Clinical Trials Register

Summary
EudraCT Number:	2010-024129-20
Sponsor's Protocol Code Number:	ProyectoOB12
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2011-11-02
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

2010-024129-20

A.3

Full title of the trial

Oral Versus Intramuscular Cobalamin to treat Cobalamin Deficiency: Noninferiority randomised controlled trial, pragmatic and multi-center in the primary healthcare setting (OB12 project).

Administración oral frente a intramuscular de vitamina B12 para el tratamiento de pacientes con déficit de vitamina B12: Ensayo clínico de no-inferioridad, pragmático, aleatorizado y multicéntrico en atención primaria. (Proyecto OB12).

A.3.1

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

Oral Versus Intramuscular Cobalamin to treat Cobalamin Deficiency: Noninferiority randomised controlled trial, pragmatic and multi-center in the primary healthcare setting (OB12 project).

A.3.2

Name or abbreviated title of the trial where available

OB12 Project

Proyecto OB12

A.4.1

Sponsor's protocol code number

ProyectoOB12

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	Consorcio de Apoyo a la Investigación Biomédica en red (CAIBER)
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	Dirección General de Farmacia y Productos Sanitarios. Ministerio de Sanidad, Política Social e Igualdad
B.4.2	Country	Spain
B.4.1	Name of organisation providing support	Consorcio de Apoyo a la Investigación Biomédica en red (CAIBER)
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Agencia Pedro Laín Entralgo
B.5.2	Functional name of contact point	Área de Investigación
B.5.3	Address:
B.5.3.1	Street Address	C/Gran Vía 27
B.5.3.2	Town/ city	Madrid
B.5.3.3	Post code	28013
B.5.3.4	Country	Spain
B.5.4	Telephone number	+34913089437
B.5.5	Fax number	+34913089525
B.5.6	E-mail	nodisponible@nodisponible.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	Yes
D.2.1.1.1	Trade name	OPTOVITE® B12 1.000 gammas
D.2.1.1.2	Name of the Marketing Authorisation holder	LABORATORIOS NORMON, S.A.
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intramuscular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	CIANOCOBALAMINA
D.3.9.1	CAS number	68-19-9
D.3.9.3	Other descriptive name	CYANOCOBALAMIN
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1000
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
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)	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	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	Yes
D.3.11.13.1	Other medicinal product type	Una vitamina
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	Yes
D.2.1.1.1	Trade name	OPTOVITE® B12 1.000 gammas
D.2.1.1.2	Name of the Marketing Authorisation holder	LABORATORIOS NORMON, S.A.
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	CIANOCOBALAMINA
D.3.9.1	CAS number	68-19-9
D.3.9.3	Other descriptive name	CYANOCOBALAMIN
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1000
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
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)	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	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	Yes
D.3.11.13.1	Other medicinal product type	Una vitamina

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

Vitamin B12 (cianocobalamin) defficiency

Deficit vitamina B12 (cianocobalamina)

E.1.1.1

Medical condition in easily understood language

Vitamin B12 defficiency

Deficit vitamina B12

E.1.1.2

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.0
E.1.2	Level	PT
E.1.2	Classification code	10047609
E.1.2	Term	Vitamin B12 deficiency
E.1.2	System Organ Class	10027433 - Metabolism and nutrition 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

Evaluate the effectiveness of orally administered vitamin B12 compared with intramuscular to reestablish the seric level of vitamin B12 at 8, 26 and 52 weeks in patients ≥ 65 years with B12 deficiency, attended in the primary care centers in the Community of Madrid.

Evaluar la efectividad de la vitamina B12 administrada vía oral comparada con la vía intramuscular para restablecer el nivel sérico de vitamina B12 a las 8, 26 y 52 semanas en los pacientes mayores o iguales a 65 años con déficit de B12, atendidos en los centros de atención primaria de la Comunidad de Madrid

E.2.2

Secondary objectives of the trial

1.Evaluate the safety of both treatment groups.
2.Analyze the quality of life measured by Euroqol-5D.
3.Describe the satisfaction and preferences with specific questions designed for this project, in both treatment groups.
4.Analyze the degree of compliance measured by counting the unused vials in the oral treatment and the number of injections received in the intramuscular treatment.
5.Describe the sociodemographic profile, living habits and the clinical manifestations of patients with vitamin B12 deficiency

1-Evaluar la seguridad entre ambas ramas de tratamiento
2-Analizar la calidad de vida medida con el Euroqol-5D.
3-Describir la satisfacción y las preferencias referidas mediante preguntas específicas diseñadas para este proyecto, en ambas ramas de tratamiento.
4-Analizar el grado de adherencia medido mediante el recuento de viales no usados en el tratamiento oral y el número de inyecciones recibidas en el tratamiento intramuscular.
5-Describir el perfil sociodemográfico, los hábitos de vida y las manifestaciones clínicas de los pacientes con déficit de vitamina B12.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

-Age 65 years or older.
-Patients who visit for any reason in primary care and accept participating (signed informed consent).
-Vitamin B12 < 179 pg/ml.

1-Edad mayor o igual a 65 años.
2-Pacientes que consultan por cualquier motivo en atención primaria y aceptan participar con la firma del consentimiento informado.
3-Niveles de vitamina B12 menores a 179 pg/ml.

