Clinical Trials Register

Summary
EudraCT Number:	2011-005441-13
Sponsor's Protocol Code Number:	REBORNE-OrthoCT1
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:	2012-12-19
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

2011-005441-13

A.3

Full title of the trial

Evaluation of efficacy and safety of autologous MSCs combined to biomaterials to enhance bone healing in patients with delayed consolidation after long bone fracture requiring graft apposition or alternative orthobiologics

Valutazione dell'efficacia e della sicurezza dell'uso di cellule staminali mesenchimali autologhe combinate a biomateriali per potenziare la guarigione ossea in pazienti che presentano un ritardo di consolidazione in seguito a frattura delle ossa lunghe e che necessitano di osteosintesi o di trattamento secondo tecniche ortobiologiche

A.3.1

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

Development of a therapy to treat patients with delayed consolidation after fracture of long bones

Sviluppo di una terapia per il trattamento di pazienti che presentano un ritardo di consolidazione in seguito a frattura delle ossa lunghe

A.3.2

Name or abbreviated title of the trial where available

Reborne - OrthoCT 1

A.4.1

Sponsor's protocol code number

REBORNE-OrthoCT1

A.5.4

Other Identifiers

Name:

C11-12

Number:

Codice protocollo del promotore

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	INSERM - Institut National de la Sant� et de la Recherche m�dicale
B.1.3.4	Country	France
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	FP7
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Istituto Ortopedico Rizzoli
B.5.2	Functional name of contact point	Nicola Baldini
B.5.3	Address:
B.5.3.1	Street Address	Via di Barbiano 1/10
B.5.3.2	Town/ city	Bologna
B.5.3.3	Post code	40136
B.5.3.4	Country	Italy
B.5.4	Telephone number	+39 051 6366897
B.5.5	Fax number	+ 39 051 6366748
B.5.6	E-mail	nicola.baldini@ior.it

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	ORTHO-1 BM MSC
D.3.2	Product code	NA
D.3.4	Pharmaceutical form	Implant
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Other use (Noncurrent)
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.3	Other descriptive name	Cultured Autologous Mesenchymal Cells mixed with the biomaterial MBCP+TM
D.3.10	Strength
D.3.10.1	Concentration unit	U/ml unit(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20000000
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)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Yes
D.3.11.3.1	Somatic cell therapy medicinal product	Yes
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)	Yes
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Closed or open Gustilo I and II humerus, tibial or femur diaphyseal or metaphysodiaphyseal fracture

Fratture diafisiarie o metafiso-diafisiarie di omero, tibia o femore, derivanti da traumi isolati chiusi o aperti di tipo I e II secondo Gustilo

E.1.1.1

Medical condition in easily understood language

Patients with delayed consolidation after long bone fracture requiring graft apposition or alternative orthobiologics

Pazienti che presentano un ritardo di consolidazione in seguito a frattura delle ossa lunghe e necessitano di osteosintesi o di trattamento secondo tecniche ortobiologiche

E.1.1.2

Therapeutic area

Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Surgical Procedures, Operative [E04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	PT
E.1.2	Classification code	10017081
E.1.2	Term	Fracture delayed union
E.1.2	System Organ Class	10028395 - Musculoskeletal and connective tissue disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To assess the safety of apposition of biomaterial with autologous MSCs at the fracture site

Valutare la sicurezza dell’impianto di biomateriale e MSC autologhe nel sito della frattura

E.2.2

Secondary objectives of the trial

To obtain consolidation, without increasing the complication rate, of diaphyseal and/or metaphysodiaphyseal fractures (femur, tibia, humerus)status delayed union (after 3 months), treated by standard care procedures plus apposition of biomaterial with autologous MSCs at the fracture site

Ottenere la consolidazione i fratture diafisarie e/o metadiafisiarie (femore, tibia, omero) con ritardo di guarigione (superiore a 3 mesi), trattate con tecniche standard più l’applicazione di un biomateriale combinato con cellule staminali mesenchimali autologhe

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

· Age 18 to 65, both sexes
· Traumatic isolated closed or open Gustilo I and II humerus, tibial or femur
diaphyseal or metaphysodiaphyseal fracture status delayed union or nonunion
· At least 3 months from acute fracture
· Able to provide informed consent, and signed informed consent
· Patients (by themselves) should have medical health care coverage to be
included in a research study
· Able to understand and accept the study constraints

- Soggetti di entrambi i sessi ed età compresa fra 18 a 65 anni - Fratture diafisiarie o metadiafisiarie di omero, tibia o femore con ritardata o mancata consolidazione derivanti da traumi isolati chiusi o aperti di tipo I e II secondo Gustilo - Almeno 3 mesi dopo la frattura - Soggetti capaci di fornire e firmare il consenso informato - Soggetti dotati di copertura medico-sanitaria - Soggetti capaci di comprendere e accettare i vincoli dello studio.

