2. Overview
• What has the DIAN –L study taught us?
• DIAN – TU – the treatment trial
– The rationale
– Who is eligible
– What is involved
3. Dominantly Inherited Alzheimer Network
• International observational trial (US, UK, Australia) started 2011
• Patients with a family history of dominantly inherited Alzheimer’s
disease
• Both at risk and affected participants (>280; 33 DRC)
• Biomarker study (Blood, CSF)
• Imaging
• Clinical assessment
• Only UK site - Dementia Research Centre, NHNN, Queen Square
4. •Courtesy of Tammie Benzinger and Tyler Blazey
Amyloid deposition may begin at least 15 years prior to
dementia onset in mutation carriers
5. Motivation for prevention studies
Completing/Completed
Phase III trials
Newer
Phase II/III trials
Prevention
studies
http://adni.loni.ucla.edu/about/biomarkers/
6. •Current therapeutic trials may be too late: proposed therapeutics
for Alzheimer’s disease currently target slowing or halting the
underlying disease (disease modifying), but are not likely to
reverse the extensive neuronal death present at the onset of
symptoms.
•There is certain risk (~100% with known mutation in PS1, PS2 or
APP) of the disease which enables prevention studies and
increases the power of treating minimally symptomatic patients.
•Disease modifying therapeutics are largely developed with animal
models based on human disease causing mutations. Thus, AD
caused by known autosomal dominant mutations is most likely to
respond to these proposed disease modifying treatments.
•Results from treatment trials in autosomal dominant AD will bridge
cellular and mouse therapeutic research with sporadic AD
therapeutic research.
Rationale for treatment trials in individuals at risk for
Autosomal Dominant Alzheimer’s disease
7. Treatment approach
• Immunotherapy approach
- Using drugs that stimulate the immune
system in order to remove abnormal
proteins that have been deposited
- Many current studies use monoclonal
antibodies - bind to proteins and stimulate
the immune system in order to remove
amyloid
8. DIAN TU trial
• Aim: To assess the safety, tolerability and biomarker
efficacy of gantenerumab and solanezumab in
subjects who are known to have an Alzheimer's
disease causing mutation.
9. What’s the treatment?
• Two different treatment options
• Both monoclonal antibodies that bind to amyloid (abnormal
protein) in the brain and remove it
– Solanezumab (given by infusion)
– Gantenerumab (given by subcutaneous injection)
• Monthly treatment
• Participants randomly assigned to either treatment option
• May get placebo (dummy) drug (3:1 chance of getting active
drug in mutation positive participants)
• Two year duration
10. Who’s eligible?
• Age 18 years and above
• Be ‘at risk’ for Familial AD (have a first degree relative with
a known disease-causing mutation)
• Be -15 years to +10 years from predicted age of onset of
symptoms
• Can be asymptomatic or mildly affected
• Does NOT need to know mutation status and does NOT
need to learn status to participate
11. DIAN TU trial – what will it entail?
• Annual visit
– Clinical assessments
– Cognitive testing
– MRI scan
– PET scanning (at UCLH and Cambridge)
– Blood tests
– Lumbar puncture
– Collateral source questionnaires
12. DIAN TU trial – what will it entail?
• Monthly visits to the DRC
• Depending on the drug arm, participants will receive either a monthly
subcutaneous injection or intravenous infusion
13. FAQs
• Can participants taking medications for memory
impairment (e.g. donepezil) remain on their
medications during trial participation?
Yes, but we ask that the dose stays the same. You would
discuss this with the study nurse.
14. FAQs
• Who decides whether participants get the active drug
or placebo?
A computer system randomly assigns participants to active
drug or placebo. The assignment to drug or placebo is
“blinded” which means neither the participant nor any member
of the study team will know whether the individual is receiving
the study medication or placebo. All mutation negative
participants will be assigned to placebo for safety purposes.
15. FAQs
• Will the study personnel know participants’ genetic
status?
No. Genetic status of participants will not be known by study
personnel. Participants will remain blinded to their genetic
status unless they have previously found this out. If participants
wish to know their gene status, they will be referred for genetic
counselling. Participants who know that they are gene negative
are not eligible.
16. FAQs
• If you have side effects from a drug, does mean that
you are mutation positive?
No. Even people on placebo may have side-effects. A side effect
is likely to be mild and may not be different from everyday type
discomforts such as headache, fatigue and nausea. All side
effects that you experience will be documented.
17. DIAN Expanded Registry
•Provides an overview of Autosomal Dominant Alzheimer’s
disease
(ADAD), links to other web resources (alzforum.org).
•Operational as of Feb 2012
•Posts of past webinars
•Register an interest in participation in DIAN-TU
18. Contact details
• Dr Chris Lane (Clinical Research Fellow) –
c.lane@ucl.ac.uk
• Jane Douglas (Clinical Trials nurse) –
jane.douglas@ucl.ac.uk or 02034483560
So we know they will develop at some point and we know when that is likely to be because of their parent. Age they are likely to get is the same as their parents.
In summary, our findings indicate that the Alzheimer's disease process begins more than 20 years before the clinical onset of dementia. Treatment and prevention trials can incorporate these pathophysiological changes to gauge the likelihood of future clinical success. Secondary prevention trials that are designed to prevent or delay cognitive and clinical impairment may ultimately test the amyloid hypothesis, just as the cholesterol hypothesis of heart disease was tested three decades ago.33
