Clinical Trials Register

Summary
EudraCT Number:	2013-000307-17
Sponsor's Protocol Code Number:	DIAN-TU-001
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Temporarily Halted
Date on which this record was first entered in the EudraCT database:	2013-11-12
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

2013-000307-17

A.3

Full title of the trial

A Phase II/III randomized, double-blind, placebo-controlled multi-center study of 2 potential disease modifying therapies in individuals at risk for and with dominantly inherited Alzheimer's disease (ADAD)

Estudio de fases II/III multicéntrico, aleatorizado, doble ciego y controlado con placebo sobre 2 terapias con potencial para influir sobre la enfermedad en individuos que padecen o presentan riesgo de padecer enfermedad de Alzheimer hereditaria dominante

A.3.1

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

Dominantly Inherited Alzheimer Network Trial: An Opportunity to Prevent Dementia. A Study of Potential Disease Modifying Treatments in Individuals at Risk for or With a Type of Early Onset Alzheimer's Disease Caused by a Genetic Mutation

La finalidad de este estudio de investigación es evaluar dos posibles tratamientos modificadores de la enfermedad, en comparación con placebo (no contiene componentes activos) para el tratamiento de la enfermedad de Alzheimer autosómica dominante (EAAD) a fin de determinar si uno o ambos previenen, retrasan o corrigen las alteraciones cerebrales que se asocian al desarrollo de los síntomas de la enfermedad

A.3.2

Name or abbreviated title of the trial where available

DIAN-TU

A.4.1

Sponsor's protocol code number

DIAN-TU-001

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01760005

A.5.4

Other Identifiers

Name:

The Alzheimer's Association Grant

Number:

DIAN TTU-12-243040

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	Washington University in St. Louis
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	Hoffman LaRoche; Eli Lilly; The Alzheimer's Association; AVID Radio Pharmaceuticals
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	Washington University in St. Louis
B.5.2	Functional name of contact point	Susan Mills, Sr. Project Manager
B.5.3	Address:
B.5.3.1	Street Address	4488 Forest Park Ave., Suite 301,
B.5.3.2	Town/ city	St Louis
B.5.3.3	Post code	MO 63108
B.5.3.4	Country	United States
B.5.4	Telephone number	+1-949-293-5290
B.5.5	Fax number	1-314-747-7060
B.5.6	E-mail	millss@neuro.wustl.edu

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	Solanezumab
D.3.2	Product code	LY2062430
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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Solanezumab
D.3.9.1	CAS number	955085-14-0
D.3.9.2	Current sponsor code	LY2062430
D.3.9.3	Other descriptive name	SOLANEZUMAB
D.3.9.4	EV Substance Code	SUB37126
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	not less then
D.3.10.3	Concentration number	20
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	No
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	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	Gantenerumab
D.3.2	Product code	RO4909832
D.3.4	Pharmaceutical form	Lyophilisate for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Gantenerumab
D.3.9.1	CAS number	645-35-2
D.3.9.2	Current sponsor code	ro4909832
D.3.9.3	Other descriptive name	HISTIDINE HYDROCHLORIDE
D.3.9.4	EV Substance Code	SUB14110MIG
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	75
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	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
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Powder for solution for injection
D.8.4	Route of administration of the placebo	Subcutaneous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Autosomal Dominant Alzheimer's disease

Enfermedad de Alzheimer autosomica dominante

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	16.1
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

E1. Assess safety and tolerability of gantenerumab and solanezumab in individuals who have mutations causing dominantly inherited Alzheimer?s disease.
2. Assess biological efficacy/target engagement of gantenerumab and solanezumab in individuals who have mutations causing dominantly inherited Alzheimer?s disease as measured by the primary biomarker measure for each drug. Primary endpoints are specified for each drug based on mechanism of action. Depending on proposed mechanism of action, the primary biomarker endpoint will be either 1) change in amyloid deposition as measured by [11C]PiB-PET composite standardized uptake value ratio (C-SUVR, average of precuneus, caudate, gyrus rectus, occipital cortex, parietal cortex, prefrontal cortex and temporal cortex) or, 2) changes in free and total amyloid beta (A?) isoforms in CSF.

