details are not provided.

A **placebo** is utilized in the trial to further assess the efficacy of the experimental treatment. The placebo is referred to as Placebo (NDec) and does not contain any active substances. The form and route of administration for the placebo are not specified in the data. The placebo is used to provide a baseline for evaluating the effects of the experimental medication in hydroxyurea-non-eligible patients with sickle cell disease.

The efficacy of the clinical trial evaluating oral decitabine-tetrahydrouridine (NDec) in patients with sickle cell disease will be assessed using specific primary and secondary endpoints. The primary endpoint is the change from baseline (week 0) to week 24 in total **haemoglobin** levels measured in g/dL. This parameter will provide a direct measure of the treatment's impact on haemoglobin levels, which is a critical factor in managing sickle cell disease.

Secondary endpoints include a range of pharmacokinetic and pharmacodynamic measures. These include the maximum concentration (Cmax) of decitabine and tetrahydrouridine at week 24, changes in DNMT1 and CDA activity, and changes in foetal haemoglobin levels and proportions. Additionally, changes in haemolysis measures such as absolute reticulocyte count, indirect bilirubin, and lactate dehydrogenase will be evaluated. Clinical outcomes such as the number of vaso-occlusive crises, acute chest syndrome events, and red blood cell units transfused will also be monitored from baseline to week 48. The number of adverse events of grade 3 or higher will be recorded up to week 52.

These efficacy parameters will be collected and analyzed at specified timepoints throughout the trial, using validated laboratory tests and clinical assessments. The comprehensive evaluation of these endpoints will provide a robust assessment of the treatment's efficacy in improving clinical outcomes for patients with sickle cell disease.