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Trial details
ACENT 1
Current status:
Approved
|
Date registered:
26/03/2024
|
Date last updated:
01/02/2024
Trial version(s)
Current: 14/12/2023
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Main Information
Primary registry identifying number
LBCTR2024015480
Protocol number
NN7533-4470
MOH registration number
Trial already registered with the MoPH
Study registered at the country of origin
Type of registration
Prospective
Date of registration in national regulatory agency
15/01/2024
Primary sponsor
Novo Nordisk
Primary sponsor: Country of origin
Denmark
Public title
ACENT 1
Acronym
Scientific title
A multicentre trial evaluating the efficacy and safety of oral decitabine-tetrahydrouridine (NDec) in patients with sickle cell disease
Acronym
Brief summary of the study: English
Sickle cell disease (SCD) pathophysiology is driven by the polymerisation of mutated sickle cell haemoglobin (HbS) in red blood cells. Foetal haemoglobin (HbF) decreases polymerisation of HbS but is epigenetically silenced in early infancy and onward by DNA methyltransferase 1 (DNMT1). A mechanism to re-induce HbF expression is via epigenetic therapy by inhibiting DNMT1 activity. NDec is an oral formulation of a combination of decitabine and tetrahydrouridine. Decitabine depletes DNMT1 while tetrahydrouridine inhibits cytidine deaminase, the enzyme that otherwise rapidly deaminates/inactivates decitabine. The primary purpose of this trial is to investigate two dosing regimens of oral decitabinetetrahydrouridine (NDec) in terms of treatment-related effects on total haemoglobin and HbF as well as clinical efficacy and safety parameters compared with placebo in patients with SCD who are not receiving hydroxyurea (HU) treatment at screening (HU-non-eligible patients). An active comparator HU treatment arm is included to allow exploratory comparisons between NDec and HU in patients receiving HU treatment at screening (HU-active patients).
Brief summary of the study: Arabic
الفيزيولوجيا المرضية لمرض فقر الدم المنجلي (SCD) مدفوعة ببلمرة الهيموغلوبين المنجلي المتحور (HbS) في خلايا الدم الحمراء. يقلل الهيموغلوبين الجنيني (HbF) من بلمرة HbS ولكن يتم إسكاته وراثيا في مرحلة الطفولة المبكرة وما بعدها بواسطة DNA methyltransferase 1 (DNMT1). آلية إعادة تحفيز تعبير HbF هي عن طريق العلاج اللاجيني عن طريق تثبيط نشاط DNMT1. NDec عبارة عن تركيبة فموية لمزيج من ديسيتابين وتتراهيدرويوريدين. يستنفد ديسيتابين الDNMT1 بينما يثبط رباعي هيدرووريدين الديأميناز السيتيدين، وهو الإنزيم الذي يزيل / يعطل ديسيتابين بسرعة. الغرض الأساسي من هذه التجربة هو التحقيق في نظامين لجرعات ديسيتابينيتتراهيدروريدين عن طريق الفم (NDec) من حيث التأثيرات المرتبطة بالعلاج على إجمالي الهيموغلوبين و HbF بالإضافة إلى الفعالية السريرية ومعايير السلامة مقارنة بالدواء الوهمي في المرضى الذين يعانون من SCD الذين لا يتلقون علاج هيدروكسي يوريا (HU) عند الفحص (المرضى غير المؤهلين ل HU). يتم تضمين ذراع علاج HU للمقارنة النشطة للسماح بإجراء مقارنات استكشافية بين NDec و HU في المرضى الذين يتلقون علاج HU عند الفحص (المرضى النشطين في HU).
Health conditions/problem studied: Specify
Patients with Sickle Cell Disease.
Interventions: Specify
Patients will be receiving a new medication oral decitabinetetrahydrouridine (NDec).
Key inclusion and exclusion criteria: Inclusion criteria
Key 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 VOCs within the last 12 months prior to the screening visit - Haemoglobin ≥5.0 g/dL and ≤10.5 g/dL at visit 1 - Absolute reticulocyte (absolute) count above ULN at visit 1 - Body weight 40 to 125 kg (inclusive)
Key inclusion and exclusion criteria: Gender
Both
Key inclusion and exclusion criteria: Age minimum
18
Key inclusion and exclusion criteria: Age maximum
75
Key inclusion and exclusion criteria: Exclusion criteria
Key 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 >800 x 109/L at visit 1 - Absolute neutrophil count ≤1.5 x 109/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 or - 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
Type of Study
Type
Interventional
Type of intervention
Pharmaceutical
Trial scope
Other
Trial scope: Specify scope
Efficacy and safety
Study design: Allocation
Randomized controlled trial
Study design: Masking
Blinded (masking used)
Study design: Control
Placebo
Study phase
2
Study design: Purpose
Treatment
Study design: Assignment
Parallel
IMP has market authorization
No
Name of IMP
Oral decitabine-tetrahydrouridine
Type of IMP
Others
Type of IMP: Specify
Small Molecule
Pharmaceutical class
Haemoglobin F inducer
Therapeutic indication
Patients with sickle cell disease
Therapeutic benefit
NDec is being investigated for efficacy and safety for use as a disease-modifying treatment to prevent complications associated with SCD. NDec specifically targets the root cause of the disease (polymerization of haemoglobin S (HbS)), and treatment might therefore provide therapeutic benefits and improve outcomes. Among clinical benefits, patients may have fewer and/or less severe VOCs and a reduced need for blood transfusion when treated with NDec. They may also experience fewer hospital visits/admissions into hospital, and fewer days spent in hospital. Patients treated with NDec might also experience improvements in laboratory parameters predicting clinical benefits in laboratory parameters, including, but not limited to, an increase in total Hb and HbF levels and decreases in measures of haemolysis. HbF decreases erythrocyte sickling and subsequent haemolysis. Clinical observations and standard clinical practice indicate that an increase in total haemoglobin by decreasing haemolytic anaemia is clinically meaningful (improvement in an established surrogate for clinical benefit).
