Clinical Trials Register

Summary
EudraCT Number:	2020-003467-26
Sponsor's Protocol Code Number:	NN7769-4516
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:	2021-10-18
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2020-003467-26

A.3

Full title of the trial

Safety, efficacy and exposure of subcutaneously administered NNC0365-3769 (Mim8) prophylaxis in children with haemophilia A with or without FVIII inhibitors

Sicurezza, efficacia ed esposizione del trattamento in profilassi con NNC0365-3769 (Mim8) somministrato per via sottocutanea in bambini affetti da emofilia A con o senza inibitori del FVIII

A.3.1

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

A research study investigating Mim8 in children with haemophilia A with or without inhibitors

Studio di ricerca per indagare su Mim8 in bambini con emofilia A con o senza inibitori

A.3.2

Name or abbreviated title of the trial where available

FRONTIER 3

A.4.1

Sponsor's protocol code number

NN7769-4516

A.5.3

WHO Universal Trial Reference Number (UTRN)

U1111-1255-1540

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/450/2000

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 (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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	NNC0365-3769 A
D.3.2	Product code	[NNC0365-3769 A]
D.3.4	Pharmaceutical form	Solution for injection/infusion
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.3.9.2	Current sponsor code	NNC0365-3769
D.3.9.3	Other descriptive name	NNC0365-3769
D.3.9.4	EV Substance Code	SUB198393
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	10 to 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	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	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 A with inhibitors

Emofilia A
Emofilia A con inibitori

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 VIII with antibodies to clotting factor replacement therapy

Disturbi della coagulazione, carenza ereditata del fattore VIII di coagulazione/con anticorpi contro la terapia sostitutiva del fattore di coagulazione

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	10053751
E.1.2	Term	Hemophilia A with anti factor VIII
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 investigate the safety of Mim8 prophylaxis in children with haemophilia A with or without FVIII inhibitors.

Investigare la sicurezza della profilassi di Mim8 in bambini con emofilia A con o senza inibitori del FIII

E.2.2

Secondary objectives of the trial

Investigate the efficacy of Mim8 prophylaxis in children with haemophilia A with or without FVIII inhibitors.
Evaluate the consumption of coagulation factor replacement product per bleed treatment (number of injections) with Mim8 prophylaxis in children with haemophilia A with or without FVIII inhibitors.
Evaluate the development of anti-Mim8 antibodies with Mim8 prophylaxis in children with haemophilia A with or without FVIII inhibitors.
Investigate exposure of Mim8 after once-weekly and once-monthly subcutaneous dosing in children with haemophilia A with or without FVIII inhibitors.
Evaluate treatment burden with Mim8 prophylaxis in children with haemophilia A with or without FVIII inhibitors, as reported by their caregivers.
Investigate treatment preference among caregivers of previously treated children with haemophilia A with or without FVIII inhibitors.
Evaluate aspects of physical functioning with Mim8 prophylaxis in children with haemophilia A with or without FVIII inhibitors.

Studiare efficacia profilassi con Mim8 in bambini con emofilia A con/senza inibitori FVIII.
Valutare consumo per episodio sanguinamento di un prodotto sostitutivo del fattore di coagulazione (numero iniezioni) rispetto al trattamento in profilassi con Mim8 in bambini con emofilia A con/senza inibitori FVIII.
Valutare sviluppo anticorpi anti-Mim8 con profilassi con Mim8 in bambini con emofilia A con/senza inibitori FVIII.
Studiare l’esposizione di Mim8 dopo la somministrazione sottocutanea una volta a settimana/mese in bambini con emofilia A con/senza inibitori FVIII.
Valutare l’onere del trattamento con la profilassi con Mim8 in bambini con emofilia A con/senza inibitori del FVIII, come riferito dagli assistenti alle cure.
Studiare la preferenza di trattamento tra gli assistenti alle cure di bambini con emofilia A precedentemente trattati con/senza inibitori FVIII.
Valutare aspetti della funzionalità fisica con la profilassi con Mim8 in bambini con emofilia A con/senza inibitori FVIII.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Informed consent obtained before any study-related activities. Study related activities are any procedures that are carried out as part of the study, including activities to determine suitability for the study.
2. Male and female participants with the diagnosis of congenital haemophilia A of any severity based on medical records.
3. Aged 1-11 years (both inclusive) at the time of signing informed consent.
4. For previously treated participants:
a. Participant has been prescribed treatment with FVIII concentrate or bypassing agent in the last 26 weeks prior to screening.
b. Participants with endogenous FVIII activity above or equal to 1%, based on medical records, must have at least 1 treated bleed during the previous 26 weeks before screening for which factor VIII concentrate or bypassing agent has been prescribed (No requirements for participants with FVIII activity below 1%).
5. For previously untreated participants:
a. Diagnosis of severe haemophilia A (endogenous FVIII activity below 1%) based on medical records.
6. Child and parent/caregiver willingness and ability to comply with scheduled visits and study procedures, including the completion of diary
and patient-reported outcomes questionnaires.

