Clinical Trials Register

Summary
EudraCT Number:	2014-002007-13
Sponsor's Protocol Code Number:	IG0904
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2015-07-15
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

Spain - AEMPS

A.2

EudraCT number

2014-002007-13

A.3

Full title of the trial

A multicenter, randomized, placebo-controlled, double-blind and crossover pilot trial with human alpha-1 antitrypsin in patients with chronic fatigue syndrome

Ensayo clínico piloto, multicéntrico,aleatorizado, controlado con placebo, a doble ciego y cruzado con alfa-1 antitripsina humana en pacientes con síndrome de fatiga crónica

A.3.1

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

A pilot clinical trial with human alpha-1 antitrypsin in patients with chronic fatigue syndrome

Ensayo clínico piloto con alfa-1 antitripsina humana en pacientes con síndrome de fatiga crónica

A.4.1

Sponsor's protocol code number

IG0904

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	Instituto Grifols, S.A.
B.1.3.4	Country	Spain
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	Instituto Grifols, S.A.
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	Instituto Grifols, S.A.
B.5.2	Functional name of contact point	Department of Clinical Trials
B.5.3	Address:
B.5.3.1	Street Address	Polígono Levante, Can Guasch, 2
B.5.3.2	Town/ city	Parets del Vallés
B.5.3.3	Post code	08150
B.5.3.4	Country	Spain
B.5.4	Telephone number	+34935710700
B.5.5	Fax number	+34935710381
B.5.6	E-mail	IGregulatory.affairs@grifols.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	Prolastina
D.2.1.1.2	Name of the Marketing Authorisation holder	Grifols Deutschland GmbH
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	Powder and solvent for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
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	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	Yes
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	Salina Fisiológica Grifols
D.2.1.1.2	Name of the Marketing Authorisation holder	Labortorios Grifols, 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.3.1	Product name	Normal Saline Grifols
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
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 infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Patients with chronic fatigue syndrome

Pacientes con síndrome de fatiga crónica

E.1.1.1

Medical condition in easily understood language

Patients with chronic fatigue syndrome

Pacientes con síndrome de fatiga crónica

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	18.0
E.1.2	Level	PT
E.1.2	Classification code	10008874
E.1.2	Term	Chronic fatigue syndrome
E.1.2	System Organ Class	10018065 - General disorders and administration site conditions

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.0
E.1.2	Level	SOC
E.1.2	Classification code	10018065
E.1.2	Term	General disorders and administration site conditions
E.1.2	System Organ Class	10018065 - General disorders and administration site conditions

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 potential clinical effect of weekly intravenous infusions of human alpha-1 antitrypsin (AAT) in subjects suffering from CFS by means of the change in elastase activity in peripheral blood mononuclear cells (PBMC).

Evaluar el posible efecto clínico de la infusión intravenosa semanal con AAT humana en pacientes con SFC mediante el cambio en la actividad de la elastasa en células mononucleares de sangre periférica (PBMC).

E.2.2

Secondary objectives of the trial

Safety of AAT therapy in subjects with CFS and without congenital deficiency of AAT will also be assessed.

Se evaluará también la seguridad del tratamiento continuado con AAT humana en sujetos afectados por SFC sin deficiencia congénita de AAT.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male or female aged 18 to 65 years.
2. Subjects with a BMI ? 30 Kg/m2.
3. Subjects who meet ?Myalgic Encephalomyelitis: International Consensus Criteria, 2011? and with a diagnostics of CFS for more than 12 months.
4. Subjects who understand and voluntarily signed by written his/her clinical trial participation consent.
5. Subjects who judged to be reliable and demonstrated a degree of understanding that allowed them to communicate intelligibly, according to the investigator?s criteria, so it can be successfully applied the monitoring clinical instruments of CFS proposed in the clinical trial.
6. Subjects must be willing to comply with all aspects of the clinical trial protocol, including blood sampling and limitation in medication to alleviate CFS-symptoms.
7. Subjects who have successfully completed the Screening Period.
8. Subjects with elastase activity in PBMC exceeding 150 units/mg prior to start Run-in Period (Week -6).
9. Subjects who have successfully completed the Run-in Period.
10. Subjects with elastase activity in PBMC exceeding 150 units/mg at the Baseline Visit 1 (Week 0).

