Clinical Trials Register

Summary
EudraCT Number:	2010-024265-40
Sponsor's Protocol Code Number:	KETA-FAN
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:	2012-03-16
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

2010-024265-40

A.3

Full title of the trial

Perineural vs systemic N-methyl-D-aspartate (NMDA) receptors antagonism with ketamine as a reverser of peripheral and central sensitization in phantom limb pain

ANTAGONISMO DE LOS RECEPTORES N-METIL-D-ASPARTATO (NMDA) PERINEURALES VS. SISTÉMICOS CON KETAMINA COMO REVERSOR DE LA SENSIBILIZACIÓN PERIFÉRICA Y CENTRAL EN DOLOR DEL MIEMBRO FANTASMA

A.3.1

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

Administration of Ketamine, an anaesthetic drug, in the perineural space vs intravenous, to reverse the peripheral and central pain sensitization in phantom limb pain, a phenomena thought to be linked with the N-methyl-D-aspartate (NMDA) receptors which are activated both in the peripheral and central nervous system and are related to the maintenance of pain.

Administración de ketamina, un anestésico, en el espacio perineural vs intravenoso, para revertir la sensibilización periférica y central en el dolor del miembro fantasma, un fenómeno que se cree que está relacionado con los receptores N-metil-D-aspartato (NMDA) que se activan tanto en el sistema nervioso central y periférico y están relacionados con el mantenimiento del dolor.

A.3.2

Name or abbreviated title of the trial where available

no aplicable

A.4.1

Sponsor's protocol code number

KETA-FAN

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	HOSPITAL UNIVERSITARI DE BELLVITGE
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	Agencia Española de Medicamentos y Productos Sanitarios. Ministerio de Sanidad, Política Social e Ig
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	HOSPITAL UNIVERSITARI DE BELLVITGE
B.5.2	Functional name of contact point	SERVICIO DE ANESTESIOLOGIA
B.5.3	Address:
B.5.3.1	Street Address	C/ FEIXA LLARGA S.N.
B.5.3.2	Town/ city	L'HOSPITALET DE LLOBREGAT
B.5.3.3	Post code	08907
B.5.3.4	Country	Spain
B.5.4	Telephone number	34932607323
B.5.5	Fax number	34932607848
B.5.6	E-mail	mayorale@bellvitgehospital.cat

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	Ketolar
D.2.1.1.2	Name of the Marketing Authorisation holder	PARKE DAVIS, S.L.
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.3.1	Product name	Ketamina
D.3.2	Product code	Ketamina perineural
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	Perineural use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ketamina
D.3.9.1	CAS number	79499-51-7
D.3.9.2	Current sponsor code	ketamina
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	50
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	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	Ketolar
D.2.1.1.2	Name of the Marketing Authorisation holder	PARKE DAVIS, S.L.
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.3.1	Product name	Ketamina
D.3.2	Product code	Ketamina intravenosa
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	Intravenous drip use (Noncurrent)
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ketamina
D.3.9.1	CAS number	79499-51-7
D.3.9.2	Current sponsor code	ketamina intravenosa
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	50
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	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for injection/infusion in pre-filled syringe
D.8.4	Route of administration of the placebo	Parenteral use (Noncurrent)

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Phantom limb pain

Dolor de miembro fantasma

E.1.1.1

Medical condition in easily understood language

Chronic Pain in the distribution of an amputated limb

Dolor crónico en la distribución de una extremidad amputada

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10034804
E.1.2	Term	Phantom limb pain
E.1.2	System Organ Class	10029205 - Nervous system 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 determine whether blocking NMDA receptors (N-methyl-D-aspartate) at peripheral perineural can reverse phantom limb pain. The molecular mechanisms of peripheral and central sensitization, necessarily involve the glutamate-NMDA system, which can be blocked by the anesthetic drug ketamine albeit at the expense of unacceptable side effects from excessive doses. His administration at low doses, but in the target organ may reduce these adverse reactions and be more effective.