1. Modulo di consenso informato ottenuto prima di qualsiasi attività correlata allo studio. Per attività correlate allo studio si intende qualunque procedura espletata nell’ambito dello studio, incluse le attività per determinare l’idoneità allo stesso.
2. Partecipanti di sesso maschile e femminile con diagnosi di emofilia A congenita di qualsiasi gravità in base alle cartelle cliniche.
3. Età 1-11 anni (estremi compresi) al momento della firma del modulo di consenso informato.
4. Per i pazienti precedentemente trattati:
a. Al partecipante è stato prescritto un trattamento con FVIII concentrato o agente bypassante nelle ultime 26 settimane prima dello screening.
b. Partecipante con attività di FVIII endogeno =1%, in base alle cartelle cliniche, deve aver avuto almeno 1 sanguinamento trattato durante le 26 settimane precedenti lo screening per cui è stato prescritto fattore VIII concentrato o un agente by-passante (nessun requisito per i pazienti con attività di FVIII <1%).
5. Per i pazienti precedentemente non trattati con FVIII:
a. Diagnosi di emofilia A grave (attività di FVIII endogeno <1%) in base alle cartelle cliniche.
6. Disponibilità e capacità da parte del bambino e del genitore/assistente di attenersi alle visite programmate e alle procedure dello studio, compresa la compilazione del diario e dei questionari sugli esiti riferiti dal paziente.

E.4

Principal exclusion criteria

1. Known or suspected hypersensitivity to study product or related products.
2. Previous participation in this study. Participation is defined as signed informed consent.
3. Exposure to non-factor haemostatic products for bleeding prophylaxis within 6 months (or 5 half-lives of the medicinal product, whichever is shorter) prior to planned first dose, for participants not included in the run-in.
4. Known congenital or acquired coagulation disorders other than haemophilia A.
5. Other conditions (e.g. autoimmune disease) or laboratory abnormality that may increase risk of bleeding or thrombosis, as evaluated by the investigator.
6. Any disorder, except for conditions associated with haemophilia A, that in the investigator's opinion might jeopardise the participant's safety or compliance with the protocol.
7. Mental incapacity, unwillingness to cooperate or a language barrier precluding adequate understanding and cooperation.
8. Lack of adequate parental/caregiver support to enter accurately and timely information regarding treatment and bleeding episodes into an (electronic) diary.
9. Previous or current treatment for thromboembolic disease (with the exception of previous catheter-associated thrombosis for which anti-thrombotic treatment is not currently ongoing) or signs of thromboembolic disease.
10. Major surgery planned to take place after screening.
11. Immune tolerance induction planned to take place after treatment initiation.
12. Hepatic dysfunction defined as aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) above 3 times the upper limit of normal
combined with total bilirubin above 1.5 times the upper limit of normal measured at screening.
13. Serum creatinine above 1.5 x upper limit of normal (ULN), measured at screening.
14. Pregnancy (female participants).

