Clinical Trials Register

Summary
EudraCT Number:	2017-002925-39
Sponsor's Protocol Code Number:	CMAA868A2201
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2021-09-03
Trial results	View 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

2017-002925-39

A.3

Full title of the trial

A multicenter, randomized, open-label, blinded endpoint evaluation, active-controlled Phase 2 study to compare the efficacy and safety of s.c. MAA868 versus s.c. enoxaparin in adult patients undergoing unilateral total knee arthroplasty

Studio di fase 2, multicentrico, randomizzato, in aperto, verso controllo attivo, con valutazione dell¿endpoint in cieco, per confrontare l¿efficacia e la sicurezza di MAA868 s.c. rispetto a enoxaparina s.c. in pazienti adulti sottoposti ad artroplastica totale unilaterale del ginocchio

A.3.1

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

Prevention of blood clots following surgery for knee replacement

Prevenzione dei coaguli di sangue dopo l'intervento chirurgico del ginocchio

A.3.2

Name or abbreviated title of the trial where available

Prevention of blood clots following surgery for knee replacement

Prevenzione dei coaguli di sangue dopo l'intervento chirurgico del ginocchio

A.4.1

Sponsor's protocol code number

CMAA868A2201

A.5.1

ISRCTN (International Standard Randomised Controlled Trial) Number

ISRCTN12345678

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT12345678

A.5.3

WHO Universal Trial Reference Number (UTRN)

U1234-1234-1234

A.5.4

Other Identifiers

Name:

Number:

CMAA868A2201

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	NOVARTIS PHARMA AG
B.1.3.4	Country	Switzerland
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	Novartis Pharma AG
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Novartis Farma
B.5.2	Functional name of contact point	Regulatory Affairs
B.5.3	Address:
B.5.3.1	Street Address	Largo Umberto Boccioni, 1
B.5.3.2	Town/ city	Origgio (VA)
B.5.3.3	Post code	21040
B.5.3.4	Country	Italy
B.5.4	Telephone number	0296541
B.5.5	Fax number	029659066
B.5.6	E-mail	info.studiclinici@novartis.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	NA
D.3.2	Product code	MAA868
D.3.4	Pharmaceutical form	Solution for injection
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	MAA868
D.3.9.3	Other descriptive name	MAA868
D.3.9.4	EV Substance Code	SUB188882
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	150
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.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	CLEXANE - 4000 UI AXA SOLUZIONE INIETTABILE 6 SIRINGHE PRERIEMPITE DA 0.4 ML
D.2.1.1.2	Name of the Marketing Authorisation holder	SANOFI-AVENTIS S.P.A.
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	Clexane
D.3.4	Pharmaceutical form	Solution for injection
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	ENOXAPARINA SODICA
D.3.9.1	CAS number	9041-08-1
D.3.9.2	Current sponsor code	NA
D.3.9.4	EV Substance Code	SUB11933MIG
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	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	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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

venous thromboembolism

tromboembolismo venoso

E.1.1.1

Medical condition in easily understood language

venous thromboembolism

tromboembolismo venoso

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10066899
E.1.2	Term	Venous thromboembolism
E.1.2	System Organ Class	100000004866

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Occurrence of confirmed composite endpoint of asymptomatic deep venous thrombosis (DVT), confirmed symptomatic venous thromboembolic events (VTE), fatal pulmonary embolism (PE) or unexplained death.

L¿obiettivo primario di questo studio ¿ di valutare se almeno una dose di MAA868 ¿ non inferiore a enoxaparina 40 mg, fino al Giorno 14 dopo la randomizzazione, considerando l¿incidenza di VTE totali aggiudicati in pazienti sottoposti a TKA unilaterale. Se la non-inferiorit¿ ¿ soddisfatta, sar¿ verificata la superiorit¿.

E.2.2

Secondary objectives of the trial

- Occurrence of confirmed composite endpoint of major bleeding and clinically relevant non-major (CRNM) bleeding events.
- Occurrence of confirmed composite endpoint of asymptomatic deep vein thrombosis (DVT), confirmed symptomatic venous thromboembolic
events (VTE), fatal pulmonary embolism (PE) or unexplained death.

