Clinical Trials Register

Summary
EudraCT Number:	2022-001671-14
Sponsor's Protocol Code Number:	221AD305
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:	2022-08-03
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

2022-001671-14

A.3

Full title of the trial

A Phase 3b/4 Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Verify the Clinical Benefit of Aducanumab (BIIB037) in Participants with Alzheimer's Disease

Estudio en fase IIIb/IV, aleatorizado, doble ciego, controlado con placebo y de grupos paralelos para verificar el beneficio clínico de aducanumab (BIIB037) en participantes con enfermedad de Alzheimer

A.3.1

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

A Study to Verify the Clinical Benefit of Aducanumab in Participants with Early Alzheimer's Disease

Estudio para verificar el beneficio clínico de aducanumab en participantes con enfermedad de Alzheimer temprana

A.3.2

Name or abbreviated title of the trial where available

ENVISION

A.4.1

Sponsor's protocol code number

221AD305

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	Biogen Idec Research Limited
B.1.3.4	Country	United Kingdom
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	Biogen Idec Research Limited
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Biogen Idec Research Limited
B.5.2	Functional name of contact point	Biogen España
B.5.3	Address:
B.5.3.1	Street Address	Paseo de la Castellana, 41
B.5.3.2	Town/ city	Madrid
B.5.3.3	Post code	28046
B.5.3.4	Country	Spain
B.5.4	Telephone number	+34913107110
B.5.5	Fax number	+34913107181
B.5.6	E-mail	clinicaltrials@biogen.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	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	Aducanumab
D.3.2	Product code	BIIB037
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Aducanumab
D.3.9.1	CAS number	N/A
D.3.9.2	Current sponsor code	BIIB037
D.3.9.4	EV Substance Code	SUB180599
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	100
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	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
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	Recombinant monoclonal antibody

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

Alzheimer's Disease

Enfermedad de Alzheimer

E.1.1.1

Medical condition in easily understood language

Alzheimer's Disease

Enfermedad de Alzheimer

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	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10001896
E.1.2	Term	Alzheimer's disease
E.1.2	System Organ Class	100000004852

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 verify the clinical benefit of monthly doses of aducanumab in slowing cognitive and functional impairment as measured by changes in the CDR-SB score as compared with placebo in participants with early Alzheimer's disease.

Verificar el beneficio clínico de dosis mensuales de aducanumab en la ralentización del deterioro cognitivo y funcional, según lo determinado por los cambios en la puntuación CDR-SB en comparación con placebo en participantes con enfermedad de Alzheimer temprana.

E.2.2

Secondary objectives of the trial

Key Secondary Objectives:
To assess the effect of monthly doses of aducanumab as compared with placebo on clinical decline as measured by the iADRS.
To assess the effect of monthly doses of aducanumab as compared with placebo on clinical decline as measured by ADCS-ADL-MCI.
To assess the effect of monthly doses of aducanumab as compared with placebo on clinical decline as measured by ADASCog13.
To assess the effect of monthly doses of aducanumab as compared with placebo on clinical decline as measured by the MMSE.
To assess the effect of monthly doses of aducanumab as compared with placebo on clinical decline as measured by NPI- 10.

Objetivos secundarios clave:
Evaluar el efecto de las dosis mensuales de aducanumab en comparación con placebo en el deterioro clínico según lo determinado mediante la escala iADRS.
Evaluar el efecto de las dosis mensuales de aducanumab en comparación con placebo en el deterioro clínico según lo determinado mediante el cuestionario ADCS-ADL-MCI.
Evaluar el efecto de las dosis mensuales de aducanumab en comparación con placebo en el deterioro clínico según lo determinado mediante la escala ADAS-Cog13.
Evaluar el efecto de las dosis mensuales de aducanumab en comparación con placebo en el deterioro clínico según lo determinado mediante el examen MMSE.
Evaluar el efecto de las dosis mensuales de aducanumab en comparación con placebo en el deterioro clínico según lo determinado mediante el inventario NPI-10.

