Clinical Trials Register

Summary
EudraCT Number:	2020-003485-39
Sponsor's Protocol Code Number:	NN7533-4470
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2022-05-27
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

Italy - Italian Medicines Agency

A.2

EudraCT number

2020-003485-39

A.3

Full title of the trial

A multicentre trial evaluating the efficacy and safety of oral decitabinetetrahydrouridine (NDec) in patients with sickle cell disease

Studio multicentrico per valutare l’efficacia e la sicurezza di decitabina-tetraidrouridina (NDec) orale in pazienti affetti da anemia falciforme

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Research study investigating how well NDec works in people with sickle cell disease

Studio clinico per valutare l’efficacia di NDec in persone affette da anemia falciforme

A.3.2

Name or abbreviated title of the trial where available

Ascent 1

A.4.1

Sponsor's protocol code number

NN7533-4470

A.5.3

WHO Universal Trial Reference Number (UTRN)

U1111-1255-1324

A.5.4

Other Identifiers

Name:

Ascent 1

Number:

NN7533-4470

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	NOVO NORDISK. S.P.A.
B.1.3.4	Country	Italy
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Novo Nordisk A/S
B.5.2	Functional name of contact point	Clinical Transparency (2834)
B.5.3	Address:
B.5.3.1	Street Address	Novo Allé
B.5.3.2	Town/ city	Bagsværd
B.5.3.3	Post code	2880
B.5.3.4	Country	Denmark
B.5.6	E-mail	clinicaltrials@novonordisk.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Siklos
D.2.1.1.2	Name of the Marketing Authorisation holder	Addmedica
D.2.1.2	Country which granted the Marketing Authorisation	Italy
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	SIKLOS
D.3.2	Product code	[NA]
D.3.4	Pharmaceutical form
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Idrossicarbamide
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	Hydroxycarbamide
D.3.9.4	EV Substance Code	SUB08076MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1000
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/20/2338
D.3 Description of the IMP
D.3.1	Product name	Decitabine/Terahydrouridine A 5/250mg
D.3.2	Product code	[NN7533]
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	DECITABINA
D.3.9.1	CAS number	2353-33-5
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	Decitabine
D.3.9.4	EV Substance Code	SUB06932MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	5
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Tetraidrossiurudina
D.3.9.1	CAS number	18771-50-1
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	Tetrahydrouridine
D.3.9.4	EV Substance Code	SUB33651
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	250
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Sickle cell disease

Anemia falciforme

E.1.1.1

Medical condition in easily understood language

Chronic, inherited blood disorder that impacts haemoglobin, a protein found in red blood cells (RBCs) that carries oxygen throughout the body.

DIsordine cronico ereditario del sangue che impatta l'emoglobina, una proteina nei globuli rossi (RBC) che trasporta l'ossigeno nel corpo.

E.1.1.2

Therapeutic area

Diseases [C] - Blood and lymphatic diseases [C15]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	SOC
E.1.2	Classification code	10010331
E.1.2	Term	Congenital, familial and genetic disorders
E.1.2	System Organ Class	10010331 - Congenital, familial and genetic disorders

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To investigate the efficacy of two dosing regimens of oral decitabinetetrahydrouridine (NDec) combination as measured by improvement in haemoglobin compared to placebo in hydroxyurea (HU)-non-eligible patients with sickle cell disease (SCD).

Valutare l’efficacia di due regimi posologici della combinazione orale di decitabina-tetraidrouridina (NDec) misurata in base al miglioramento dell’emoglobina rispetto al placebo in pazienti HU-non eleggibili con anemia falciforme (AF).

E.2.2

Secondary objectives of the trial

1. To investigate the safety and tolerability of NDec in HU-non-active patients with SCD compared to placebo
2. To evaluate clinical efficacy measures of NDec in HU-non-active patients with SCD compared to placebo
3. To further describe the pharmacokinetics and pharmacodynamics of NDec in HU-non-active patients with SCD

1. Valutare la sicurezza e la tollerabilità di NDec in pazienti con AF HU-non eleggibili rispetto al placebo
2. Valutare le misure di efficacia clinica di NDec in pazienti con AF HU-non eleggibili rispetto al placebo
3. Descrivere ulteriormente la farmacocinetica e la farmacodinamica di NDec in pazienti con AF HU-non eleggibili.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Age above or equal to 18 years at the time of signing informed consent
• Confirmed diagnosis of SCD (including HbSS, HbSC, HbSß0 thalassaemia and HbSß+ thalassaemia)
• 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
• Reticulocyte count >1.5 x ULN at visit 1
• Body weight 40 to 125 kg (inclusive)

- Età maggiore o uguale a 18 anni al momento della firma del modulo di consenso informato
- Diagnosi confermata di AF (incluse talassemia HbSS, HbSC, HbSß0 e talassemia HbSß+)
- Aver manifestato 2-10 episodi di VOC documentati negli ultimi 12 mesi prima della visita di screening
- Emoglobina compresa tra =5,0 g/dl e =10,5 g/dl alla Visita 1
- Conta reticolocitaria >1,5 x limite superiore della norma (ULN) alla Visita 1
- Peso corporeo compreso tra 40 e 125 kg (entrambi inclusi)

E.4

Principal 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 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 or is of child-bearing potential and not using highly effective methods of contraception (or adequate contraceptive measures as required by local regulation or practice) starting at screening and throughout the trial period and for 6 months after the last dose of trial product
• Male of reproductive age 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 (or adequate contraceptive measure as required by local regulation or practice) from trial start to:
o Six (6) months after the last dose of trial product for patients on NDec/Placebo
o Six (6) months after the last dose of trial product for patients outside US and CA randomised to HU
o Twelve (12) months after the last dose of trial product for patients randomised to HU in US and CA

