Research Study Investigating How Well NDec Works in People With Sickle Cell Disease

Study Overview
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Brief Summary
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This study examines how well a new, potential medicine called NDec works and is tolerated in people with sickle cell disease. NDec is a combination of two medicines (decitabine-tetrahydrouridine). Both medicines are new for the treatment of sickle cell disease. Participants who are not taking Hydroxyurea (HU) will get NDec, NDec and placebo, or placebo. Participants who are on HU treatment before joining the study will get NDec, NDec and placebo, or continue on HU. Which treatment participants get is decided by chance. Participants getting NDec and/or Placebo will get capsules to take twice weekly. The study will last for about a year.

Official Title
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A Multicentre Trial Evaluating the Efficacy and Safety of Oral Decitabine Tetrahydrouridine (NDec) in Patients With Sickle Cell Disease

Conditions
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Sickle Cell Disease

Intervention / Treatment
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* Drug: NDec - oral decitabine-tetrahydrouridine
* Drug: HU - Hydroxyurea
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age above or equal to 18 years at the time of signing informed consent Confirmed diagnosis of SCD (including HbSS, HbSC, HbSβ0 thalassaemia and HbSβ+ thalassaemia or other Sickle Cell disease variants) 2-10 episodes of documented vaso-occlusive crisis (VOCs) within the last 12 months prior to the screening visit Haemoglobin greater than or equal to 5.0 g/dL and below or equal to 10.5 g/dL at visit 1 Absolute reticulocyte count above upper limit of the normal (ULN) at visit 1 Body weight 40 to 125 kg (inclusive). Exclusion Criteria: Patient is on chronic transfusion therapy as defined by receiving scheduled (pre-planned) series of blood transfusion (simple or exchange) for prophylactic purposes, or the patient is likely to begin chronic transfusion therapy during the course of the trial, or has received RBC or whole blood transfusion for any reason within 28 days of visit 1 Receipt of erythropoietin or other haematopoietic growth factor treatment within 28 days of signing ICF, or planned treatment with these agents during the trial Receipt of voxelotor, crizanlizumab or L-glutamine treatment within 12 weeks of signing the informed consent form, or planned treatment with such agents during the trial Platelet count greater than 800 x 10^9/L at visit 1 Absolute neutrophil count below or equal to 1.5 x 10^9/L at visit 1 Any condition/concurrent chronic disease involving the stomach or small intestine which may affect drug absorption, as per investigator's judgement Female who is pregnant, breast-feeding or intends to become pregnant within 6 months after the final trial product administration child-bearing potential and not using highly effective methods of contraception and whose male partner is not using effective contraception, at screening and until 6 months after the last dose of trial product Male with female partner of childbearing potential who does not agree to use condom and whose female partner of childbearing potential is not using a highly effective contraceptive measure from trial start to: Six (6) months after the last dose of trial product for patients on NDec/Placebo Six (6) months after the last dose of trial product for patients outside US and CA randomised to HU Twelve (12) months after the last dose of trial product for patients randomised to HU in US and CA

Ages Eligible for Study
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Minimum Age: 18 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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HU-non-eligible - NDec plus placebo<br>HU-non eligible patients randomised to treatment with NDec on one day and placebo on the other day | Drug: NDec - oral decitabine-tetrahydrouridine<br>* Participants will get capsules (oral administration) to take once or twice weekly. The number of capsules will be based on their body weight<br>Drug: Placebo<br>* Participants will get capsules (oral administration) to take once or twice weekly. The number of capsules will be based on their body weight<br>|
| Experimental: HU-non-eligible - NDec plus NDec<br>HU-non eligible patients randomised to treatment with NDec on both days | Drug: NDec - oral decitabine-tetrahydrouridine<br>* Participants will get capsules (oral administration) to take once or twice weekly. The number of capsules will be based on their body weight<br>|
| Placebo Comparator: HU-non-eligible - Placebo plus placebo<br>HU-non eligible patients randomised to treatment with placebo on both days | Drug: Placebo<br>* Participants will get capsules (oral administration) to take once or twice weekly. The number of capsules will be based on their body weight<br>|
| Experimental: HU-active - NDec plus placebo<br>HU-active patients randomised to treatment with NDec on one day and placebo on the other day | Drug: NDec - oral decitabine-tetrahydrouridine<br>* Participants will get capsules (oral administration) to take once or twice weekly. The number of capsules will be based on their body weight<br>Drug: Placebo<br>* Participants will get capsules (oral administration) to take once or twice weekly. The number of capsules will be based on their body weight<br>|
| Experimental: HU-active - NDec plus NDec<br>HU-active patients randomised to treatment with NDec on both days | Drug: NDec - oral decitabine-tetrahydrouridine<br>* Participants will get capsules (oral administration) to take once or twice weekly. The number of capsules will be based on their body weight<br>|
| Active Comparator: HU-active - HU<br>HU-active patients randomised to continue on open-label HU treatment | Drug: HU - Hydroxyurea<br>* Participants will get capsules daily (oral administration) according to local labelling<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in total haemoglobin | measured in g/dL | From baseline (week 0) to week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax for decitabine from pharmacokinetic assessment | measured in ng/mL | At week 24 | 
| Cmax for tetrahydrouridine from pharmacokinetic assessment | measured in ng/mL | At week 24 | 
| Change in DNA methyltransferase 1 (DNMT1) activity | measured in MFI units | From baseline (week 0) to week 24 | 
| Change in cytidine deaminase (CDA) activity | µmol/L/min | From baseline (week 0) to week 24 | 
| Change in foetal haemoglobin (g/dL) | measured in g/dL | From baseline (week 0) to week 24 | 
| Change in foetal haemoglobin as a proportion of total haemoglobin (%HbF) | measured in % | From baseline (week 0) to week 24 | 
| Change in F-cell level as a proportion of total red blood cell (RBC) (%F-cells) | measured in % | From baseline (week 0) to week 24 | 
| Change in haemolysis measure: absolute reticulocyte count | measured in cells × 10^9/L | From baseline (week 0) to week 24 | 
| Change in haemolysis measure: indirect bilirubin | measured in mg/dL | From baseline (week 0) to week 24 | 
| Change in haemolysis measure: lactate dehydrogenase | measured in U/L | From baseline (week 0) to week 24 | 
| Number of vaso-occlusive crises | number of events | From baseline (week 0) to week 48 | 
| Number of acute chest syndrome | number of events | From baseline (week 0) to week 48 | 
| Number of RBC units transfused | measured in Units | From baseline (week 0) to week 48 | 
| Number of adverse events of grade 3 or higher | number of events | From baseline (week 0) to week 52 |