Clinical Trials Register

Summary
EudraCT Number:	2013-000307-17
Sponsor's Protocol Code Number:	DIAN-TU-001
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	GB - no longer in EU/EEA
Date on which this record was first entered in the EudraCT database:	2013-09-03
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

UK - MHRA

A.2

EudraCT number

2013-000307-17

A.3

Full title of the trial

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

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

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	Hoffmann LaRoche Eli Lilly; The Alzheimer's Association; AVID Radio Pharmaceuticals; National Institutes of Health (NIH)
B.4.2	Country	United States
B.4.1	Name of organisation providing support	Janssen Research and Development, LLC
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, Assoc Director, Clin O
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	susanmills@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	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	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	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	150
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	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

Dominantly Inherited Alzheimer Disease (DIAD)

E.1.1.1

Medical condition in easily understood language

Alzheimer's disease

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Assess cognitive efficacy of gantenerumab, solanezumab in individuals who have mutations causing dominantly inherited Alzheimer’s disease as measured by change in the DIAN-TU cognitive composite score between baseline and a minimum of 4 years. Comparisons will be made between each drug and placebo but not between the active drugs.

E.2.2

Secondary objectives of the trial

1. Assess safety and tolerability of each study drug in individuals who have mutations causing dominantly inherited Alzheimer’s disease. 2.Biomarker Endpoints used at interim analysis: Assess target engagement of each study drug in individuals who have mutations causing dominantly inherited Alzheimer’s disease as measured by the change from baseline to interim analysis for the biomarker measure for each drug. The biomarker endpoints are specified for each drug based on mechanism of action. Comparisons between the active drug and pooled placebo will be made at each interim for a study drug arm, however there will be no comparisons between active drugs.
3.Comparisons between each drug and placebo for change in values between baseline and endpoint for additional clinical and cognitive measures

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

Addendum 1: Tau Imaging Version 3.0, 29 Mar 2016

E.3

Principal inclusion criteria

Subjects must meet ALL inclusion criteria:

1. -15 to +10 EYO (secondary prevention population): within -15 to +10 years of the estimated age at symptom onset, or, if symptomatic, within 10 years of their age at symptom onset; CDR 0 to 1, inclusive; known
carrier or at 50% risk (affected parent or sibling); or
2. Younger than -15 EYO (primary prevention population): more than 15 years younger (<-15) than estimated age at symptom onset, CDR 0, known carrier or mutation in their family pedigree; if the at-risk parent
is deemed a non-carrier at any point, subject will be withdrawn from tudy. Subjects meeting inclusion #2 (primary prevention) are only eligible for the cognitive run-in (CRI) period of this protocol.
3. Are able and willing to complete all study-related testing, evaluations and procedures.

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.

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy endpoint will be the relative rate of cognitive decline between active drug and pooled placebo using the DIAN-TU Cognitive Composite score after treatment for a minimum of 4 years.
The DIAN-TU composite score is calculated from four cognitive measures: 1) The Delayed Recall of the International Shopping List Test, 2) The Delayed Recall score of the Logical Memory IIa subtest from the Wechsler Memory Scale-Revised, 3) The Digit Symbol Substitution Test total score from the Wechsler Adult Intelligence Scale-Revised, and 4) The Mini Mental State Examination total score.

E.5.1.1

Timepoint(s) of evaluation of this end point

A minimum of 4 years (last subject enrolled) with anticipation of a maximum of 7 years (first subject enrolled).

E.5.2

Secondary end point(s)

Assess safety and tolerability of each study drug in individuals who have mutations causing dominantly inherited Alzheimer’s disease.

The biomarker endpoints used for the interim biomarker analyses are specific for each drug based on mechanism of action. These are listed in the drug-specific appendices. Biomarker endpoints will assess change between baseline and endpoint for:
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 biomarker endpoint 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 (Bateman et al., 2012). The composite PiB standardized uptake value ratio (C-SUVR, the composite SUVR of precuneus, caudate, gyrus rectus, occipital cortex, parietal cortex, prefrontal cortex and temporal cortex) is used as the biomarker endpoint.
2) Change in total amyloid-beta 1-42 (Aβ42) in CSF. The concentrations of CSF total Aβ42 will be the biomarker endpoint for solanezumab, specifically different treatment effects on total CSF Aβ42. An increase in total CSF Aβ42 is consistent with target engagement in the central compartment (Siemers et al., 2010).
3)Change in CSF amyloid-beta peptide concentration as measured by Aβ40, will be the biomarker endpoint for JNJ-54861911.