1. Hombre o mujer de 18 a 65 años.
2. Sujetos con un IMC ? 30 Kg/m2
3. Sujetos que cumplan los criterios propuestos por ?Myalgic Encephalomyelitis International Consensus Criteria, 2011? y con un diagnóstico de SFC de más de 12 años.
4. Sujetos que entiendan y voluntariamente firmen su consentimiento de participación en el ensayo.
5. Sujetos considerados fiables y que demuestren un grado de compresión que permita la comunicación con ellos. Esto permitirá aplicar los instrumentos de seguimiento clínico de SFC propuestos en el ensayo clínico.
6. Sujetos dispuestos a cumplir con todos los aspectos del protocolo del ensayo clínico, incluyendo la extracción de muestras de sangre y la limitación de la medicación para aliviar los síntomas de SFC.
7. Sujetos que hayan completado adecuadamente el Periodo de Cribado.
8. Sujetos con una actividad de la elastasa en PBMC que excede 150 unidades/mg antes de empezar el Periodo de Pre-inclusión.
9. Sujetos que hayan completado adecuadamente el Periodo de Pre-inclusión.
10. Sujetos con una actividad de la elastasa en PBMC que excede 150 unidades/mg antes de la Visita basal (Semana 0).

E.4

Principal exclusion criteria

1. Subjects with any severe congenital deficiency of AAT.
2. Subjects who are active smokers within 6 months prior to Enrollment Visit.
3. Subjects currently receiving, or having received within 3 months prior to the Enrollment Visit treatment with human AAT.
4. Subjects with a history of intolerance to any component or excipient of the investigational products (AAT, chloride, phosphate, sodium).
5. Subjects with a history of anaphylactic reactions or severe reactions to any blood-derived product.
6. Subjects with a history of chronic alcoholism or illicit drug abuse (addiction) in the preceding 12 months prior to the Enrollment Visit.
7. Subjects with a known selective IgA deficiency and serum antibodies anti-IgA.
8. Subjects with any medical condition in the moment of the Enrollment Visit determined by laboratory tests, which is likely to significantly interfere in the clinical manifestation of CFS. Here are detailed some of these medical conditions:
? Serum AST, ALT, ALP or total bilirubin levels exceeding more than 1.5 times the upper limit of normal (ULN) for the expected normal range for the testing laboratory.
? Serum creatinine or urea levels exceeding more than 1.5 time the ULN for the expected normal range for the testing laboratory.
? Serum CK totals levels exceeding the ULN for the expected normal range for the testing laboratory.
? Serum TSH levels exceeding the ULN for the expected normal range for the testing laboratory.
? Serum title of ANA exceeding 1:160 dilutions.
? Positive serum FR as per positivity criteria established for the testing laboratory.
9. Subjects suffering from a disease or medical condition that could increase associated risks to subjects? participation in the clinical trial, or interfere with the interpretation of the study results, and according to the investigator?s criteria, it would be inappropriate for the subjects? participation in the clinical trial. These diseases include, but are not limited to major depressive disorders with psychotic or melancholic features as bipolar disorders, schizophrenia, dementia, anorexia or nervous bulimia.
10. Subjects currently receiving, or have received within 3 months prior to the Enrollment Visit, any investigational medicinal product or device.
11. Females who are pregnant, breastfeeding, of child-bearing potential, or unwilling to practice a highly effective method of contraception (oral, injectable or implanted hormonal methods of contraception, placement of an intrauterine device or intrauterine system, condom or occlusive cap with spermicidal foam/gel/film/cream/suppository, male sterilization, or true abstinence*) throughout the study.
* True abstinence: When this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods], declaration of abstinence for the duration of a trial, and withdrawal are not acceptable methods of contraception.)
12. Subjects pending for a resolution of a dispute or compensatory process, caused by their medical condition.