Conocer si el bloqueo de los receptores NMDA (N-Metil-D-Aspartato) periféricos a nivel perineural puede revertir el dolor de miembro fantasma. Los mecanismos moleculares de sensibilización periférica y central, involucran necesariamente el sistema Glutamato-NMDA, que puede ser bloqueado con el fármaco anestésico Ketamina aunque a expensas de efectos secundarios inaceptables por las excesivas dosis administradas. Su administración a dosis bajas, pero en los órganos diana, podría disminuir estas reacciones adversas y ser más eficaz.

E.2.2

Secondary objectives of the trial

? Assessment of variability and maintenance of analgesic quality in 3 months follow-up
? Verify the existence of a parallel between the perineural blood flow and severity of pain and / or phantom limb sensation
? Assessment of the different profile of adverse reactions expected between intravenous administration and perineural
? Assessment of neuropathic pain descriptors items spontaneous and evoked, quality of life, depression and anxiety.

? Valoración de la variabilidad y mantenimiento de la calidad analgésica en 3 meses de seguimiento
? Comprobar la existencia de un paralelismo entre el flujo sanguíneo perineural y la severidad del dolor y/o sensación de miembro fantasma
? Valoración del diferente perfil de reacciones adversas esperado entre la administración endovenosa y perineural
? Valoración de los ítems descriptores del dolor neuropático espontáneo y evocado, calidad de vida, depresión y ansiedad.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

?Amputees above or under the knee
?Indication of amputation must be non-diabetic ischemic
?Phantom limb pain of at least 10 days and moderate to severe (visual analogue scale VAS> 5 in a period of 3 consecutive days)
?Adults over 18 y
?Informed consent
?Ability to answer the questionnaires of pain, function and quality of life

?Pacientes con amputación supra o infracondílea de una extremidad inferior
?La indicación de la amputación deberá ser isquémica no diabética
?Dolor de miembro fantasma de al menos 10 días de duración y de intensidad moderada a severa (Escala visual analógica-EVA>5 en un periodo de 3 días consecutivos)
?Mayores de edad
?Consentimiento informado
?Capacidad para responder a las cuestionarios de dolor, funcionalidad y calidad de vida

E.4

Principal exclusion criteria

? Prior amputation of the same or other limb
? Severe psychiatric illness including schizophrenia
? Contraindication to the use of ketamine
? Absolute contraindications for the performance of anesthetic blocks (infectious, hematologic)
? Patient compensation pending litigation related to the pathology
? Another type of chronic pain, especially neuropathic pain, which in the opinion of the investigator may interfere with the assessment by the patient
? States of generalized hyperalgesia, in the opinion of the investigator, may interfere with the assessment of pain (eg Fibromyalgia)
? Use of Opioids (Tramadol excluded if <200 mg / d)
? Use of Gabapentin at doses> 900 mg / d or Pregabalin> 150 mg / d
? Use of Amitriptyline
? Uncontrolled hypertension
? Cranial hypertension
? Central Nervous System Neoplasms
? Diabetic neuropathy
? Electrocardiogram with alterations considered exclusive by the clinician (particularly long QTc)
? Children under 18 y
? Inability to respond to the scales

?Amputación previa de la misma extremidad o de otra
?Enfermedad psiquiátrica grave incluida esquizofrenia
?Contraindicación al uso de ketamina
?Contraindicaciones absolutas para la realización del bloqueo anestésico (infecciosas, hematológicas)
?Paciente pendiente de litigio por compensación económica relacionada con la patología
?Otro tipo de dolor crónico, especialmente neuropático, que a juicio del investigador pueda interferir en la valoración por el paciente
?Cuadros de hiperalgesia generalizada que, a juicio del investigador, puedan interferir en la valoración del dolor (ej: Fibromialgia)
?Uso de opioides excluido Tramadol a < 200 mg/d
?Uso de Gabapentina a dosis > 900 mg/d o Pregabalina >150 mg/d
?Uso de Amitriptilina
?Hipertensión arterial no controlada
?Hipertensión craneal
?Neoplasias del sistema nervioso central
?Neuropatía diabética
?Electrocardiograma con alteraciones consideradas como excluyentes por el clínico (en especial QTc alargado)
?Menores de 18 a
?Incapacidad para responder a las escalas

