Clinical Trials Register

Summary
EudraCT Number:	2018-004889-34
Sponsor's Protocol Code Number:	NN7415-4311
National Competent Authority:	Croatia - MIZ
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2020-02-20
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

Croatia - MIZ

A.2

EudraCT number

2018-004889-34

A.3

Full title of the trial

Efficacy and Safety of Concizumab prophylaxis in patients with haemophilia A or B with inhibitors

Djelotvornost i sigurnost profilaktičke primjene koncizumaba kod bolesnika s hemofilijom A ili B s inhibitorima

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 with inhibitors

Kliničko ispitivanje kojim se procjenjuje djelotvornost koncizumaba kod bolesnika s hemofilijom s inhibitorima

A.3.2

Name or abbreviated title of the trial where available

explorer7

explorer 7

A.4.1

Sponsor's protocol code number

NN7415-4311

A.5.3

WHO Universal Trial Reference Number (UTRN)

U1111-1225-9670

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 Disclosure (1452)
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	EMA/OD/095/12, EMA/OD/116/17
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
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 with inhibitors
Haemophilia B with inhibitors

Hemofilija A s inhibitorima
Hemofilija B s inhibitorima

E.1.1.1

Medical condition in easily understood language

Bleeding disorders:
- inherited deficiency in clotting factor VIII with antibodies to replacement therapy
- inherited deficiency in clotting factor IX with antibodies to replacement therapy

Poremećaji krvarenja:
nasljedni nedostatak faktora zgrušavanja VIII ili IX s protutijelima na
nadomjesnu terapiju faktorima zgrušavanja

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	10053751
E.1.2	Term	Hemophilia A with anti 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	10053752
E.1.2	Term	Hemophilia B with anti 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

To compare effect of concizumab prophylaxis to no prophylaxis (on-demand treatment with bypassing agents) in reducing the number of bleeding episodes in adult and adolescent patients with haemophilia A or B with inhibitors

Usporedba učinka na smanjenje broja krvarenja profilaktički
primijenjenog koncizumaba u odnosu na liječenje prema potrebi
lijekovima koji zaobilaze aktivnost faktora zgrušavanja (eng. bypassing
agents) kod adolescenata i odraslih ispitanika s hemofilijom A ili B i
razvijenim inhibitorima.

E.2.2

Secondary objectives of the trial

1. To compare the patient reported outcomes (PROs) after treatment with concizumab prophylaxis vs no prophylaxis in adult and adolescent patients with haemophilia A or B with inhibitors
2. To investigate the safety of concizumab prophylaxis in adult and adolescent patients with haemophilia A or B with inhibitors
3. To investigate the PK and PD parameters of concizumab prophylaxis in adult and adolescent patients with haemophilia A or B with inhibitors

1.Usporedba ishoda prijavljenih od strane ispitanika (eng. patient
reported outcomes) nakon profilaktičke primjene koncizumaba u odnosu
na neprofilaksu kod adolescenata i odraslih ispitanika s hemofilijom A ili
B koji imaju razvijene inhibitore
2.procjena sigurnosti profilaktičke primjene koncizumaba kod
adolescenata i odraslih ispitanika s hemofilijom A ili B koji imaju
razvijene inhibitore
3.procjena farmakokinetičkih i farmakodinamičkih parametara
koncizumaba u prevenciji krvarenja kod adolescenata i odraslih
ispitanika s hemofilijom A ili B koji imaju razvijene inhibitore.

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 or older years at the time of signing informed consent
- Congenital Haemophilia A or B of any severity with documented history of inhibitor (0.6 BU or more)
- Patient has been prescribed, or in need of, treatment with bypassing agents in the last 24 weeks prior to screening (for patients not previously enrolled in NN7415-4310 (explorer 4))

-Informirani pristanak dobiven prije bilo kakvih aktivnosti vezanih uz
ispitivanje. Te aktivnosti su bilo kakvi postupci provedeni kao dio
ispitivanja, uključujući postupke za procjenu prikladnosti za ispitivanje
-muškarci u dobi ≥12 godina u trenutku potpisivanja informiranog
pristanka
-prirođena hemofilija A ili B bilo kojeg stupnja težine s dokumentiranom
povijesti prisutnosti inhibitora (≥0.6 BU)
-pacijentu je bilo propisano, ili je imao potrebu za lijekovima koji
zaobilaze aktivnost faktora zgrušavanja (eng. bypassing agents) u
posljednja 24 tjedana prije probira (ne odnosi se na ispitanike koji u ovo
ispitivanje prelaze iz ispitivanja NN7415-4310 (explorer 4))

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
- Ongoing or planned Immune Tolerance Induction treatment
- 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.)

-Poznata preosjetljivost ili sumnja na svaku sastavnicu ispitivanog lijeka ili srodnih lijekova
-Poznati nasljedni ili stečeni poremećaj krvarenja različit od kongenitalne hemofilije
- Planirana indukcija imunološke tolerancije ili u trajanju
- Povijest tromboembolijskih bolesti (uključuje arterijsku i vensku trombozu kao i infarkt miokarda, plućnu emboliju, cerebralni infarkt/tromboza, duboku vensku trombozu, ostale klinički značajne tromboembolijske događaje te okluziju perifernih arterija. Trenutne kliničke znakove ili liječenje tromboembolijskih bolesti. Pacijenti koji su prema procijeni ispitivača u skupini visokog rizika za razvoj tromboembolijskog događaja (Rizični faktori za tromboembolijski događaj mogu uključivati, ali nisu ograničeni na: hiperkolesterolemiju, šećernu bolest, hipertenziju, pretilost, pušenje, obiteljsku anamnezu tromboembolijskih događaja, arteriosklerozu, ostala stanja povezana s povišenim rizikom za razvoj tromboembolijskog događaja.)