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

Approximately 400 participants are expected to enroll in each of the following 3 biomarker sub-studies:
1. Measurement of amyloid plaque burden in certain areas of the brain as measured by amyloid PET
2. Measurement of neurofibrillary tangle burden in certain areas of the brain as measured by tau PET
3. Measurement of disease- or treatment-related CSF biomarkers

Se espera que se inscriban aproximadamente 400 participantes en cada uno de los 3 subestudios de biomarcadores siguientes:
1. Medición de la carga de placas de amiloide en ciertas áreas del cerebro medida mediante TEP de amiloide
2. Medición de la carga de ovillos neurofibrilares en ciertas áreas del cerebro medida mediante TEP de tau
3. Medición de biomarcadores del LCR relacionados con la enfermedad o con el tratamiento

E.3

Principal inclusion criteria

Key Inclusion Criteria:
- The participant must have confirmed amyloid beta pathology by CSF (historical CSF test results not allowed) or amyloid PET
- The participant must have a history of subjective memory decline with gradual onset and slow progression over the 6 months before Screening, confirmed by study partner
- The participant must have 1 informant/care partner who, in the Investigator's opinion, has frequent and sufficient contact with the participant (at least 10 hours/week in person or by phone) as to be able to provide accurate information about the participant's cognitive and functional abilities over time
- The participant must meet all of the following clinical criteria for MCI due to Alzheimer's disease or mild Alzheimer's disease according to NIA-AA criteria [Albert 2011; McKhann 2011]:
a. Have an MMSE score between 22 and 30 inclusive
b. Have a CDR memory score >0.5
c. Have a CDR-GS of 0.5 or 1.0
d. Have a RBANS score of 85 or lower indicative of objective cognitive impairment (based upon the DMI score).
- The participant must be in good health, apart from a clinical diagnosis of early Alzheimer's disease, as determined by the Investigator based on medical history and screening assessments
- The participant must consent to ApoE genotyping
- Must consent to apolipoprotein E (ApoE) genotyping. (Note: Participants are not required to be ApoE ε4 carriers)

Criterios de inclusión principales:
- El participante debe tener patología β-amiloide confirmada mediante LCR (no se permiten los resultados de las pruebas históricas de LCR) o TEP de amiloide
- El participante debe tener antecedentes de deterioro de la memoria subjetiva con inicio gradual y progresión lenta durante los 6 meses anteriores a la selección, confirmados por el acompañante del estudio
- El participante debe tener a 1 informante o cuidador que, en opinión del investigador, tenga un contacto frecuente y suficiente con el participante (al menos 10 horas/semana de forma presencial o por teléfono) como para poder proporcionar información precisa sobre las capacidades cognitivas y funcionales del participante a lo largo del tiempo
- El participante deberá cumplir todos los criterios clínicos siguientes para el DCL debido a enfermedad de Alzheimer o enfermedad de Alzheimer leve de acuerdo con los criterios del Instituto Nacional sobre el Envejecimiento y la Asociación de Alzheimer (NIA-AA) [Albert 2011; McKhann 2011]:
a. tener una puntuación del examen MMSE entre 22 y 30, ambas inclusive;
b. tener una puntuación de memoria CDR >0,5;
c. tener una CDR-GS de 0,5 o 1,0;
d. tener una puntuación RBANS de 85 o inferior indicativa de deterioro cognitivo objetivo (según la puntuación DMI).
- El participante debe gozar de buena salud, además de un diagnóstico clínico de enfermedad de Alzheimer en fase inicial, según lo determine el investigador, de acuerdo con su historial médico y las evaluaciones de selección
- El participante debe dar su consentimiento para la genotipificación de ApoE
- Debe dar su consentimiento para la determinación de la genotipificación de la apolipoproteína E (ApoE). (Nota: No es necesario que los participantes sean portadores de ApoE ε4)