1. Ipersensibilità accertata o sospetta al prodotto in studio o ai prodotti correlati.
2. Precedente partecipazione a questo studio. La partecipazione è definita dall’avvenuta firma del modulo di consenso informato.
3. Esposizione a prodotti emostatici non contenenti un fattore di coagulazione per la profilassi del sanguinamento nei 6 mesi (o 5 emivite del prodotto medicinale, a seconda di quale sia più breve) precedenti alla prima dose programmata, per i pazienti non inclusi nel run-in.
4. Disturbi della coagulazione noti congeniti o acquisiti diversi dall’emofilia A.
5. Altre condizioni (per es. malattia autoimmune) o anomalie di laboratorio che possono aumentare il rischio di sanguinamento o trombosi, come da valutazione dello sperimentatore.
6. Qualsiasi disturbo, ad eccezione delle condizioni associate all’emofilia A, che, a giudizio dello sperimentatore, potrebbe mettere a rischio la sicurezza del paziente o l’aderenza al protocollo.
7. Incapacità mentale, mancanza di volontà di cooperare o una barriera linguistica che precluda comprensione e cooperazione adeguate.
8. Mancanza di un adeguato supporto da parte del genitore/assistente per inserire informazioni accurate e tempestive relative al trattamento e agli episodi di sanguinamento in un diario (elettronico) del paziente.
9. Precedente o attuale trattamento per malattia tromboembolica (ad eccezione di una precedente trombosi associata a catetere per la quale il trattamento antitrombotico non sia attualmente in corso) o segni di malattia tromboembolica.
10. Intervento di chirurgia maggiore programmato dopo lo screening.
11. Induzione della Tolleranza Immunologica (ITI) programmata dopo l’inizio del trattamento.
12. Disfunzione epatica definita come livelli di aspartato aminotransferasi (AST) e/o alanina aminotransferasi (ALT) >3 volte il limite superiore della normalità in combinazione con livelli di bilirubina totale >1,5 volte il limite superiore della normalità misurati allo screening.
13. Creatinina sierica superiore a 1,5 volte il limite superiore della normalità (ULN), misurata allo screening.
15. Gravidanza (partecipanti di sesso femminile)

E.5 End points

E.5.1

Primary end point(s)

Number of treatment emergent adverse events

Numero di eventi avversi emergenti dal trattamento

E.5.1.1

Timepoint(s) of evaluation of this end point

From treatment initiation to follow up visit (week 0 to week 72)

Dall’inizio del trattamento alla visita di follow-up (dalla settimana 0 alla settimana 72)

E.5.2

Secondary end point(s)

1. Number of treated bleeds
2. Number of treated spontaneous bleeds
3. Number of treated traumatic bleeds
4. Number of treated joint bleeds
5. Number of treated target joint bleeds
6. Number of injection site reactions
7. Consumption of factor product per bleed treatment
8. Occurrence of anti-Mim8 antibodies
9. Mim8 plasma concentration
10. Change in physical function domain of Paediatric Quality of Life inventory (PEDS-QL) Generic Core Scales
11. Treatment preference for Mim8 versus previous treatment using Caregiver Haemophilia Patient Preference Questionnaire (Caregiver HPPQ)
12. Change in participants' treatment burden using the Haemophilia treatment experience measure (Hemo TEM)

1. Numero di emorragie trattate
2. Numero di emorragie spontanee trattate
3. Numero di emorragie traumatiche trattate
4. Numero di emorragie in articolazioni trattate
5. Numero di emorragie in articolazioni bersaglio trattate
6. Numero di reazioni nel sito di iniezione
7. Consumo del fattore di coagulazione per trattamento antiemorragico
8. Insorgenza di anticorpi anti-Mim8
9. Concentrazione plasmatica di Mim8
10. Variazione della funzione fisica rispetto alle scale PEDS-QL Generic Core
11. Preferenza di trattamento per Mim8 rispetto al trattamento precedente utilizzando il questionario H-PPQ dell’assistente
12. Variazione dell’onere di trattamento dei partecipanti utilizzando Hemo-TEM

E.5.2.1

Timepoint(s) of evaluation of this end point

1-6 . From treatment initiation to end of treatment (week 0 to week 52)
7. From run-in initiation to end of treatment (week -26 to week 52)
8-10. From treatment initiation to end of treatment (week 0 to week 52)
11. Once during treatment (week 26)
12. From treatment initiation to end of treatment (week 0 to week 52)

1-6 . Dall’inizio del trattamento a fine trattamento (dalla Settimana 0 alla Settimana 52)
7. Dall’inizio del run-in a fine trattamento (dalla Settimana -26 alla Settimana 52)
8-10. Dall’inizio del trattamento a fine trattamento (dalla Settimana 0 alla settimana 52)
11. Una volta durante il trattamento (Settimana 26)
12. Dall’inizio del trattamento a fine trattamento (dalla 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

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

E.8.1.1

Randomised

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

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

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

China

India

Israel

Japan

Korea, Republic of

Russian Federation

Taiwan

United States

Switzerland

European Union

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

Yes

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)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

F.1.3

Elderly (>=65 years)

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

2021-11-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-11-17

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

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