E.5 End points

E.5.1

Primary end point(s)

The number of treated spontaneous and traumatic bleeding episodes

Broj liječenih spontanih i traumatskih epizoda krvarenja.

E.5.1.1

Timepoint(s) of evaluation of this end point

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

Prema potrebi (grana 1): Od randomizacije (tjedan 0) sve do početka terapije koncizumabom (najmanje 24 tjedna)
Koncizumab (grana 2): Od početka novog režima doziranja koncizumabom (tjedan 0) sve do točke primarne analize (najmanje 32 tjedna)

E.5.2

Secondary end point(s)

1. Change in 36 Item short form health survey version 2 (SF36v2) bodily pain
2. Change in SF36v2 physical functioning
3. Number of treated spontaneous bleeding episodes
4. Number of treated joint bleeds
5. Number of treated target joint bleeds
6. Number of thromboembolic events
7. Number of thromboembolic events
8. Number of hypersensitivity type reactions
9. Number of hypersensitivity type reactions
10. Number of injection site reactions
11. Number of injection site reactions
12. Number of patients with antibodies to concizumab
13. Number of patients with antibodies to concizumab
14. Pre-dose (trough) concizumab plasma concentration (Ctrough)
15. Pre-dose peak thrombin generation
16. Pre-dose free tissue factor pathway inhibitor (TFPI) concentration
17. Maximum concizumab plasma concentration (Cmax)
18. Area under the concizumab plasma concentration-time curve (AUC)

1. Promjena u upitniku za ispitanike (SF36v2) vezano za tjelesnu bol
2. Promjena u SF36v2 vezano za tjelesno funkcioniranje
3. Broj liječenih spontanih epizoda krvarenja
4. Broj liječenih krvarenja u zglobovima
5. Broj liječenih krvarenja u ciljnim zglobovima
6. Broj tromboembolijskih događaja
7. Broj tromboembolijskih događaja
8. Broj reakcija preosjetljivosti
9. Broj reakcija preosjetljivosti
10. Broj reakcija na mjestu injiciranja
11. Broj reakcija na mjestu injiciranja
12. Broj pacijenata s protutijelima na koncizumab
13. Broj pacijenata s protutijelima na koncizumab
14. Koncentracija koncizumaba u plazmi prije doziranja
15. Najviši iznos parametra stvaranja trombina prije doziranja
16. Koncentracija slobodnog TFPI faktor inhibitora (TFPI – tissue factor pathway inhibitor) prije doziranja
17. Maksimalna plazmatska koncentracija koncizumaba (Cmax)
18. Površina ispod krivulje ovisnosti koncentracije koncizumaba o vremenu (AUC)

E.5.2.1

Timepoint(s) of evaluation of this end point

1-2:Start of treatment (week (wk) 0), wk 24
3-5:On demand (arm 1): Randomisation (wk 0) to start of concizumab (min. 24 wks)
Concizumab (arm 2): Start of new concizumab dosing (wk 0) to primary analysis cut-off (min. 32 wks)
6, 8, 10 & 12:
On demand (arm 1 main part):
-Randomisation to on demand treatment to start of concizumab
Concizumab (arms 2-4):
-Before pause: Start of concizumab (wk 0) to 7 wks after treatment pause
-After pause: From start of concizumab (wk 0) to primary analysis cut-off (min. 32 wks)
7, 9, 11 & 13:
Concizumab:
-Before pause: Start of treatment (wk 0) to 7 wks after treatment pause
-After pause: Start of concizumab to end of trial (wk 167)
14-16:Prior to concizumab dose at wk 24 (after restart)
17-18:0-24 hrs (0: time of concizumab dose at wk 24 (after restart))

1-2 Pocetak lijecenja (0-24tj)
3-5 Prema potrebi (grana1): Randomizacija (tj0) do pocetka koncizumaba (najmanje 24tj)
Koncizumab (grana2): Početak novog doziranja (tj0) do točke primarne analize (najmanje 32tj)
6,8,10,12
Prema potrebi (grana 1 glavni dio):
-Od randomizacije na liječenje prema potrebi do pocetka koncizumaba
Koncizumab (grane 2-4):
-Prije pauze: Početak koncizumaba (tj0) do 7tj nakon prestanka
-Nakon pauze: Od početka koncizumaba (tj0) do točke primarne analize (najmanje 32tj)
7,9,11,13
Koncizumab
-Prije pauze: Pocetak terapije (tj0) do 7tj nakon prestanka terapije
-Nakon pauze: Pocetak koncizumaba do završetka (tj167)
14-16 Prije doze koncizumaba u tj24 (nakon ponovnog pocetka)
17-18 0-24h (0: vrijeme doze koncizumaba u tj24 (nakon ponovnog pocetka))

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

dvije randomizirane skupine na lijeku (profilaksa/ ne profilaksa) i dvije nerandomizirane skupine

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

Režim liječenja prije ulaska u ispitivanje će odrediti raspodjelu u jednu od četiri grana

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

Australia

Canada

European Union

India

Japan

Korea, Republic of

Malaysia

Mexico

Norway

Russian Federation

Serbia

South Africa

Turkey

Ukraine

United States

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:

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

136

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

2020-01-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-09-19

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

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Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
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