Secondary study endpoints will also measure change between baseline and endpoint and will include:

Clinical measures to be obtained at baseline, and annual visits will be administered at the host DIAN-TU site include:
• Clinical Dementia Rating (CDR), including CDR Sum of Boxes (CDR-SB) and clinician’s diagnostic assessment
• Geriatric Depression Scale (GDS)
• Neuropsychiatric Inventory Questionnaire (NPI-Q)
• Functional Assessment Scale (FAS)
• Mini Mental State Examination (MMSE)

Cognitive measures to be obtained at baseline and annual visits will be administered at host DIAN-TU site include:
• International Shopping List Test (12-Item Word List Learning): 3 learning trials, Immediate Recall, 30-min Delayed Recall (Cogstate)
• Groton Maze Learning Test: Timed Chase Task, 5 learning Trials, Immediate Recall, 30-min Delayed/Reversed Recall (Cogstate)
• Cogstate Detection Task
• Cogstate Identification Task
• Cogstate One Card Learning Test
• Cogstate One-Back Task
• Behavioral Pattern Separation Object Task
• Memory Complaint Questionnaire (MAC-Q)
• Trailsmaking Test Part A & B
• WMS-R Digit Span
• WAIS-R Digit-Symbol Substitution Test
• Raven’s Progressive Matrices (Set A)
• Category Fluency (Animals & Vegetables)
• WMS-R Logical Memory (Immediate & Delayed Recall)

A subset of these measures will be administered by the site or home health nurse at 24 week intervals when not the annual visits. This subset includes:
• International Shopping List Test (12-ltem Word List Learning): 3 learning trials, Immediate Recall,30-min Delayed Recall (Cogstate)
• Groton Maze Learning Test: Timed Chase Task, 5 learning Trials, Immediate Recall, 30 min Delayed/Reversed Recall (Cogstate)
• Cogstate Detection Task
• Cogstate Identification Task
• Cogstate One Card Learning Test
• Cogstate One-Back Task
• Trails making test parts A & B
• WMS-R Digit Span
• WAIS-R Digit-Symbol Substitution Test
• WMS-R Logical Memory (Immediate & Delayed Recall)
• For the CRI period and drug arms other than gantenerumab and
solanezumab, additional cognitive battery subset tests include:
- Category Fluency (Animals & Vegetables)
- Mini Mental State Examination (MMSE)

E.5.2.1

Timepoint(s) of evaluation of this end point

• For Solanezumab and Gantenerumab arms: a single biomarker interim analysis will be done when 100% of the active subjects have completed 2 years of randomized treatment (Visit 28)
• For JNJ-5486199 arm: An interim analysis of the cognitive composite endpoint to assess whether JNJ-54861911 has achieved significant slowing in cognitive decline, will be conducted when all the subjects complete 3-year randomized treatment.Potential biomarker interim analyses that may be performed for this drug arm: futility IA of CSF Aβ40 after 1-year treatment for 50% of randomized subjects
• Clinical and cognitive measures to be obtained at baseline and annual visits.
• A subset of cognitive measures will be administered at 24 week intervals when not the annual visits.

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

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

Yes

E.8.4

The trial involves multiple sites in the 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

Brazil

Canada

China

Colombia

France

Germany

Ireland

Italy

Japan

Mexico

Netherlands

Spain

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

Drug arms will close when the last patient enrolled, in concurrently
enrolling drug arms ,completed 4 years of treatment.
Subjects can continue in the CRI period until a study drug arm is
opened for randomization, but no longer than approximately 2 years.

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:

384

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

121

F.4.2.2

In the whole clinical trial

444

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)

If a drug/arm demonstrates clinical/cognitive benefit, the patient will be
invited to an Open-label extension study.
After the study ends or after the OLE the patient will receive 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

2013-10-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-01-08

P. End of Trial
P.	End of Trial Status	GB - no longer in EU/EEA

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