Clinical Trials Register

Summary
EudraCT Number:	2018-004891-36
Sponsor's Protocol Code Number:	NN7415-4307
National Competent Authority:	Portugal - INFARMED
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2019-11-13
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

Portugal - INFARMED

A.2

EudraCT number

2018-004891-36

A.3

Full title of the trial

Efficacy and Safety of Concizumab prophylaxis in patients with haemophilia A or B without inhibitors

A.3.1

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

Research study to look at how well the drug concizumab works in your body if you have haemophilia without inhibitors

A.3.2

Name or abbreviated title of the trial where available

explorer8

A.4.1

Sponsor's protocol code number

NN7415-4307

A.5.3

WHO Universal Trial Reference Number (UTRN)

U1111-1225-9722

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 Alle 1
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D.2.5.1	Orphan drug designation number	EMA/OD/095/12, EMA/OD/116/17 (withdrawn)
D.3 Description of the IMP
D.3.1	Product name	Concizumab C 100 mg/mL PDS290
D.3.4	Pharmaceutical form	Solution for injection in pre-filled pen
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	concizumab
D.3.9.3	Other descriptive name	CONCIZUMAB
D.3.9.4	EV Substance Code	SUB192373
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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	EMA/OD/095/12, EMA/OD/116/17 (withdrawn)
D.3 Description of the IMP
D.3.1	Product name	Concizumab C 40 mg/mL PDS290
D.3.4	Pharmaceutical form	Solution for injection in pre-filled pen
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	concizumab
D.3.9.3	Other descriptive name	CONCIZUMAB
D.3.9.4	EV Substance Code	SUB192373
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	40
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Haemophilia A
Haemophilia B

E.1.1.1

Medical condition in easily understood language

Bleeding disorder, inherited deficiency in clotting factor VIII
Bleeding disorder, inherited deficiency in clotting factor IX

E.1.1.2

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10018938
E.1.2	Term	Haemophilia A (Factor VIII)
E.1.2	System Organ Class	100000004850

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10018939
E.1.2	Term	Haemophilia B (Factor IX)
E.1.2	System Organ Class	100000004850

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

1. To compare effect of concizumab prophylaxis (PPX) to no prophylaxis (on-demand (OD) treatment with factor) in reducing the number of bleeding episodes in adult and adolescent patients with haemophilia A without inhibitors
2. To compare effect of concizumab prophylaxis to no prophylaxis (on-demand treatment with factor) in reducing the number of bleeding episodes in adult and adolescent patients with haemophilia B without inhibitors

E.2.2

Secondary objectives of the trial

1. To compare the effect of concizumab prophylaxis to the patients’ previous prophylaxis treatment in reducing the number of bleeding episodes in adult and adolescent patients with haemophilia A without inhibitors
2. To compare the effect of concizumab prophylaxis to the patients’ previous prophylaxis treatment in reducing the number of bleeding episodes in adult and adolescent patients with haemophilia B without inhibitors
3. To investigate the safety of concizumab prophylaxis in adult and adolescent patients with haemophilia A or B without inhibitors
4. To investigate the PK and PD parameters of concizumab prophylaxis in adult and adolescent patients with haemophilia A or B without inhibitors

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Informed consent obtained before any trial-related activities. Trial-related activities are any procedures that are carried out as part of the trial, including activities to determine suitability for the trial
- Male aged 12 years or older at the time of signing informed consent.
- Congenital severe haemophilia A (FVIII less than 1%) or B (FIX 2% or less)

E.4

Principal exclusion criteria

- Known or suspected hypersensitivity to any constituent of the trial product or related products
- Known inherited or acquired coagulation disorder other than congenital haemophilia
- Presence of confirmed inhibitors 0.6 BU or greater at screening
- History of thromboembolic disease (includes arterial and venous thrombosis including myocardial infarction, pulmonary embolism, cerebral infarction/thrombosis, deep vein thrombosis, other clinically significant thromboembolic events and peripheral artery occlusion). Current clinical signs of, or treatment for thromboembolic disease. Patients who in the judgement of the investigator are considered at high risk of thromboembolic events (thromboembolic risk factors could include, but are not limited to, hypercholesterolemia, diabetes mellitus, hypertension, obesity, smoking, family history of thromboembolic events, arteriosclerosis, other conditions associated with increased risk of thromboembolic events.)

