Clinical Trials Register

Summary
EudraCT Number:	2014-004271-22
Sponsor's Protocol Code Number:	INSIGHT006:FLU-IVIG
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:	2015-03-03
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

2014-004271-22

A.3

Full title of the trial

Anti-Influenza Hyperimmune Intravenous Immunoglobulin, Clinical Outcome Study, (INSIGHT 006: FLU-IVIG)

Inmunoglobulina intravenosa hiperinmune antigripal?, Ensayo Clínico de Objetivo Clínico (INSIGHT 006: FLU-IVIG)

A.3.1

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

FLU-IVIG

A.4.1

Sponsor's protocol code number

INSIGHT006:FLU-IVIG

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	Regents of the University of Minnesota
B.1.3.4	Country	United States
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	National Institute of Allergy and Infectious Diseases (NIAID)
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	National Institute of Allergy and Infectious Diseases (NIAID)
B.5.2	Functional name of contact point	Richard T. Davey
B.5.3	Address:
B.5.3.1	Street Address	10 Center Drive, Room 4-1479, MSC 1460
B.5.3.2	Town/ city	Bethesda MD
B.5.3.3	Post code	20892-1460
B.5.3.4	Country	United States
B.5.4	Telephone number	+13014968029
B.5.5	Fax number	+13014805560
B.5.6	E-mail	rdavey@niaid.nih.gov

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	Anti-Influenza Immune Globulin (Human) Intravenous Injection
D.3.4	Pharmaceutical form	Infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Anti-influenza immune globulin (human) intravenous injection
D.3.9.3	Other descriptive name	ANTI-INFLUENZA IMMUNE GLOBULIN (HUMAN) INTRAVENOUS INJECTION (ANTI-INFLUENZA IVIG)
D.3.9.4	EV Substance Code	SUB170873
D.3.10	Strength
D.3.10.1	Concentration unit	mg/l milligram(s)/litre
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	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)	Yes
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.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	Solvent for 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

Influenza A and B

Gripe A y B

E.1.1.1

Medical condition in easily understood language

Influenza

Gripe

E.1.1.2

Therapeutic area

Diseases [C] - Virus Diseases [C02]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	17.1
E.1.2	Level	PT
E.1.2	Classification code	10022000
E.1.2	Term	Influenza
E.1.2	System Organ Class	10021881 - Infections and infestations

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The purpose of this randomised trial is to test whether giving a single infusion of high-dose anti-influenza IVIG (active drug) compared to normal-saline (placebo), to adults hospitalised with influenza A or B, reduces the severity of influenza and hastens full recovery.

El propósito de este ensayo aleatorizado es estudiar si la administración de una infusión única de una inmunoglobulina antiinfluenza a dosis altas (fármaco activo) comparada con la administración de suero salino (placebo) en adultos hospitalizados por gripe A o B reduce la gravedad de la gripe y acelera la recuperación completa.

E.2.2

Secondary objectives of the trial

1) Change from baseline to Day 3 in NEW score. 2) The ordinal primary outcome assessed at Days 1-7, 14 and 28. 3) Number of days hospitalized. 4) Composite of mortality or hospitalization at Days 7, 14 and 28. 5) Requirement for invasive mechanical ventilation or admission to the ICU (among those not enrolled from the ICU). 6) Percent of patients shedding virus at Day 3. 7) Hemagglutination Inhibition (HAI) antibody level changes through Day 7. 8) Grade 3 and 4 adverse events. 9) Serious adverse events. 10) Percent of patients developing bronchitis, pneumonia or other complications
through Day 28. 11) Mortality. 12) Mortality. 13)Complications of influenza such as bronchitis and pneumonia. 14) Percent of patients shedding virus at Day 3. 15) To compare the IVIG and placebo groups for haemagglutination inhibition titre (influenza antibodies) levels at Days 1, 3 and 7. 16) To compare the IVIG and placebo groups for major clinical outcomes in subgroups

1) Cambios desde el momento basal al Día 3 en la puntuación EsAP (NEW). 2) La evaluación primaria ordinal en los Días 1 a 7, 14 y 28. 3) Número de días de hospitalización. 4) Evaluación compuesta de hospitalización y mortalidad en los Días 7, 14 y 28. 5) Requerir ventilación mecánica invasiva o ingreso en la UCI (para aquellos pacientes que no estaban en la UCI). 6) Porcentaje de pacientes que no presentan virus en el Día 3. 7) Comparar los niveles de títulos HAI en los grupos de IGIV y placebo en los Días 1, 3 y 7. 8) Acontecimientos adversos grado 3 y 4. 9) AAG. 10) Porcentaje de pacientes que desarrollan bronquitis, neumonía u otras complicaciones hasta el Día 28. 11) Mortalidad. 12) Complicaciones de la gripe, tales como bronquitis y neumonía. 13) Comparar las valoraciones clínicas principales en ambos grupos por subgrupos definidos por características basales