1. Evaluar la seguridad y toleravilidad de gantenerumab and solanezumab en indiciduos que contienen las mutaciones que causan la enfermedad de Alzheimer autosomica dominante.
2. Evaluar la eficacia biologica de gantenerumab y solanezumab en individuos que tienen la muatcion que causa la enfermedad de Alzheimer dominante hereditaria

E.2.2

Secondary objectives of the trial

Secondary study endpoints will include:
1) Change in amyloid deposition as measured by [11C]PiB-PET C-SUVR (used as a secondary outcome measure when not the primary outcome measure).
2) Change in CSF amyloid-beta peptide concentrations (used as a secondary outcome measure when not the primary outcome measure).
3) Change of CSF biomarkers tau and ptau181 values compared between subjects on active drug (gantenerumab or solanezumab) and mutation carriers in the pooled placebo group.
4) Rate of brain atrophy in treatment groups vs. pooled placebo group as measured by cortical thickness of regions of interest (volumetric MRI).
5) Change in FDG-PET metabolism in specific regions of interest in treated group as compared to pooled placebo group.
6) Exploratory cognitive and behavioral outcome measures
7) Exploratory imaging measures
8) Assess longitudinal change in biomarker and cognitive measures in individuals who do not have mutations causing dominantly inherited Alzheimer?s disease

Los criterios de valoración secundarios son, entre otros:
1. Cambio en los depósitos de amiloide medidos a través de la media combinada del SUVR en [11C]-PiB-PET
2.Cambio en las concentraciones de péptido amiloide β en el LCR 3.Cambio en los biomarcadores τ y p-τ181 del LCR comparados entre los sujetos tratados con fármaco activo (gantenerumab o solanezumab) y los portadores de mutación en el grupo combinado tratado con placebo.
4.Índice de atrofia cerebral en los grupos con tratamiento activo en comparación con el grupo combinado tratado con placebo medido por el espesor cortical de las regiones de interés,RM volumétrica
5.Cambio en el metabolismo de la FDG-PET en regiones específicas de interés en el grupo de tratamiento activo con respecto al grupo combinado tratado con placebo
6.Criterios de valoración exploratorios cognitivos y conductuales
7.Imágenes exploratorias

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Subjects must meet ALL inclusion criteria:

1.Know they have an AD-causing mutation or be unaware of their genetic status and have a 50% chance of having an AD-causing mutation (e.g. parent or sibling with known AD-causing mutation)
2.Are within -15 to + 10 years of the parental age of symptom onset
3. CDR 0-1 inclusive
4. Are able to undergo MRI, LP, PET, and complete all study related testing and evaluations.

E.4

Principal exclusion criteria

Subjects will be excluded if they have a major or unstable illness or are unable to complete all study related testing. Exclusions include implanted metal that cannot be removed for MR scanning, required anticoagulation and pregnancy. Baseline MRI scan indicative of any other significant abnormality, including more than 4 definite micro hemorrhages. Clinically relevant abnormalities in chemistry, hematology or coagulation studies.

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy endpoint is specific for each drug based on mechanism of action. Each primary endpoint for study drugs is listed in the drug-specific appendix. Endpoints include:

1) Cerebral amyloid imaging using [11C]PiB-PET. Change in the amount of fibrillar amyloid deposition as measured by [11C]PiB-PET scans is the primary outcome for gantenerumab. Most mutation carriers who are in the range of -15 to + 10 years of dementia onset have increased [11C]PiB-PET signal in some brain regions (see Figure 1 above and Bateman et al., 2012). The composite PiB standardized uptake value ratio (C-SUVR, the composite SUVR of precuneous, caudate, gyrus rectus, occipital cortex, parietal cortex, prefrontal cortex and temporal cortex) is used as the primary outcome.

2) Free and Total Abeta isoforms in CSF. The concentrations of CSF A? species will be the primary outcome for solanezumab, specifically different treatment effects on free (unbound) CSF A?42 (increase or no change) and free CSF A?40 (decrease) with comparable treatment-associated increases in CSF total (bound + unbound) A?42 and total A?40 after 104 weeks. An increase, or ?normalization? of free CSF A?42 levels, is postulated to represent increased egress of A?42 from brain to CSF (Siemers et al., 2010).