E.4

Principal exclusion criteria

Key Exclusion Criteria:
- Any uncontrolled medical or neurological/neurodegenerative condition (other than Alzheimer's disease) that, in the opinion of the Investigator, might be a contributing cause of the participant's cognitive impairment
- Clinically significant and/or unstable psychiatric illness within 6 months prior to Screening
- Transient ischemic attack or stroke or any unexplained loss of consciousness within 1 year prior to Screening
- History of severe allergic or anaphylactic reactions or of hypersensitivity to any of the inactive ingredients in the drug product
- Participation in any study with purported disease-modifying effect in Alzheimer's disease within 12 months prior to Screening unless documentation of receipt of placebo is available
- Current use or previous use of medications with a purported disease modifying effect in Alzheimer's disease, outside of investigational studies
- Use of any medications that, in the opinion of the Investigator, may contribute to cognitive impairment, put the participant at higher risk for AEs, or impair the participant's ability to perform cognitive testing or complete study procedures
- Use of any investigational drug
- Prior exposure to aducanumab either commercially or by participation in a previous study with aducanumab. (Participants are eligible if they did not receive active aducanumab.)
- A negative PET scan result with any amyloid-targeting ligand within 12 months prior to Screening
NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Criterios de exclusión principales:
- Cualquier afección médica o neurológica/neurodegenerativa no controlada (distinta de la enfermedad de Alzheimer) que, en opinión del investigador, pueda ser una causa que contribuya al deterioro cognitivo del participante
- Enfermedad psiquiátrica clínicamente significativa y/o inestable en los 6 meses previos a la selección
- Accidente isquémico transitorio, accidente cerebrovascular o pérdida de conciencia sin explicación en el plazo de 1 año antes de la selección
- Antecedentes de reacciones alérgicas o anafilácticas graves o bien de hipersensibilidad a alguno de los excipientes del fármaco
- Participación en cualquier estudio con supuesto efecto modificador de la enfermedad para la enfermedad de Alzheimer en los 12 meses previos a la selección, a menos que esté disponible la documentación de haber recibido placebo
- Uso actual o uso previo de medicamentos con supuesto efecto modificador de la enfermedad en la enfermedad de Alzheimer, fuera de los estudios de investigación
- El uso de cualquier medicamento que, a juicio del investigador, pueda contribuir al deterioro cognitivo, exponer al participante a un mayor riesgo de sufrir AA o deteriorar la capacidad del participante para realizar pruebas cognitivas o completar los procedimientos de estudio
- Uso de cualquier fármaco en investigación
- Exposición previa a aducanumab, ya sea comercialmente o mediante la participación en un estudio previo con aducanumab (los participantes son aptos si no recibieron aducanumab activo)
- Resultado negativo en una TEP con ligandos de detección de amiloides en los 12 meses previos a la selección
NOTA: También aplican otros criterios de Inclusión/Exclusión definidos en el protocolo.

E.5 End points

E.5.1

Primary end point(s)

Change from baseline in CDR-SB score

Cambio con respecto al inicio en la puntuación CDR-SB

E.5.1.1

Timepoint(s) of evaluation of this end point

Week 78

Semana 78

E.5.2

Secondary end point(s)

1. Change from baseline in iADRS score
2. Change from baseline in ADCS-ADL-MCI score
3. Change from baseline in ADAS-Cog13 score
4. Change from baseline in MMSE score
5. Change from baseline in NPI-10 score
6. Change from baseline in PET Signal
7. Change from baseline in Tau PET Signal
8. Change from baseline in CDR-SB Score
9. Change from baseline in GST Composite Z-Score

1. Cambio con respecto al inicio en la puntuación de la escala iADRS
2. Cambio con respecto al inicio en la puntuación del cuestionario ADCS-ADL-MCI
3. Cambio con respecto al inicio en la puntuación de la escala ADAS-Cog13
4. Cambio con respecto al inicio en la puntuación del examen MMSE
5. Cambio con respecto al inicio en la puntuación del inventario NPI-10
6. Cambio con respecto al inicio en la señal de TEP
7. Cambio con respecto al inicio en la señal de TEP de tau
8. Cambio con respecto al inicio en la puntuación CDR-SB
9. Cambio con respecto al inicio en la puntuación Z compuesta de GST

E.5.2.1

Timepoint(s) of evaluation of this end point

1. Week 78, Week 106
2. Week 78, Week 106
3. Week 78, Week 106
4. Week 78, Week 106
5. Week 78, Week 106
6. Week 78, Week 104
7. Week 78, Week 104
8. Week 106
9. Week 78, Week 106

1. Semana 78, semana 106
2. Semana 78, semana 106
3. Semana 78, semana 106
4. Semana 78, semana 106
5. Semana 78, semana 106
6. Semana 78, semana 104
7. Semana 78, semana 104
8. Semana 106
9. Semana 78, semana 106

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

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Verify the Clinical Benefit of the IMP

Verificar el beneficio clínico del PEI

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)

Yes

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

Australia

Brazil

Canada

China

Mexico

United States

Switzerland

United Kingdom

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

UVUP (última visita del último paciente)

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:

195

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

1317

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

There maybe some patients who are incapable of giving consent personally.

Puede que algunos pacientes sean incapaces de dar su consentimiento personalmente.

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

323

F.4.2.2

In the whole clinical trial

1512

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)

No further provisions are made for access to the study treatment. If aducanumab is proven to be beneficial, all regulatory requirements regarding poststudy access will be met.

No hay más disposiciones para acceder al tratamiento del estudio. Si se demuestra que aducanumab es beneficioso, se cumplirán todos los requisitos normativos sobre el acceso posterior al estudio.

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	DrugDev
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

2022-10-06

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-10-05

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

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IMP with orphan designation in the indication
Orphan Designation Number:
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