E.4

Principal exclusion criteria

1.Having received treatment for B12 deficiency in the last 5 years.
2.Severe neurological symptomatology.
3.Folic acid < 2.3ng/ml.
4.Renal insufficiency in stage 4 (FGE from 15 to 29ml/min)
5.Malabsorption:
-Surgery or process with gastrointestinal affectation (affecting terminal ileon)
-intestinal inflammatory process: Crohn, ulcerous colitis
-celiac disease
-chronic pancreatitis.
6.Myelodysplastic syndrome and/or other malignant hematological processes.
7.Hemophiliacs and other coagulation pathologies that contraindicate IM administration,
8.Severe systemic disease.
9.Prior administration (28 days ) of any research treatment.
10.Patients diagnosed with HIV, HBV or HBC in treatment.
11.Hypersensitivity to this substance, to cobalt or to any of its ingredients.
12.Anticoagulated patients.
13.Patients who moved or who could not meet the requirements of the study.
14.Patients with limitations for oral administration.

1-Haber recibido en los últimos 5 años tratamiento por B12 por prescripción médica.
2-Pacientes con sintomatología neurológica severa.
3-Niveles de ácido fólico menor a 2,3ng/ml.
4-Insuficiencia renal en estadio 4 (FGE de 15 a 29ml/min).
5-Malabsorción:
-Cirugía o proceso con afectación gastrointestinal (que afecte íleon terminal).
-Proceso inflamatorio- intestinal: Crohn, Colitis Ulcerosa.
-Celiaquía.
-Pancreatitis crónica.
6-Síndrome mielodisplásico y/o otros procesos malignos hematológicos.
7-Hemofílicosy otras patologías de la coagulación en las que esté contraindicada la vía parenteral.
8-Enfermedad sistémica severa.
9-Administración previa de cualquier tratamiento en investigación en los 28 días previos a la fecha de inclusión en el estudio.
10-Pacientes diagnosticados de VIH, VHB o VHC que estén recibiendo tratamiento.
11-Hipersensibilidad al fármaco, al cobalto o a algunos de sus excipientes.
12-Pacientes anticoagulados.
13-Pacientes desplazados o que no pudieran cumplir los requerimientos del estudio.
14-Pacientes con limitaciones para la administración oral.

E.5 End points

E.5.1

Primary end point(s)

Main outcome variable measured in both groups: Normalization of the levels of plasmatic vitamin B12 (B12>179pg/ml, at 8, 26, 52 weeks)=YES /NO

Resultado principal medido en ambos grupos: Normalización de los niveles de vitamina B12 plasmáticos (B12 mayor a 179pg/ml, a las 8, 26,52 semanas) igual SÍ /NO

E.5.1.1

Timepoint(s) of evaluation of this end point

At 8, 26, 52 study weeks

En las semanas 8, 26 y 52 del estudio

E.5.2

Secondary end point(s)

Variables Secondary Result
-Level of vitamin B12 (pg/ml)
-Adverse events: description, onset and resolution, intensity (degree), evaluation of the relationship of causality with the medication and severity criteria mesured in all visits.
-Compliance with treatment: measured by counting the unused vials in the oral treatment and the number of injections received in the intramuscular treatment.
-Quality of life, measured by Euroqol-5D questionnaire.
-Satisfaction and preferences of patients about form of administration: this will be evaluated at the end of the study with a specific question.

Resultado secundarias
-Nivel de vitamina B12 (pg/ml).
-Acontecimientos adversos. Se medirá en todas las visitas la aparición de acontecimientos adversos: descripción, comienzo y resolución, intensidad (grado), evaluación de la relación de causalidad con la medicación y criterios de gravedad.
-Adherencia al tratamiento: medido mediante el recuento de viales no usados en el tratamiento oral y el número de inyecciones recibidas en el tratamiento intramuscular.
-Calidad de vida, medida por el cuestionario Euroqol-5D.
-Satisfacción y preferencias de los pacientes sobre la vía de administración: se evaluará al final del estudio mediante una pregunta específica.

E.5.2.1

Timepoint(s) of evaluation of this end point

Throughout the study

A lo largo de todo el estudio

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

E.6.5

Efficacy

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

Yes

E.6.13.1

Other scope of the trial description

Evaluate the effectiveness of orally administered vitamin B12 compared with intramuscular

Evaluar la efectividad de la vitamina B12 administrada vía oral comparada con la vía intramuscular

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)

E.7.4

Therapeutic use (Phase IV)

Yes

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

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

Mismo medicamento distinta vía de administración(oral)

Same drug different way of administration(oral)

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

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

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

When the 320 study subjects requiered and the 1 year follow up are achieved

Hasta que se consigan los 320 pacientes necesarios con su correspondiente periodo de
seguimiento de 1 año.

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

Information not present in EudraCT

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

Information not present in EudraCT

F.1.1.3

Newborns (0-27 days)

Information not present in EudraCT

F.1.1.4

Infants and toddlers (28 days-23 months)

Information not present in EudraCT

F.1.1.5

Children (2-11years)

Information not present in EudraCT

F.1.1.6

Adolescents (12-17 years)

Information not present in EudraCT

F.1.2

Adults (18-64 years)

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

320

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

F.3.3.1

Women of childbearing potential not using contraception

Information not present in EudraCT

F.3.3.2

Women of child-bearing potential using contraception

Information not present in EudraCT

F.3.3.3

Pregnant women

Information not present in EudraCT

F.3.3.4

Nursing women

Information not present in EudraCT

F.3.3.5

Emergency situation

Information not present in EudraCT

F.3.3.6

Subjects incapable of giving consent personally

Information not present in EudraCT

F.3.3.7

Others

Information not present in EudraCT

F.4 Planned number of subjects to be included

F.4.1

In the member state

320

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)

Not different from the expected normal treatment

No tratamiento distinto del normal esperado

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

2011-06-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-02-08

P. End of Trial
P.	End of Trial Status	Completed

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