Clinical Trials Register

Summary
EudraCT Number:	2012-002010-39
Sponsor's Protocol Code Number:	ORTHO-2
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2014-01-09
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

Spain - AEMPS

A.2

EudraCT number

2012-002010-39

A.3

Full title of the trial

Evaluation of safety and feasibility of bone marrow derived autologous MSCs to enhance bone healing in patients with avascular necrosis of femoral head

Evaluación de la seguridad del uso de células mesenquimales autólogas en la curación de la necrosis avascular de cadera

A.3.1

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

Evaluation of safety of celular therapy derived of bone marrow to help bone healing in patients with avascular necrosis of the hip

Evaluación de la seguridad del uso de células mesenquimales autólogas en la curación de la necrosis avascular de cadera

A.3.2

Name or abbreviated title of the trial where available

REBORNE (ORTHO-2CT)

A.4.1

Sponsor's protocol code number

ORTHO-2

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	Universidad Autónoma de Madrid
B.1.3.4	Country	Spain
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	European Comission
B.4.2	Country	Belgium
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Dept of Clinical Pharmacology-Universitary Hospital Puerta de Hierro
B.5.2	Functional name of contact point	Dra. Cristina Avendaño
B.5.3	Address:
B.5.3.1	Street Address	Manuel de Falla,1
B.5.3.2	Town/ city	Majadahonda
B.5.3.3	Post code	28220
B.5.3.4	Country	Spain
B.5.4	Telephone number	003491191 64 79
B.5.6	E-mail	cristina.avendano@uam.es

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	Cultured Mesenchymal Cells from bone marrow isolation
D.3.4	Pharmaceutical form	Suspension for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intraosseous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Cultured autologous bone marrow stem adult Mesenchymal Cells expanded
D.3.9.3	Other descriptive name	MSCs
D.3.10	Strength
D.3.10.1	Concentration unit	CFU/ml colony forming 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)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Yes
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	Yes
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	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

Early avascular necrosis of the femoral head (MRI diagnosis): Ficat and Arlet 0, 1, or 2 (Steinberg stages 0, I, IIA, IIB, or IIC)

Necrosis avascular de cadera

E.1.1.1

Medical condition in easily understood language

Avascular necrosis of the femoral head

Necrosis avascular de cadera

E.1.1.2

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	16.1
E.1.2	Level	SOC
E.1.2	Classification code	10028395
E.1.2	Term	Musculoskeletal and connective tissue disorders
E.1.2	System Organ Class	10028395 - Musculoskeletal and connective tissue disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	16.1
E.1.2	Level	LLT
E.1.2	Classification code	10003860
E.1.2	Term	Avascular necrosis femoral head
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 evaluate the safety and feasibility of the treatment of early avascular necrosis of the femoral head with expanded bone marrow autologous stem cells to enhance bone healing, after core decompression through percutaneous forage

To obtain bone healing, without Evaluar la seguridad y viabilidad de las Células Madre Mesenquimales (CMMs) autólogas derivadas de médula ósea colocadas en el sitio de necrosis de pacientes con Necrosis Avascular de Cabeza Femoral (NACF) precoz.

E.2.2

Secondary objectives of the trial

To obtain bone regeneration maintaining head sphericity, without increasing the
complication rate, of femoral head with symptomatic avascular necrosis of
femoral head (ANFH)

Lograr la regeneración ósea en pacientes sintomáticos con NACF primaria, manteniendo la esfericidad y sin incrementar la tasa de complicación

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

-Age 18 to 65, both sexes
-Early avascular necrosis of the femoral head (MRI diagnosis): Ficat and Arlet 0, 1, or 2 (Steinberg stages 0, I, IIA, IIB, or IIC)
-Symptomatic osteonecrosis with less than 6 months of evolution
-Able to provide informed consent, and signed informed consent
-Medical health care coverage
-Able to understand and accept the study constraints

edad 18 to 65, ambos sexos
Necrosis avascular de cadera estadios precoces : Ficat y Arlet 0, 1, o 2 (Steinberg 0, I, IIA, IIB, o IIC)
Sintomática de menos de 6 meses de evolución
Capaz de otorgar consentimiento informado firmado