Biospecimen retention
Samples with DNA**
Biospecimen description
Genetic variation may impact a patient’s response to trial treatment, susceptibility to, and severity and progression of disease. Variable response to trial treatment may be due to genetic determinants that impact drug absorption, distribution, metabolism and excretion, mechanism of action of the drug, disease aetiology, and/or molecular subtype of the disease being treated. Therefore, where local regulations and IRB/IEC allow, samples will be collected for DNA analysis from consenting patients. DNA samples will be used for research related to NDec and SCD and other heamatological diseases. Genetic research may consist of the analysis of one or more candidate genes, or the analysis of genetic markers throughout the genome or analysis of the entire genome as appropriate.
Target sample size
87
Actual enrollment target size
Date of first enrollment: Type
Anticipated
Date of first enrollment: Date
26/02/2024
Date of study closure: Type
Anticipated
Date of study closure: Date
31/08/2025
Recruitment status
Pending
Date of completion
IPD sharing statement plan
No
IPD sharing statement description
Not applicable
Additional data URL
Summary Results
Secondary Identifying Numbers
Full name of issuing authority
Secondary identifying number
Sources of Monetary or Material Support
Name
Novo Nordisk A/S
Secondary Sponsors
Name
Contact for Public/Scientific Queries
Contact type
First name
Last name
Address
Country
Telephone
Email
Affiliation
Public
Badiaa
Masri
Sin el Fil, Azar building
Lebanon
009613003245
bams@novonordisk.com
Novo Nordisk Pharma SARL
Scientific
Antoine
Gebrayel
Sin el Fil, Azar Building
Lebanon
0096176586409
aogb@novonordisk.com
Novo Nordisk Pharma SARL
Centers/Hospitals Involved in the Study
Center/Hospital name
Name of principles investigator
Principles investigator speciality
Ethical approval
Nini Hospital
Dr. Adlette Inati
Paediatric Haematologist Oncologist
Approved
Ethics Review
Ethics approval obtained
Approval date
Contact name
Contact email
Contact phone
Nini Hospital
11/12/2023
Elias Bitar
NA
00961 6 431 400 Ext: 3164
Countries of Recruitment
Name
Lebanon
Turkey
United States of America
France
Spain
Italy
South Africa
Canada
Greece
India
United Kingdom
Health Conditions or Problems Studied
Condition
Code
Keyword
Sickel Cell
Sickle-cell disorders (D57)
Sickle cell disease (SCD) Foetal haemoglobin (HbF) mutated sickle cell haemoglobin (HbS)
Interventions
Intervention
Description
Keyword
HU-non-eligible block
NDec once weekly: 1 dose of active treatment and 1 dose of placebo on 2 consecutive days NDec twice weekly: 1 dose of active treatment on each of 2 consecutive days Placebo: 1 dose of placebo on each of 2 consecutive days
decitabine-tetrahydrouridine (NDec) Placebo
HU-active block
HU
hydroxyurea HU
Primary Outcomes
Name
Time points
Measure
Change in total haemoglobin
From baseline (week 0) to week 24
g/dL
Key Secondary Outcomes
Name
Time points
Measure
Cmax for decitabine from pharmacokinetic assessment
At week 24
ng/mL
Cmax for tetrahydrouridine from pharmacokinetic assessment
At week 24
ng/mL
Change in DNMT1 activity
From baseline (week 0) to week 24
MFI
Change in CDA activity
From baseline (week 0) to week 24
μmol/L/min
Change in foetal haemoglobin (g/dL)
From baseline (week 0) to week 24
g/dL
Number of adverse events ofgrade 3b or higher
From baseline (week 0) to week 52
Number of events
Trial Results
Summary results in Lebanon
Study results globally
Date of posting of results summaries
Date of first journal publication of results
Results URL link
Baseline characteristics
Participant flow
Adverse events
Outcome measures
URL to protocol files
Link(s) to publications related to the study
Changes History
Change
Date
Download as PDF
Save a PDF copy of the summary of the trial