E.5 End points

E.5.1

Primary end point(s)

Improvement in phantom limb pain> 40% at 7 days after administration of perineural vs. perineural ketamine (Mean score in Visual Analog Scale in the last 24 h; VAS-24h)

Mejoría del dolor (Escala Visual Analógica media en las últimas 24 h; EVA-24h) de miembro fantasma >40% a los 7 días de la administración de Ketamina perineural vs. endovenosa

E.5.1.1

Timepoint(s) of evaluation of this end point

Day 7

Día 7

E.5.2

Secondary end point(s)

? Assessment of variability and maintenance of analgesic quality over time (mean VAS-24h score at 7 days - 1 month - 3 months)
? Analysis of the response to heat by Peltier probe (Thermotest-CHEPS) at the front of the arm before and 30 minutes after using the perineural blockade limits. Intra-and interindividual comparison in addition to our normal population. Repeated test at 7 days - 1 month - 3 months. This should give us information on the systemic antinocicetive response in addition to detecting basal central sensitization phenomena.
? Verify the existence of a parallelism between the perineural blood flow and severity of pain and / or phantom limb sensation, maximum flow rate measured by Doppler ultrasound in nerve trunks terminals (Basal - 7 days - 1 month - 3 months)
? Assessment of the different profile of adverse reactions expected between intravenous and perineural administration of ketamine: sedation (Ramsay), interrogation of tactile hallucinations, visual and auditory.
? Differences in other self-administered scale values (Basal - 7 days - 1 month - 3 months)
? Neuropathic pain questionnaire
? Depression and Anxiety Scale HADS
? EUROQOL-5D quality of life
? Patient and the clinician impression of change
? Phantom limb sensation questionnaire
? Description of changes in anatomical distortion

?Valoración de la variabilidad y mantenimiento de la calidad analgésica en el tiempo (EVA media 24h a los 7 días - 1 mes ? 3 meses)
?Análisis de la respuesta al calor por sonda Peltier (Thermotest-Cheps) en la cara anterior del brazo antes y 30 minutos después del bloqueo perineural utilizando el método de los límites. Comparación intra e interindividual además de con nuestra población de normalidad. Repetición de la prueba a los 7 días - 1 mes ? 3 meses. Esto nos debería dar información sobre la respuesta antinocicetiva sistémica de los fármacos de estudio además de detectar fenómenos de sensibilización central basales. El estudio será siempre realizado por el mismo técnico y facultativo, utilizando el mismo equipo y en condiciones similares de temperatura ambiente.
?Comprobar la existencia de un paralelismo entre el flujo sanguíneo perineural y la severidad del dolor y/o sensación de miembro fantasma: Velocidad de flujo máxima medida por eco-doppler en troncos nerviosos terminales (Basal - 7 días - 1 mes ? 3 meses)
?Valoración del diferente perfil de reacciones adversas esperado entre la administración endovenosa y perineural de ketamina: Sedación (Ramsay), interrogatorio sobre alucinaciones táctiles, visuales y auditivas.
?Diferencias en las otras escalas valoradas auto-administradas (Basal - 7 días - 1 mes ? 3 meses)
oCuestionario de valoración del dolor neuropático (Bouhassira)
oDepresión y Ansiedad ? Escala HADS
oEUROQOL-5D de calidad de vida
oImpresión global de cambio por el paciente y el clínico
oCuestionario de intensidad de sensación de miembro fantasma
oDescripción de los cambios de la distorsión anatómica

E.5.2.1

Timepoint(s) of evaluation of this end point

7 days - 1 month - 3 months

7 días - 1 mes ? 3 meses

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

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

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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

other route of administration

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.8.5

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

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

El final del estudio se define como la última visita de seguimiento del último paciente incluido en el estudio.

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)

Yes

F.1.3.1

Number of subjects for this age range:

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.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)

Usual practice clinical treatment as judge by the investigator

Tratamiento habitual según el criterio clínico del investigador

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

2011-10-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-05-12

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

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