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
-Stages 3 or more (Ficat and Arlet) or III or more (Steinberg) of severe femoral head osteonecrosis, primarily based on diagnosis by imaging (X-Rays, MRI).
-Flattening or collapse of the femoral head (Steinberg stage IV) or articular cartilage collapse at the time of core decompression surgery.
-Septic arthritis.
-Stress fracture.
-Non-osteonecrosis metabolic bone diseases (particularly Paget's disease of bone, osteogenesis imperfecta, primary hyperparathyroidism, fibrous dysplasia monostotic, polyostotic McCune-Albright syndrome] and osteopetrosis).
-Any active bisphosphonate treatment or any history of intravenous (IV) treatment.
-History of prior or concurrent diagnosis of HIV-, Hepatitis-B- or Hepatitis-C-infection (confirmed by serology or PCR)
-Active hepatitis B or hepatitis C infection at the time of screening. Known allergies to products involved in the production process of MSC.
-History of neoplasia or current neoplasia in any organ.
-Corticoid or immunosuppressive therapy more than one week in the two months prior to study inclusion
-Patients who will require continuous, systemic, high dose corticosteroid therapy (more than 7.5 mg/day) within 6 months after surgery.
-Patients who are in active treatment for cancer or blood dyscrasia, or have received chemotherapy, radiotherapy or immunotherapy in the past 2 years.
-History of regular alcohol consumption exceeding 2 drinks/day (1 drink = 150 mL of wine or 360 mL of beer or 45 mL of hard liquor) within 6 months of screening and/or history of illicit drug use.
-Serum AST (SGOT)/ALT (SGPT) > 2.5 X (institutional standard range).
-MRI-incompatible internaldevices (pacemakers, aneurysm clips, etc).
-Body mass index (BMI) of 40 kg/m² or greater.
-Patients unable to tolerate general anesthesia defined as an American Society of Anesthesiologists (ASA) criteria of > 2.
-Insulin dependent diabetes
-Patients with poorly controlled diabetes mellitus (HbA1C > 8%), or with peripheral neuropathy, or known concomitant vascular problems.
-Patients receiving treatment with hematopoietic growth factors or anti-vasculogenesis or antiangiogenesis treatment.
-Traumatic osteonecrosis.
-Adult in the care of a guardian (Subject legally protected)
-Impossibility to meet at the appointments for the clinical follow up.

-Embarazo, lactancia, mujer fértil sin métodos anticonceptivos adecuados.
-Participación en otro ensayo clínico en los tres meses previos
-estadios 3 or más (Ficat y Arlet) o III or más (Steinberg) de necrosis avascular de cadera.
-Colapso de la cabeza femoral o del cartilago articular
-Artritis séptica.
-Fractura de stress.
-enfermedades metabólicas del hueso(Paget, osteogenesis imperfecta, hiperparatiroidismo, ..).
-Tratamiento activo con bifosfonatos
- Infección por VIH, Hepatitis-B- o Hepatitis-C
-Historia de neoplasiaen cualquier organo.
-Corticoides o inmunosupresores durante más de una semana en los 2 meses previos ala inclusión
-Necesidad de tto con corticoides sistémicos altas dosis
-Consumo regular de alcohol de más de 2 bebidas/día

E.5 End points

E.5.1

Primary end point(s)

Safety endpoints include:
-Early local complication rate, as the percentage of patients with local complications within three months after surgery.
- Global complication rate, as the percentage of patients with local or general complications at 52 weeks

Tasa de complicaciones precoces (% pacientes con complicaciones locales 3 meses tras la cirugia).
Tasa de compliación global (% de pacientes con complicaciones locales o generales en las 52 semanas tras cirugia).

E.5.1.1

Timepoint(s) of evaluation of this end point

Complication rates at weeks : 6, 12, 24, 52 weeks

Complicaciones a las 6,12, 24, 52 semanas

E.5.2

Secondary end point(s)

-Local and general complication rate at 104 weeks regarding potential effects in the FU of patients after introducing MSCs
-Number of patients with no progression to the next stage (defined as 0 to 1, 1 to 2, 2 to 3) at 12 months.
?-Number of patients with no radiological or MRI progression at 6 weeks (X-ray), 12 weeks (X-ray, MRI), 24 weeksX-ray), and 52 weeks (X-ray, MRI), in proportion of the recruited, treated patients. Data and images will be reviewed by an adjudication committee at the end of the study following a pre established procedure
-Amount of necrotic bone in the femoral head at 12 weeks and 52 weeks in MRI, compared with preoperative status. This will be measured according to a standardised protocol.
-Changes in serum levels of bone turnover markers(in a centralized laboratory) at 12 and 24 weeks after treatment
-Pain assessed by a Visual Analogue Scale at 12 , 24 and 52 weeks

Tasa de complicaciones locales y generales a las 104 semanas.
Nº pacientes que no progresan al siguiente estadio a los 12 meses.
Nº de pacientes sin progresion Rx o RM a 6 semanas, 12 , 24 y 52 semanas.
Cambio en marcadores séricos de recambio óseo
Dolor por EAV

E.5.2.1

Timepoint(s) of evaluation of this end point

6, 12, 24, 52 and 104 weeks

6, 12, 24, 52 y 104 semanas

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

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

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.8.3

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

E.8.6.2

Trial being conducted completely outside of the EEA

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:

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

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)

If bone healing has not occurred or there is a progresion of avascular necrosis, the patient may require additional treatment and an additional follow-up, under the care of the Hospital, the treating physician or service, or the provider in charge of
his process, even if unrelated to the study.

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

2014-01-10

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-04-18

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

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