Entre los criterios de valoración se encuentran:

1) Imágenes de amiloide cerebral mediante [11C]PiB-PET. La cantidad de depósito de amiloide fibrilar determinada mediante exploraciones de [11C]PiB-PET constituye el criterio principal de valoración de gantenerumab. La mayoría de los portadores de mutaciones que se encuentran en el intervalo entre -15 y + 10 de inicio de la demencia presentan un aumento de la señal de [11C]PiB-PET en ciertas regiones cerebrales (véanse la figura 1 y Bateman et al., 2012b). Como criterio principal de valoración se utilizará la media del cociente del valor de captación estandarizado en [11C]PiB-PET (AVG-SUVR, SUVR medio de la precuña, el caudado, la circunvolución recta, la corteza occipital, la corteza parietal y la corteza prefrontal).

2) Aβ42 libre en el LCR. Las concentraciones de la especie Aβ en el LCR serán el criterio principal de valoración para solanezumab, y específicamente los distintos efectos del tratamiento sobre el Aβ42 libre (no ligado) en el LCR (incremento o sin variaciones) y el Aβ40 libre en el LCR (disminución) con incrementos similares asociados al tratamiento en el Aβ42 libre total (ligado + no ligado) y en el Aβ40 total en el LCR al cabo de 108 semanas. Se considera que un incremento o “normalización” de las concentraciones de Aβ42 libres en el LCR representa una mayor salida de Aβ42 desde el cerebro hacia el LCR (Siemers et al., 2010).

E.5.1.1

Timepoint(s) of evaluation of this end point

Timepoint of evaluation at week 0, 52 & 104

Evaluaciones en las semanas: 0, 52 y 104.

E.5.2

Secondary end point(s)

Secondary study endpoints will include:
1) Change in amyloid deposition as measured by [11C]PiB-PET C-SUVR (used as a secondary outcome measure when not the primary outcome measure).
2) Change in CSF amyloid-beta peptide concentrations (used as a secondary outcome measure when not the primary outcome measure).
3) Change of CSF biomarkers tau and ptau181 values compared between subjects on active drug (gantenerumab or solanezumab) and mutation carriers in the pooled placebo group.
4) Rate of brain atrophy in treatment groups vs. pooled placebo group as measured by cortical thickness of regions of interest (volumetric MRI).
5) Change in FDG-PET metabolism in specific regions of interest (e.g., precuneus) in treated group as compared to pooled placebo group measured.

Los criterios secundarios de valoración del estudio son, entre otros, los siguientes:

1) Cambio en los depósitos de amiloide determinados mediante la media combinada del SUVR en [11C]-PiB-PET (utilizado como criterio secundario de valoración cuando no se use como criterio principal de valoración).
2) Cambio en las concentraciones de péptido amiloide β en el LCR (utilizado como criterio secundario de valoración cuando no se use como criterio principal de valoración).
3) Cambio en los biomarcadores τ y p-τ181 del LCR comparados entre los sujetos tratados con fármaco activo (gantenerumab o solanezumab) y los portadores de mutación en el grupo combinado tratado con placebo.
4) Índice de atrofia cerebral en los grupos con tratamiento activo en comparación con el grupo combinado tratado con placebo determinado por el espesor cortical de las regiones de interés (RM volumétrica).
5) Cambio en el metabolismo de la FDG-PET en regiones específicas de interés (p. ej., en la precuña) en el grupo de tratamiento activo con respecto al grupo combinado tratado con placebo.

E.5.2.1

Timepoint(s) of evaluation of this end point

Same criteria as above for the primary endpoint.

Mismo criterio que en la variable principal

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

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

tolerability

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)

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

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

Canada

France

Italy

Spain

Sweden

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

The end of the study is week 112 (protocol p76/114); for gantenerumab = week 112 (page 95/114);
ref xxxii: for Solanezumab =week 104 + End of Stufy visit needed if there are safety concerns that require follow-up (= week 112)

El final del ensayo es en la semana 112(Portocolo: p76/114); para gantenerumab= semana 112 (pagina 95/114); ref xxxii. para solanezumab = semana 104 + visita final del ensayo si hay problemas de seguridad que requieren seguimiento (= semana 112)

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:

189

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.4.2

For a multinational trial

F.4.2.1

In the EEA

105

F.4.2.2

In the whole clinical trial

210

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)

Standard of care

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	Washington University in St. Louis School of Medicine
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

2014-03-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-02-27

P. End of Trial
P.	End of Trial Status	Temporarily Halted

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IMP with orphan designation in the indication
Orphan Designation Number:
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