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.…
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
Alzheimer's disease
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary efficacy hypothesis of the study is that the active drug group will
have a slower rate of progression on the cognitive composite endpoint compared
to the mutation*carrier placebo group after treatment for a minimum of 4 years.
The DIAN*TU cognitive composite score is calculated from four cognitive
measures:
1) The Delayed Recall score 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.
Secondary outcome
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 the clinical and cognitive measures
listed below.
Clinical measures to be obtained at baseline, and annual visits will be
administered at the host DIAN*TU site include:
o Clinical Dementia Rating* (CDR), including Clinical Dementia Rating Sum of
Boxes* (CDR*SB) and clinician*s diagnostic assessment
o Geriatric Depression Scale (GDS)
o Neuropsychiatric Inventory Questionnaire (NPI*Q)
o Functional Assessment Scale (FAS)
o Mini*Mental State Examination (MMSE)
o Cognitive measures to be obtained at baseline and annual visits will be
administered at host DIAN*TU site include:
o International Shopping List Test (12*Item Word List Learning):
3 learning trials, Immediate Recall, 30*min Delayed Recall (Cogstate)
o Groton Maze Learning Test: Timed Chase Task, 5 learning Trials, Immediate
Recall, 30*min Delayed/Reversed Recall (Cogstate)
o Cogstate Detection Task
o Cogstate Identification Task
o Cogstate One Card Learning Test
o Cogstate One*Back Task
o Behavioral Pattern Separation Object Task
o Memory Complaint Questionnaire (MAC*Q)
o Trailmaking Test parts A & B
o WMS*R Digit Span
o WAIS*R Digit*Symbol Substitution Test
o Raven*s Progressive Matrices (Set A)
o Category Fluency (Animals & Vegetables)
o WMS*R Logical Memory (Immediate & Delayed Recall)
o A subset of clinical and cognitive measures will be administered by the site
or home health nurse at 24*week intervals when not the
annual visits. This subset includes:
o International Shopping List Test (12*ltem Word List Learning):
3 learning trials, Immediate Recall,30*min Delayed Recall (Cogstate)
o Groton Maze Learning Test: Timed Chase Task, 5 learning Trials, Immediate
Recall,30* min Delayed/Reversed Recall (Cogstate)
o Cogstate Detection Task
o Cogstate Identification Task
o Cogstate One Card Learning Test
o Cogstate One*Back Task
o Trailmaking Test parts A & B
o WMS*R Digit Span
o WAIS*R Digit*Symbol Substitution Test
o WMS*R Logical Memory (Immediate & Delayed Recall)
o For the CRI period and drug arms other than gantenerumab and solanezumab:
o Mini*Mental State Examination (MMSE)
o Category Fluency (Animals & Vegetables)
Background summary
This study will recruit subjects from the Dominantly Inherited Alzheimer
Network (DIAN) observational study, a multicenter international study supported
by the National Institutes of Health (Grant Number U01*AG032438; RJ Bateman),
Dominantly Inherited Alzheimer Network
Trial Units (DIAN*TU) sites, DIAN*TU partner sites, DIAN Expanded Registry
(DIAN*EXR), and families identified by the sites. As part of the DIAN*TU*001
protocol, subjects undergo longitudinal assessments that include clinical
assessment, cognitive testing, magnetic resonance
imaging (MRI) and amyloid imaging, and analysis of cerebrospinal fluid.
There are DIAN observational study sites located in multiple countries
including the USA, Argentina, Australia, Germany, Japan, and the United
Kingdom. Subjects in DIAN are recruited from families that have at least one
member who has been identified as having a mutation
linked to dominantly inherited Alzheimer*s disease (DIAD). The mutations in
presenilin 1 (PSEN1), presenilin 2 (PSEN2) and amyloid precursor protein (APP)
that are associated with dominantly inherited Alzheimer*s disease have very
high penetrance (near 100%). This study will
target individuals who are either known to have a disease*causing mutation or
who are at risk for such a mutation (the child or sibling of a proband with a
known mutation) and unaware of their genetic status. Because the age at onset
of cognitive changes is relatively consistent within
each family and with each mutation, an age at onset is determined for each
affected parent or mutation as part of the DIAN observational study protocol.
This study will enroll subjects who are either asymptomatic and are within a
specific window of time of expected age at onset for their family and/or
mutation or who have symptoms of mild Alzheimer*s disease.
Study objective
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.
Study design
This study is an adaptive platform*based study, which allows flexibility to add
a new compound to the same protocol, allowing subjects to be randomized to
study drug arms open to enrollment, and to maintain a cohort of trial ready
subjects with or at risk for DIAD mutations.
Subjects have been enrolled to the gantenerumab and solanezumab study drug
arms, with each enrolled subject randomized to active drug or the corresponding
placebo. Gantenerumab en solanezumab treatment arms are not applicable in the
Netherlands.
Intervention
NA
Study burden and risks
Plaque removal effect was demonstrated in the prodromal study WN25203 with the
higher 225 mg dose showing a stronger effect of removal. These results for the
first time showed the effect of immunotherapies against A* in early (prodromal)
AD. In dominantly inherited Alzheimer*s disease (DIAD), amyloid deposition is
present at early stages of the disease when no memory impairment is present.
Thus, the current dose and the higher doses to be administered are expected to
be effective in DIAD.
The mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2) and amyloid
precursor protein (APP) that are associated with DIAD and which subjects in
this study who receive active study drug will have tested positive for, have
very high penetrance (near 100%). AD is a progressive and ultimately fatal
disease and no disease modifying treatment is available to date.
Besides injection site reactions which, however appear of mild intensity in
most subjects and not limiting the maintenance of subjects in the long-term
treatment trial, ARIAs represent a side effect of concern in the development of
immune-therapeutics targeting A* in the brain. These changes may include
micro-hemorrhage, vasogenic edema/effusion and infarction; they are most often
asymptomatic, but symptoms have been reported in some cases.
Therefore, dedicated monitoring and action plans for ARIAs are implemented in
respective multiple dose clinical trials of gantenerumab including the
DIAN-TU-001 study. Given the experiences made with gantenerumab thus far, the
proposed risk minimization plan including frequent MRI monitoring and reads by
independent experts together with an ARIA based dose intervention algorithm
appears to be effective in preventing clinical sequelae to the subjects treated
with gantenerumab.
South Euclid Ave, Campus Box 8111 660
Saint Louis MO 63110
US
South Euclid Ave, Campus Box 8111 660
Saint Louis MO 63110
US
Listed location countries
Age
Inclusion criteria
* *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)
* 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 study
* Are able and willing to complete all study*related testing, evaluations, and procedures
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 therapy and pregnancy.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2013-000307-17-NL |
| ClinicalTrials.gov | NCT01760005 |
| CCMO | NL69009.029.19 |