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

INSIGHT Genomics Study, Protocol No. 004 version 2.0, dated 27 August 2013: The purpose of this study is to obtain a whole blood sample from which DNA will be extracted to study polymorphisms in immune response genes and other genetic variants that may be associated with an increased risk of disease progression among individuals with infectious diseases of public health importance who are enrolled in qualifying INSIGHT studies. Identifying genomic loci associated with disease progression and resistance/susceptibility to infections, will inform risk stratification for individual patients, but more importantly may reveal new pathways and therapeutic targets for modulation of the host response. Although very large studies are required to identify disease associations genome-wide, much can be achieved using a hypothesis-driven approach to explore phenotypic associations identified through other clinical studies. In order to utilize current and future advances in genetic technology (i.e., whole genome sequencing) to better understand the role of host genetics in the pathophysiology of infections of public health importance, there is a need to link genetic data with clinical outcomes data in large, well-characterized populations.

Estudio Genético de INSIGHT, Protocolo INSIGHT 004 versión 2.0, de fecha 27 Agosto 2013: El propósito de este estudio es obtener sangre entera de la que se extraerá ADN para estudiar polimorfismos de los genes implicados en la respuesta inmune y otras variantes genéticas que se puedan asociar a un aumento del riesgo de progresión de la enfermedad en individuos con enfermedades infecciosas de importancia sanitaria y que participen en los estudios INSIGHT apropiados. Los pacientes podrán estratificarse según el riesgo mediante la identificación de los loci genéticos asociados a la progresión de la enfermedad y la resistencia/susceptibilidad a las infecciones. Pero más importante puede identificar nuevas vías y objetivos terapéuticos que modulen la respuesta del huésped. Aunque se requieren estudios muy grandes para identificar asociaciones enfermedad-genoma, se puede lograr mucho utilizando hipótesis para explorar asociaciones fenotípicas identificadas en otros ensayos clínicos. Es necesario enlazar los datos genéticos con la evolución clínica en poblaciones grandes y bien caracterizadas para utilizar los avances actuales y futuros de la tecnología genética (esto es, la secuenciación del genoma completo) para comprender mejor la función de la genética del huésped en la patofisiología de las infecciones con importancia sanitaria.

E.3

Principal inclusion criteria

1. Signed informed consent
2. Age ? 18 years of age
3. Locally determined positive influenza test (by PCR or other nucleic acid testing, or
by rapid Ag) from a specimen obtained within 2 days prior to randomization
4. Onset of illness no more than 7 days before randomization, defined as when the
patient first experienced at least one respiratory symptom or fever
5. Hospitalized (or in observation unit) for influenza, with anticipated hospitalization for
more than 24 hours. Criteria for hospitalization will be up to the individual treating
clinician.
6. For women of child-bearing potential: willingness to abstain from sexual intercourse
or use at least 1 form of hormonal or barrier contraception through Day 28 of the
study
7. Willingness to have blood and respiratory samples obtained and stored
8. NEW score ? 2 at screening

1. Firma del consentimiento informado.
2. Edad igual o superior a 18 años.
3. Prueba de gripe positiva determinada localmente de una muestra obtenida dentro de los 2 días anteriores a la aleatorización. La prueba puede ser PCR u otra prueba de ácidos nucleicos o prueba rápida de antígeno.
4. Aparición de la enfermedad dentro de los 7 días anteriores a la aleatorización, definida ésta como el primer día que el paciente experimentó un síntoma respiratorio o fiebre.
5. Hospitalización (o en unidad de observación) por gripe con una duración esperada superior a las 24 horas. El médico que atiende al paciente fijará el criterio de hospitalización.
6. En el caso de mujeres fértiles, aceptar abstenerse de relaciones sexuales o utilizar una forma de contracepción hormonal o de barrera hasta el Día 28 del estudio.
7. Aceptar la extracción y almacenamiento de muestras sanguíneas y respiratorias.
8. Puntuación de EsAP igual o superior a 2 en el momento de la selección

E.4

Principal exclusion criteria

1. Women who are pregnant or breast-feeding
2. Strong clinical evidence (in the judgment of the site investigator) that the etiology of illness is primarily bacterial in origin
3. Prior treatment with any investigational drug therapy within 30 days prior to screening
4. History of allergic reaction to blood or plasma products (as judged by the site investigator)
5. Known IgA deficiency
6. A pre-existing condition or use of a medication that, in the opinion of the site investigator, may place the individual at a substantially increased risk of thrombosis (e.g., cryoglobulinemia, severe refractory hypertriglyceridemia, or clinically
significant monoclonal gammopathy)
7. Presence of any pre-existing illness that, in the opinion of the site investigator, would place the individual at an unreasonably increased risk through participation in this study
8. Patients who, in the judgment of the site investigator, will be unlikely to comply with the requirements of this protocol
9. Medical conditions for which receipt of a 500 mL volume of intravenous fluid may be dangerous to the patient (e.g., decompensated congestive heart failure)
10. Receiving extracorporeal membrane oxygenation (ECMO)
11. Suspicion that infection is due to an influenza strain or subtype other than A(H1N1)pdm09, H3N2, or influenza B (e.g., H5N1, H7N9)