Obiettivo 1: valutare l¿effetto di MAA868 rispetto a enoxaparina in termini di incidenza di emorragie maggiori e clinicamente rilevanti non maggiori (Clinically Relevant Non-Major ¿ CRNM) (definizione della Societ¿ Internazionale Trombosi ed Emostasi, International Society for Thrombosis and Hemostasis - ISTH) fino al Giorno 14 e fino al Giorno 50 dopo la randomizzazione.
Obiettivo 2: valutare se almeno una dose di MAA868 ¿ non inferiore a enoxaparina 40 mg, fino al Giorno 50 dopo la randomizzazione e fino alla visita di fine studio (End of Study ¿ EoS), considerando l¿incidenza di VTE aggiudicati totali in pazienti sottoposti a TKA unilaterale. Se viene soddisfatta la non inferiorit¿, sar¿ verificata la superiorit¿.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Scheduled to undergo elective unilateral total knee arthroplayts (TKA).
- Willing to comply with study requirements including bilateral venography at Day 12 ± 2 days.
- Body weight between 50 kg and 130 kg inclusive.
- Normal aPTT, PT, INR at screening.
- See full list in protocol.

• Pazienti di sesso maschile e femminile (= 18 anni e < 80 anni di età)
• Pazienti che hanno programmato di sottoporsi a TKA unilaterale elettiva
• Pazienti per cui è stato ottenuto il consenso informato scritto
• Pazienti che acconsentono ad aderire ai requisiti dello studio, compresa la venografia bilaterale al Giorno 12 ± 2
• Peso corporeo compreso tra 50 e 130 kg estremi inclusi
• aPTT, PT, INR nei limiti della norma allo screening

E.4

Principal exclusion criteria

- History of arterial or venous thromboembolism;
- abnormally extended primary or secondary bleeding after trauma or intervention, stroke, transient ischemic attack or traumatic or non-traumatic intracranial bleed;
- bleeding disorder;
- MI or unstable angina pectoris within 12 months of the screening;
- Uncontrolled hypertension (SBP/DBP = 150/95 mmHg at the screening).
- Medications that increase the risk of bleeding, including antiplatelet (such as aspirin), anticoagulant and fibrinolytic agents;
- eGFR <60 mL/min/1.73m2;
- Poorly controlled diabetes (HbA1C >10%);
- Liver dysfunction (ALT/AST >3 xULN or TBL >2 x ULN);
- BMI = 40 kg/m2.
- See full list in protocol.

• Indicazione formale alla terapia anticoagulante a dose piena o doppia terapia antiaggregante (Dual Antiplatelet Therapy - DAPT)
• Anamnesi pregressa di tromboembolia venosa profonda
• Diatesi emorragica nota
• Anamnesi familiare di disturbi della coagulazione
• Lesioni gastrointestinali attive note o sospette che predispongono ad eventi emorragici
• Anamnesi di ictus, attacco ischemico transitorio o emorragia intracranica o intraoculare traumatica o non traumatica
• Intervento chirurgico maggiore o trauma maggiore nei 6 mesi precedenti
• Farmaci che aumentano il rischio di emorragia, compresi anticoagulanti, agenti fibrinolitici e DAPT; non è proibita la terapia antiaggregante singola
• Pazienti che hanno un catetere intratecale lasciato in loco dopo l’intervento chirurgico per la gestione del dolore nella Coorte B
• Instabilità emodinamica nelle 2 ore successive all’intervento chirurgico nella Coorte B
• Emoglobina < 13 g/dL negli uomini e < 12 g/dL nelle donne o anamnesi di trasfusione di sangue nel mese precedente lo screening
• eGFR < 60 mL/min/1.73m2

E.5 End points

E.5.1

Primary end point(s)

Number of patients with confirmed composite endpoint

Numero di pazienti con endpoint composito confermato

E.5.1.1

Timepoint(s) of evaluation of this end point

day 14

giorno 14

E.5.2

Secondary end point(s)

Number of patients with composite venous thromboembolic events
(VTE).

Number of patients with composite venous thromboembolic events
(VTE).; Numero di pazienti con eventi tromboembolici venosi compositi (TEV).; Numero di pazienti con eventi tromboembolici venosi compositi
(TEV).

E.5.2.1

Timepoint(s) of evaluation of this end point

day 1 to day 50 and day 1 to day 110; - day 1 to day 50 and day 1 to day 110

giorno1 al giorno 50 e giorno 1 al giorno 110; - giorno 1al giorno 50 e giorno1al giorno 110

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

Yes

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

Yes

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)

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

Yes

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

Yes

E.8.1.7.1

Other trial design description

Studio randomizzato, in aperto con aggiudicazione dell'endpoint in cieco

Randomized, open-label study with blinded endpoint adjudication

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

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

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

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

Chile

Israel

Lebanon

Malaysia

Mexico

South Africa

Turkey

Austria

Belgium

Estonia

Germany

Italy

Lithuania

Spain

Argentina

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:

150

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

450

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

300

F.4.2.2

In the whole clinical trial

600

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

2018-05-09

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-01-18

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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