Clinical Trials Register

Summary
EudraCT Number:	2020-003485-39
Sponsor's Protocol Code Number:	NN7533-4470
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2022-05-30
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

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A. Protocol Information

A.1

Member State Concerned

Spain - AEMPS

A.2

EudraCT number

2020-003485-39

A.3

Full title of the trial

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

Ensayo multicéntrico para evaluar la eficacia y la seguridad de decitabina-tetrahidrouridina (NDec) oral en pacientes con 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

Estudio de investigación sobre la eficacia de NDec en personas con anemia falciforme

A.4.1

Sponsor's protocol code number

NN7533-4470

A.5.3

WHO Universal Trial Reference Number (UTRN)

U1111-1255-1324

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 A/S
B.1.3.4	Country	Denmark
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	Novo Nordisk A/S
B.4.2	Country	Denmark
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	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.3.4	Pharmaceutical form	Capsule
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	Decitabine
D.3.9.1	CAS number	2353-33-5
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	Tetrahydrouridine
D.3.9.1	CAS number	18771-50-1
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	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
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	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	European Union
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.3.4	Pharmaceutical form	Film-coated 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	Hydroxycarbamide
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	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
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	Capsule
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.

Trastorno sanguíneo hereditario crónico que afecta la hemoglobina, una proteína que se encuentra en los glóbulos rojos (RBC) que transporta oxígeno por todo el cuerpo

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	21.0
E.1.2	Level	PT
E.1.2	Classification code	10040644
E.1.2	Term	Sickle cell disease
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 decitabine-tetrahydrouridine (NDec) combination as measured by improvement in haemoglobin compared to placebo in hydroxyurea (HU)-non-eligible patients with sickle cell disease (SCD).

Investigar la eficacia de dos regímenes posológicos de combinación oral de decitabina-tetrahidrouridina (NDec) medida en función de la mejoría de la hemoglobina en comparación con el placebo en pacientes con anemia de células falciformes (ACF) con hidroxicarbamida (HC)-no-elegible.

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.Investigar la seguridad y la tolerabilidad de NDec en pacientes con ACF sin HC activa en comparación con el placebo.
2. Evaluar las variables de la eficacia clínica de NDec en pacientes con ACF sin HC activa en comparación con el placebo.
3. Describir mejor la farmacocinética y la farmacodinamia de NDec en pacientes con ACF sin HC activa.

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, HbSβ0 thalassaemia and HbSβ+ 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)

- Edad de 18 o más años en el momento de firmar el consentimiento informado.
- Diagnóstico confirmado de ACF (incluidas HbSS, HbSC, HbSβ0-talasemia y HbSβ+ talasemia.
- 2-10 episodios de CVO documentados en los últimos 12 meses previos a la visita de selección.
- Hemoglobina mayor o igual a 5,0 g/dl y menor o igual a 10,5 g/dl en la visita 1.
- Recuento de reticulocitos mayor de 1,5 x LSN en la visita 1.
- Peso corporal de 40 a 125 kg (incluidos).

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

- Paciente en terapia de transfusión crónica, definido como la recepción de una serie programada (prevista de antemano) de transfusiones de sangre (simple o de intercambio) con fines profilácticos, o paciente que pueda comenzar terapia de transfusión crónica durante el ensayo, o que haya recibido transfusiones de eritrocitos o sangre completa por cualquier motivo en los 28 días previos a la visita 1.
- Recepción de eritropoyetina u otro tratamiento con factores de crecimiento hematopoyéticos en los 28 días previos a la firma del consentimiento informado (CI) o tratamiento previsto con estos fármacos durante el ensayo.
- Tratamiento con voxelotor, crizanlizumab o L-glutamina en los 28 días previos a la firma del consentimiento informado o tratamiento previsto con estos fármacos durante el ensayo.
- Recuento de plaquetas mayor de 800 x 109/l en la visita 1
- Recuento absoluto de neutrófilos menor de 1,5 x 109/l en la visita 1
- Cualquier trastorno o enfermedad crónica concurrente que afecte al estómago o al intestino delgado y que pueda afectar a la absorción del fármaco, según el criterio del investigador.
- Mujeres embarazadas, lactantes o que tengan intención de quedarse embarazadas en los 6 meses siguientes a la administración del producto del ensayo o que estén en edad fértil y no utilicen métodos anticonceptivos altamente eficaces (o medidas anticonceptivas adecuadas según lo exigido por la normativa o práctica locales) desde la selección, durante todo el período del ensayo y hasta 6 meses después de la última dosis del producto del ensayo.
- Varones en edad fértil con pareja femenina en edad fértil que no se comprometan a utilizar preservativo y cuya pareja femenina en edad fértil no utilice un método anticonceptivo altamente eficaz (o un método anticonceptivo adecuado conforme a la normativa o práctica locales) desde el comienzo del ensayo hasta:
a. Seis (6) meses después de la última dosis del producto del ensayo en el caso de los pacientes tratados con NDec/placebo.
b. Seis (6) meses después de la última dosis del producto del ensayo en el caso de pacientes fuera de EE. UU. Y CA aleatorizados para recibir HC.
c. Doce (12) meses después de la última dosis del producto del ensayo en los pacientes aleatorizados para recibir HC en EE. UU. y CA.

E.5 End points

E.5.1

Primary end point(s)

Change in total haemoglobin

Variación de la hemoglobina total

E.5.1.1

Timepoint(s) of evaluation of this end point

From baseline (week 0) to week 24

Entre el momento basal (semana 0) y la semana 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

Criterios de valoración farmacocinéticos y farmacodinámicos:
1. Cmáx de decitabina a partir de la evaluación farmacocinética
2. Cmáx de tetrahidrouridina a partir de la evaluación farmacocinética
3. Cambio en la actividad DNMT1
4. Cambio en la actividad CDA

Criterios de valoración de eficacia:
5. Variación de la hemoglobina fetal (g/dL)
6. Variación de la hemoglobina fetal como proporción de la hemoglobina total (%HbF)
7. Variación de la cantidad de células F como proporción del total de eritrocitos (% de células F)
8. Cambio en la medida de hemólisis: recuento absoluto de reticulocitos
9. Cambio en la medida de hemólisis: bilirrubina indirecta
10. Cambio en la medida de hemólisis: lactato deshidrogenasa
11. Número de crisis vaso-oclusivas
12. Número de síndrome torácico agudo
13. Número de unidades de RBC transfundidas

Criterios de valoración de seguridad:
14. Número de acontecimientos adversos de grado 3 o superior

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.-3. En la semana 24
3. - 10. Desde el momento basal (semana 0) hasta la semana 24
11. - 13. Desde el momento basal (semana 0) hasta la semana 48
14. Desde el momento basal (semana 0) hasta la semana 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

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

Yes

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

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

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

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

European Union

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

UVUP

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

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

2022-08-30

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-06-27

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

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