- Il paziente è sottoposto a terapia trasfusionale cronica, definita come la somministrazione di una serie programmata (pre-pianificata) di trasfusioni di sangue (semplici o a scambio) per scopi profilattici, oppure è probabile che il paziente inizi una terapia trasfusionale cronica nel corso della sperimentazione o abbia ricevuto trasfusioni di RBC o sangue intero per qualsiasi motivo entro 28 giorni dalla Visita 1
- Trattamento con eritropoietina o altro trattamento con fattori di crescita ematopoietici entro 28 giorni dalla firma del modulo di consenso informato o trattamento programmato con questi agenti durante lo studio
- Trattamento con voxelotor, crizanlizumab o L-glutammina entro 12 settimane dalla firma del modulo di consenso informato o trattamento programmato con questo agente durante lo studio
- Conta piastrinica >800 x 109/l alla Visita 1
- Conta assoluta dei neutrofili <1,5 x 109/l alla Visita 1
- Qualsiasi condizione/malattia cronica concomitante a carico dello stomaco o dell’intestino tenue che possa influire sull’assorbimento del farmaco, secondo il giudizio dello sperimentatore
- Donne in stato di gravidanza, che allattano al seno o che intendono iniziare una gravidanza entro 6 mesi dopo l’ultima dose del prodotto sperimentale o che sono in età fertile e non utilizzano metodi contraccettivi altamente efficaci (o misure contraccettive adeguate come richiesto dalla normativa o dalla pratica locale) a partire dallo screening per tutto il periodo della sperimentazione e per 6 mesi dopo l’ultima dose del prodotto sperimentale
- Soggetti di sesso maschile in età riproduttiva con partner di sesso femminile in età fertile che non accettano di utilizzare il preservativo e la cui partner in età fertile non utilizza un metodo contraccettivo altamente efficace (o una misura contraccettiva adeguata come richiesto dalla normativa o dalla pratica locale) dalla firma del modulo di consenso informato fino a:
• Sei (6) mesi dopo l’ultima dose del prodotto sperimentale per i pazienti che assumono NDec/placebo
• Sei (6) mesi dopo l’ultima dose del prodotto sperimentale per i pazienti al di fuori degli Stati Uniti e del Canada randomizzati a HU
• Dodici (12) mesi dopo l’ultima dose del prodotto sperimentale per i pazienti randomizzati a HU negli Stati Uniti e in Canada.

E.5 End points

E.5.1

Primary end point(s)

Change in total haemoglobin

Variazione dell’emoglobina totale

E.5.1.1

Timepoint(s) of evaluation of this end point

From baseline (week 0) to week 24

Dal basale (settimana 0) alla settimana 24

E.5.2

Secondary end point(s)

PK/PD endpoints:
1. Cmax for decitabine from pharmacokinetic assessment
2. Cmax for tetrahydrouridine from pharmacokinetic assessment
3. Change in DNMT1 activity
4. Change in CDA activity
Efficacy endpoints:
5. Change in foetal haemoglobin (g/dL)
6. Change in foetal haemoglobin as a proportion of total haemoglobin (%HbF)
7. Change in F-cell level as a proportion of total RBC (%F-cells)
8. Change in haemolysis measure: absolute reticulocyte count
9. Change in haemolysis measure: indirect bilirubin
10. Change in haemolysis measure: lactate dehydrogenase
11. Number of vaso-occlusive crises
12. Number of acute chest syndrome
13. Number of RBC units transfused
Safety endpoint:
14. Number of adverse events of grade 3 or higher

Endpoint di farmacocinetica e farmacodinamica:
1. Cmax per decitabina dalla valutazione farmacocinetica
2. Cmax per tetraidrouridina dalla valutazione farmacocinetica
3. Variazione dell’attività di DNMT1
4. Variazione dell’attività di CDA
Endpoint di efficacia:
5. Variazione dell’emoglobina fetale (g/dl)
6. Variazione dell’emoglobina fetale come percentuale dell’emoglobina totale (% HbF)
7. Variazione del livello di cellule F come percentuale di RBC totali (% cellule F)
8. Variazione nella misura dell’emolisi: conta assoluta dei reticolociti
9. Variazione nella misura dell’emolisi: bilirubina indiretta
10. Variazione nella misura dell’emolisi: lattato deidrogenasi
11. Numero di crisi vaso-occlusive
12. Numero di sindromi toraciche acute
13. Numero di unità di RBC trasfuse
14. Numero di eventi avversi di grado 3b o superiore

E.5.2.1

Timepoint(s) of evaluation of this end point

1. & 2. At week 24
3. - 10. From baseline (week 0) to week 24
11. - 13. From baseline (week 0) to week 48
14. From baseline (week 0) to week 52

1. & 2. Alla settimana 24
3. - 10. Dal basale (settimana 0) alla settimana 24
11. - 13. Dal basale (settimana 0) alla settimana 48
14. Dal basale (settimana 0) alla settimana 52

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Tolerability

Tollerabilità

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Double-dummy con un braccio ulteriore in aperto

Double-dummy with one additional open-label arm

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

Yes

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Diversi regimi di trattamento e placebo

Different treatment regimen and placebo

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Canada

India

South Africa

United States

Turkey

United Kingdom

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

Nessuno

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2022-08-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-06-08

P. End of Trial
P.	End of Trial Status	Ongoing

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials