What side effects are associated with this type of intervention?

Common treatments for Sickle Cell Disease, such as Hydroxyurea, can cause side effects including bone marrow suppression leading to neutropenia, thrombocytopenia, and anemia. Patients may also experience gastrointestinal symptoms like nausea and loss of appetite. Decitabine, a DNA Methyltransferase Inhibitor, can similarly cause cytopenias, febrile neutropenia, and increased risk of infections. Tetrahydrouridine, a Cytidine Deaminase Inhibitor, is less well-studied but may share similar side effects due to its role in enhancing the efficacy of Decitabine. Monitoring blood counts and managing infections are critical aspects of managing these side effects.

What prior FDA approvals exist?

The FDA has approved several treatments for Sickle Cell Disease (SCD), including Hydroxyurea, which increases fetal hemoglobin levels and reduces complications. L-glutamine oral powder (Endari) is another approved treatment that helps reduce acute complications of SCD. Voxelotor (Oxbryta) and Crizanlizumab (Adakveo) are more recent approvals; Voxelotor works by increasing hemoglobin's affinity for oxygen, while Crizanlizumab is a monoclonal antibody that reduces the frequency of vaso-occlusive crises. While Decitabine and Tetrahydrouridine are being studied in the NDec trial for their potential in SCD treatment, they are not yet FDA-approved for this specific indication.

What other types of research exist?

Promising novel alternatives to NDec for Sickle Cell Disease patients include voxelotor, which improves hemoglobin levels and reduces hemolysis, and crizanlizumab, which reduces the frequency of vaso-occlusive crises by inhibiting P-selectin. Both have shown efficacy in clinical trials and are considered significant advancements in SCD management.

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Anti-metabolites

NDec for Sickle Cell Disease (ASCENT1 Trial)

Phase 2

Recruiting

Research Sponsored by Novo Nordisk A/S

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

2-10 episodes of documented vaso-occlusive crisis (VOCs) within the last 12 months prior to the screening visit

Body weight 40 to 125 kg (inclusive)

Must not have

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 randomized to HU, Twelve (12) months after the last dose of trial product for patients randomized to HU in US and CA

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

Timeline

Screening 3 weeks

Treatment Varies

Follow Up from baseline (week 0) to week 52

Summary

This trial tests a new medicine called NDec for people with sickle cell disease. NDec combines two drugs to help manage the disease. Participants will take capsules regularly over several months to see how well the medicine works and if it is safe.

Who is the study for?

Adults over 18 with sickle cell disease (SCD), having had 2-10 pain episodes in the last year, and specific blood criteria can join. Excluded are those on chronic transfusions, recent other treatments for SCD, certain blood counts outside normal ranges, pregnant or breastfeeding women, and those not using effective contraception.

What is being tested?

The trial is testing NDec—a new oral medication combining decitabine-tetrahydrouridine—against a placebo and Hydroxyurea (HU) in people with SCD. Participants will be randomly assigned to receive either NDec capsules twice weekly or continue HU/placebo for about a year.

What are the potential side effects?

Potential side effects of NDec aren't detailed here but may include typical drug reactions such as digestive issues, possible blood count changes due to its nature as a treatment for SCD. Side effects from HU could involve skin ulcers, nausea, headache and dizziness.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I have had 2-10 painful episodes related to my condition in the last year.

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My weight is between 40 and 125 kg.

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I have been diagnosed with sickle cell disease.

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I am 18 years old or older.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I am a male willing to use a condom, and my partner uses effective birth control during the trial and for up to 12 months after.

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I am on or likely to start regular blood transfusions, or had a transfusion within the last 28 days.

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I haven't taken any blood cell growth factor treatments in the last 28 days.

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I am not pregnant, breastfeeding, nor plan to become pregnant soon.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ from baseline (week 0) to week 52

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~from baseline (week 0) to week 52

This trial's timeline: 3 weeks for screening, Varies for treatment, and from baseline (week 0) to week 52 for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Change in total haemoglobin

Secondary study objectives

Change in DNA methyltransferase 1 (DNMT1) activity

Change in F-cell level as a proportion of total red blood cell (RBC) (%F-cells)

Change in cytidine deaminase (CDA) activity

+11 more

Trial Design

6Treatment groups

Experimental Treatment

Active Control

Placebo Group

Group I: HU-non-eligible - NDec plus placeboExperimental Treatment2 Interventions

HU-non eligible patients randomised to treatment with NDec on one day and placebo on the other day

Group II: HU-non-eligible - NDec plus NDecExperimental Treatment1 Intervention

HU-non eligible patients randomised to treatment with NDec on both days

Group III: HU-active - NDec plus placeboExperimental Treatment2 Interventions

HU-active patients randomised to treatment with NDec on one day and placebo on the other day

Group IV: HU-active - NDec plus NDecExperimental Treatment1 Intervention

HU-active patients randomised to treatment with NDec on both days

Group V: HU-active - HUActive Control1 Intervention

HU-active patients randomised to continue on open-label HU treatment

Group VI: HU-non-eligible - Placebo plus placeboPlacebo Group1 Intervention

HU-non eligible patients randomised to treatment with placebo on both days

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Placebo

1995

Completed Phase 3

~2670

0 / 8Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Common treatments for Sickle Cell Disease (SCD) include hydroxyurea and hypomethylating agents like decitabine. Hydroxyurea works by increasing fetal hemoglobin (Hb F) production, which reduces the sickling of red blood cells and decreases vaso-occlusive events. Decitabine, a DNA methyltransferase inhibitor, also increases Hb F levels by demethylating DNA and reactivating the gamma-globin gene. Tetrahydrouridine, a cytidine deaminase inhibitor, enhances the efficacy of decitabine by preventing its degradation. These mechanisms are crucial for SCD patients as they help reduce the frequency and severity of painful crises and other complications by improving red blood cell function and reducing hemolysis.

5-Azacytidine increases gamma-globin synthesis and reduces the proportion of dense cells in patients with sickle cell anemia.