E.4

Principal exclusion criteria

· Pregnancy, breast feeding women and women who are of childbearing age and not practicing adequate birth control · Participation in another therapeutic trial in the previous 3 months · Delayed union or non-union related to iatrogeny · Segmental bone loss requiring specific therapy (bone transport, large structural allograft, megaprosthesis, etc) · Vascular or neural injury · Other fractures causing interference with weight bearing · Infection: skin, soft-tissue, bone or any remote infection (dental, pulmonary, gynecological) · Visceral injuries of diseases interfering with callus formation (craneoencephalic trauma, etc.) · History of bone harvesting on iliac crest contraindicating bone-marrow aspiration · Corticoid or immunosuppressive therapy more than one week in the three months prior to study inclusion · History of prior or concurrent diagnosis of HIV-, Syphilis, Hepatitis-B- or Hepatitis-C-infection (confirmed by serology or PCR) · Subject legally protected, under legal guardianship, deprived of their liberty by judicial or administrative decision, subject of psychiatric care, or admission to a health facility. · Impossibility to meet at the appointments for the follow up · Insulin dependent diabetes · Obesity (BMI > 30) · Autoimmune inflammatory disease · Current treatment by biphosphonate or stopped in the three months prior to study inclusion.

- Gravidanza o allattamento alla data dell’inclusione nello studio, rischio di una gravidanza durante il trattamento - Partecipazione ad un altro trial terapeutico nei 3 mesi precedenti - Ritardata o mancata consolidazione dovuta a cause iatrogene - Perdite ossee che richiedano una terapia specifica (trasporto osseo, innesto di grandi dimensioni, megaprotesi, ecc) - Trauma vascolare o nervoso - Altre fratture che interferiscano col carico - Infezioni (pelle, tessuti molli, osso) - Malattie con lesioni viscerali che interferiscano con la formazione del callo (es. trauma cranico) - Controindicazioni all’aspirato midollare - Assunzione di corticosteroidi o immunosoppressori per più di una settimana nei 3 mesi precedenti - Positività sierologia o PCR a HIV, epatite B o C - Adulti sotto tutela - Impossibilità a sottoporsi ai controlli - Diabete insulino-dipendente - Obesità (BMI>30) - Malattie infiammatorie autoimmuni - Trattamento con bifosfonati nei 3 mesi precedenti lo studio

E.5 End points

E.5.1

Primary end point(s)

-Local complication rate regarding the non-union treatment in the FU -Local and general complication rate regarding potential effects of introducing the biomaterial with MSC in the FU of patients.

- valutazione del tasso locale di complicanze per quanto riguarda il trattamento di mancata consolidazione durante il follow up;
- valutazione del tasso di complicanze locali e generali per quanto riguarda potenziali effetti dell’introduzione di biomateriale con MSCs durante il follow up

E.5.1.1

Timepoint(s) of evaluation of this end point

Complication rates at weeks : 6, 12, 24

Complicazioni alle settimane : 6, 12, 24

E.5.2

Secondary end point(s)

- Number of patients with proven bone healing at 6 weeks, 12 weeks, and 24 weeks - Clinical consolidation at weeks 6, 12, 24. - No reoperation done or scheduled at 24 weeks

- Numero di pazienti con provata guarigione ossea a 6 settimane, 12 settimane, e 24 settimane, in proporzione ai pazienti reclutati e trattati
- Consolidazione clinica
- Nessun reintervento effettuato o programmato
- Cambiamenti dei livelli sierici dei markers del turnover osseo

E.5.2.1

Timepoint(s) of evaluation of this end point

- number of patients with proven bone healing at 6 weeks, 12 weeks, and 24 weeks - clinical consolidation at weeks 6, 12, 24 - no reoperation done or scheduled at 24 weeks

- Numero di pazienti con provata guarigione ossea a 6 settimane, 12 settimane, e 24 settimane
- consolidazione clinica alle settimane 6, 12, 24
- Nessun reintervento effettuato o programmato a 24 settimane

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

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

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)

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

E.8.1.1

Randomised