1. Mujeres embarazadas o en periodo de lactancia.
2. Evidencia clínica importante (en opinión del investigador del centro) de que la etiología de la enfermedad es principalmente de origen bacteriano.
3. Tratamiento previo con cualquier fármaco en investigación en los 30 días anteriores al proceso de selección.
4. Historia de reacción alérgica a productos derivados de la sangre o el plasma en opinión del investigador del centro.
5. Deficiencia conocida de IgA.
6. Enfermedad previa o utilización de una medicación que en opinión del investigador del centro pueda poner al paciente en riesgo de padecer trombosis (por ejemplo, crioglobulinemia, hipertrigliceridemia refractaria severa, gammapatía monoclonal significativa).
7. Enfermedad previa que en opinión del investigador del centro supondría un aumento no razonable del riesgo durante su participación del estudio.
8. Pacientes que a juicio del investigador del centro no serán capaces de cumplir con los requisitos de este protocolo.
9. Situaciones médicas que supongan un peligro para el paciente al recibir 500 mL de líquido intravenoso, como puede ser la insuficiencia cardíaca congestiva descompensada.
10. Oxigenación de membrana extracorpórea (ECMO).
11. Sospecha de que la infección se debe a una cepa o subtipo de gripe diferente a A(H1N1)pdm09, H3N2 o gripe B (p.ej., H5N1, H7N9).

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is an ordinal outcome at Day 7 that has 6 mutually exclusive categories:
1. death;
2. in the intensive care unit (ICU);
3. non-ICU hospitalization, requiring supplemental oxygen;
4. non-ICU hospitalization, not requiring supplemental oxygen;
5. not hospitalized, but unable to resume normal activities; or
6. not hospitalized with full resumption of normal activities.

El criterio principal de evaluación es la situación del paciente en el Día 7 que tiene seis categorías mutuamente excluyentes:
1. Muerte;
2. Ingresado en Unidad de Cuidados Intensivos (UCI);
3. Hospitalizado, fuera de la UCI pero requiriendo oxigenoterapia;
4. Hospitalizado, fuera de la UCI y no requiere oxigenoterapia;
5. No hospitalizado pero no puede continuar con las actividades normales;
6. No hospitalizado y en condiciones de emprender las actividades normales.

E.5.1.1

Timepoint(s) of evaluation of this end point

Day 7

Día 7

E.5.2

Secondary end point(s)

1) Change from baseline to Day 3 in NEW score. 2) The ordinal primary outcome assessed at Days 1-7, 14 and 28. 3) Number of days hospitalized. 4) Composite of mortality or hospitalization at Days 7, 14 and 28. 5) Requirement for invasive mechanical ventilation or admission to the ICU (among those not enrolled from the ICU). 6) Percent of patients shedding virus at Day 3. 7) Hemagglutination Inhibition (HAI) antibody level changes through Day 7. 8) Grade 3 and 4 adverse events. 9) Serious adverse events. 10) Percent of patients developing bronchitis, pneumonia or other complications
through Day 28. 11) Mortality. 12) Complications of influenza such as bronchitis and pneumonia. 13) Percent of patients shedding virus at Day 3. 14) To compare the IVIG and placebo groups for haemagglutination inhibition titre (influenza antibodies) levels at Days 1, 3 and 7. 15) . To compare the IVIG and placebo groups for major clinical outcomes in subgroups defined by the following characteristics measured at baseline: Age, Gender, Race/ethnicity, Geographic region (United States, Europe, South America, Australasia)

E.5.2.1

Timepoint(s) of evaluation of this end point

See section E.5.2

Ver Sección E.5.2

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

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

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

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Argentina

Australia

Denmark

Germany

Greece

Spain

Thailand

United Kingdom

United States

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

FLU-IVIG is a randomized, double blind, placebo-controlled, multicenter, international clinical trial. Hospitalized patients with a National Early Warning (NEW) score of 2 or greater will be randomized in a 1:1 allocation to receive either IVIG plus standard of care (SOC) therapy or placebo for IVIG (a comparable volume of normal saline) plus SOC, and will then be followed for 28 days. A total of 320 adult patients will be randomized over multiple influenza seasons.

FLU-IVIG es un ensayo clínico internacional aleatorizado, doble ciego, controlado con placebo y multicéntrico. Se aleatorizarán pacientes hospitalizados con puntuación ?2 en la Escala de Alerta Precoz (EsAP) en una proporción 1:1 para recibir IGIV más tratamiento convencional o placebo de IGIV (un volumen comparable de suero salino normal) más tratamiento convencional y se seguirán durante 28 días. Se aleatorizará un total 320 pacientes adultos en múltiples epidemias estacionales de gripe

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:

250

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

None

Ninguno

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

150

F.4.2.2

In the whole clinical trial

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)

None

Ninguno

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	INSIGHT (International Network for Strategic Initiatives in Global HIV Trials)
G.4.3.4	Network Country	United States

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2015-06-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-05-14

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

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