E.5 End points

E.5.1

Primary end point(s)

E.5.1.1

Timepoint(s) of evaluation of this end point

1-2. On demand (arm 1): From randomisation after the pause (week 0) up until start of concizumab treatment (week 24).
Concizumab (arm 2): From start of the new concizumab dosing regimen (week 0) up until the confirmatory analyses cut-off (at least 32 weeks)

E.5.2

Secondary end point(s)

1. For haemophilia A patients without inhibitors: The number of treated spontaneous and traumatic bleeding episodes
2. For haemophilia B patients without inhibitors: The number of treated spontaneous and traumatic bleeding episodes
3. For haemophilia A patients without inhibitors: Number of treated spontaneous bleeding episodes
4. For haemophilia B patients without inhibitors: Number of treated spontaneous bleeding episodes
5. For haemophilia A patients without inhibitors: Number of treated spontaneous and traumatic joint bleeds
6. For haemophilia B patients without inhibitors: Number of treated spontaneous and traumatic joint bleeds
7. For haemophilia A patients without inhibitors: Number of treated spontaneous and traumatic target joint bleeds
8. For haemophilia B patients without inhibitors: Number of treated spontaneous and traumatic target joint bleeds
9. Number of thromboembolic events
10. Number of thromboembolic events
11. Number of hypersensitivity type reactions
12. Number of hypersensitivity type reactions
13. Number of injection site reactions
14. Number of injection site reactions
15. Number of patients with antibodies to concizumab
16. Number of patients with antibodies to concizumab
17. Pre-dose (trough) concizumab plasma concentration (Ctrough)
18. Pre-dose thrombin peak
19. Pre-dose free tissue factor pathway inhibitor (TFPI) concentration
20. Maximum concizumab plasma concentration (Cmax)
21. Area under the concizumab plasma concentration-time curve (AUC)

E.5.2.1

Timepoint(s) of evaluation of this end point

1-2:Arm 4:patients on stable PPX min.24wks in trial 4322:
-Previous PPX (in 4322):PPX stable-end of trial(EOT)
-Concizumab (Conci) PPX (in 4307):Maintenance dose is confirmed/increased/decreased–conf. analyses (CA) (min.24wks)
3-8:OD (arm 1):Randomisation post-pause(wk0)-dose start(wk24)
-Conci (arm 2):New regimen start(wk0)–CA(min.32wks)
9,11,13:
OD (arm 1 main part):
-Randomisation–OD treatment (Trt.) to dose start
9,11,13,15:
Conci (arm 2-4):
-Pre-pause:Dose start(wk0)–7wks post Trt. pause
-Post-pause:Dose start(wk0)–the CA(min.32wks)
Conci. (arm-1 Ext. part): Start of Conci. Trt. (wk25) to CA cut-off
10,12,14,16:
Conci:
-Pre-pause:Dose at wk0–7wks after Trt. pause
-Post-pause:dose start–EOT(wk296)
17-19.Prior dosing at wk24(post restart)
20-21.0-24 hrs (0:dose at wk24(post restart))

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

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

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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

2 randomised treatment arms (ppx/no ppx) and two non-randomised treatment arms

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Treatment regimen before entering the trial will determine the assignment to the four treatment arms

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the 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

Algeria

Malaysia

Switzerland

Bosnia and Herzegovina

Ukraine

Australia

Canada

India

Japan

Korea, Republic of

Mexico

Russian Federation

Serbia

South Africa

Thailand

Turkey

United States

European Union

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

Yes

F.1.1

Number of subjects for this age range:

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)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

113

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

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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

158

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

2019-12-18

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-03-02

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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