1. Sujetos con alguna deficiencia congénita severa de AAT.
2. Sujetos que son fumadores activos dentro de los 6 meses anteriores a la Visita de Inclusión.
3. Sujetos que esten recibiendo, o hayan recibido dentro de los 3 meses anteriores a la Visita de Inclusión tratamiento con AAT humana.
4. Sujetos con una historia de intolerancia a alguno de los componentes o excipientes del producto en investigación (AAT, cloruro, fosfato, sodio).
5. Sujetos con una historia de reacciones anafilácticas o reacciones severas a algún producto derivado de la sangre.
6. Sujetos con una historia de alcoholismo crónico o abuso ilícito de drogas (adicción) en los 12 meses anteriores a la visita de inclusión.
7. Sujetos con una deficiencia conocida de IgA y anticuerpos en suero anti-IgA.
8. Sujetos con alguna condición médica en el momento de la Visita de Inclusión determinada por los test de laboratorio, que pudiera interferir de manera significativa con las manifestaciones clínicas del SFC. Aquí se detallan algunas de las condiciones médicas:
- Valores séricos de AST, ALT, ?GT, FA o bilirrubina total 1,5 veces por encima del límite superior del intervalo de normalidad de referencia (LSN) establecido por el laboratorio del centro de investigación.
- Valores séricos de creatinina o urea 1,5 veces por encima del LSN establecido por el laboratorio del centro de investigación.
- Valores séricos de CK total por encima del LSN establecido por el laboratorio del centro de investigación.
- Valores séricos de TSH por fuera del rango de normalidad de referencia establecido por el laboratorio del centro de investigación.
- Título sérico de ANA superior a 1:160 diluciones.
- FR sérico positivo según el criterio establecido por el laboratorio del centro de investigación.
9. Estar afectado por de alguna enfermedad o condición médica que pudiera incrementar el riesgo asociado a la participación del sujeto en el ensayo clínico, o pudiera interferir en la interpretación de los resultados del estudio, y a criterio del investigador, hiciera que el sujeto fuera inapropiado para participar en el ensayo clínico. Estas enfermedades incluyen, aunque no se limitan a trastornos depresivos mayores con características psicóticas o melancólicas tales como trastorno bipolar, esquizofrenia, demencia, anorexia o bulimia nerviosa.
10. Sujetos que actualmente reciben, hayan recibido dentro de los 3 meses anteriores a la Visita de Inclusión, cualquier medicación en investigación o artefacto.
11. Mujeres embarazadas, en lactancia materna o potencialmente fértiles e incapaces de utilizar un método anticonceptivo eficaz (oral, inyectable, métodos hormonales de anticoncepción implantados, la colocación de un dispositivo intrauterino o un sistema intrauterino, preservativo o capuchón cervical con espermicida espuma/gel/película/crema/supositorio, la esterilización masculina, o abstinencia*) durante todo el estudio.
* La abstinencia: Aunque esté en consonancia con el estilo de vida habitual del sujeto (incluida abstinencia periódica [por ejemplo, el calendario, la ovulación, sintotérmico, métodos post-ovulación], declaración de abstinencia durante la duración de un juicio, y la retirada no son métodos anticonceptivos aceptables.)
12. Sujetos pendiente de la resolución de una disputa o proceso compensatorio causada por su condición médica.

E.5 End points

E.5.1

Primary end point(s)

Change in elastase activity in PBMC.

Cambio en la actividad de la elastasa en PBMC.

E.5.1.1

Timepoint(s) of evaluation of this end point

12 weeks treatment

12 semanas de tratamiento

E.5.2

Secondary end point(s)

? Change in tiredness score evaluated by Fatigue Severity Scale (FSS).
? Change in health-related quality of life measured by the Medical Outcomes Study-36 Item Short Form Health Survey (SF-36).

- Cambio de la sensación de fatiga evaluado por la Fatigue Severity Scale (FSS).
- Cambio de la calidad de vida relacionada con la salud evaluado por el cuestionario Medical Outcomes Study-36 Item Short Form Health Survey (SF-36).

E.5.2.1

Timepoint(s) of evaluation of this end point

12 weeks treatment

12 semanas de tratamiento

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

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

E.8.1.6

Cross over

Yes

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

Yes

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

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

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

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)

None.

Ninguno.

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

2015-02-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-01-30

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

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IMP with orphan designation in the indication
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