The DIAN trials aim to test potential treatments for dominantly inherited Alzheimer's disease through a two-phase study design. The first phase will evaluate biological and biomarker effects over two years. If successful, the second phase will assess cognitive benefits over three additional years. Up to five potential drug candidates have been nominated for initial testing. The expanded DIAN registry is helping recruit sufficient interested participants to power the clinical trials.

1. The DIAN Treatment Trials:
An Update
Sunday, May 6
4:00-5:00 PM CDT
Presented by Randall Bateman, MD
DIAN Therapeutic Trials Unit Director
DIAN Clinical Core Leader

2. Agenda
I. Introductions
II. DIAN Update
III. DIAN Trials update
a. Expanded Registry
b. Therapeutic Trials Topics
IV. Q & A

3. The Dominantly Inherited Alzheimer’s Network DIAN
Coordinating Center Cores
Admin – JC Morris Genetics – AM Goate
Clinical – RJ Bateman Imaging – T Benzinger
Biomarkers – AM Fagan Informatics – D Marcus
Biostatistics – C Xiong Neuropathology – NJ Cairns
Performance Sites
• United States: Washington Univ (Bateman), MGH/BWH (Sperling), Butler Hosp/Brown
Univ (Salloway), Columbia Univ (Mayeux), Indiana Univ (Ghetti), UCLA (Ringman), U of
Pittsburgh (Klunk), Mayo Clinic, Jacksonville (Graff-Radford)
• Europe: Institute of Neurology, Univ College London (Rossor), Ludwig-Maximilians-
Universität München (Danek), University of Tübingen (Jucker)
• Australia: Prince of Wales Medical Research Institutes, Sydney (Schofield), Mental Health
Health Research Institute, Melbourne (Masters), Edith Cowan Univ , Perth (Martins)
f Pittsburgh (Klunk), Mayo Clinic, Jacksonville (Graff-Radford)
Clinical Trials Committee
DIAN family participant , Paul Aisen, Randy Bateman, Neil Buckholtz, Nick Fox,
Alison Goate, Bill Klunk, Ranjit Mani, John Ringman, Laurie Ryan, Stephen Salloway,
Reisa Sperling, Chengjie Xiong

4. DIAN Clinical Core Enrollment Report
Initial Visits Follow-up Visits Follow-up Visits
Actual In-Person Remote
Year One
(9/2008-6/2009) 11 0 0
Year Two
(7/2009-6/2010) 76 0 5
Year Three
(7/2010-6/2011) 103 25 40
Year Four
(7/2011 through 2/2012) 52 34 60
YTD Totals 242 59 105

5. DIAN Therapeutic
Trials Unit (TTU) Update
• October, 2011: DIAN trials grant submitted to NIH.
• December, 2011: DIAN Pharma Consortium
formed (10 leading pharmaceutical companies)
and TTU funded
• 14 compounds nominated and reviewed:
– anti amyloid-beta, passive immunotherapies, secretase
inhibitors, others
– 5 proposed for immediate consideration.
• April, 2012: Expanded Registry launched

6. Pharma Consortium Members

7. DIAN Expanded Registry
www.dianexpandedregistry.org
Reaching out to
Participants,
Physicians
And families

8. 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, announced in April, ~65
interested participants have registered.
– Current DIAN observational study participants, family
members and those interested in future trials are
registering on the website
– Physicians and researchers interested in participating
as an investigator or referring potential patients from
their practice are also registering

9. DIAN Expanded Registry

10. DIAN Clinical Trials NIA Grant Overview
Title: Dominantly Inherited Alzheimer Network Trials: An Opportunity to Prevent Dementia .
Application submitted October 5, 2011, reviewed March 2, 2011
Summary: The application proposes to initiate DIAN clinical trials with a two-phase study to
delay, prevent, or restore cognitive loss in AD mutation carriers.
The first phase to determine the biological engagement of the drug target and impact on
biomarkers of neurodegeneration.
The second phase to determine if there is a cognitive benefit of treatment.

11. Grant Review Summary Statement
“There was much enthusiasm for this innovative
application and its efficient linking with DIAN. The overall
goal of prevention for those patients at very high risk of
AD in this cohort is highly significant. The innovative
design, strong investigative team and environment and
the compelling pilot data from the parent DIAN
participants are other big strengths of the proposed
study.”
Concern: Ability to recruit sufficient numbers of
participants (only counting numbers enrolled)

12. Trial Design Outline – Years 1 & 2
• 3 parallel, placebo controlled, double-blinded,
biomarker outcome trials
• Up to 80 participants enrolled in each trial
– 40 mutation carriers (30 on active drug treatment, 10 on
placebo)
– 10 to 40 non-carriers on placebo to maintain genetic status
blind
• Drug treatment duration = 2 years
• Placebo participants pooled from the trials to
provide a common pool of 30 placebo for
comparison of biomarker (phase IIb) outcomes.

13. Trial Design Outline Years 3-5
Outcomes:
• If one trial is successful, it will continue while enrolling a total
of 240 participants
• If none of the three original trials is successful, and three new
drugs are suitable and available, start 3 new biomarker trials.
A B C
DIAN study
3:1 active to Drug A, B, or C Years Years
placebo monthly for 22 mo 0 1 2 3 4 5 0 1 2 3 4 5
(run-in)
(pooled placebo)
A (80) A (80) D (80)
B (80) B (240) B (80) E (80)
Biomarker, clinical, and cognitive measures and
samples C (80) C (80) F (80)
Figure 1. Trial Design and Potential Outcomes. 240 participants are enrolled into a four arm study of drug A,
drug B, drug C, and placebo. Mutation negative participants are assigned placebo, while mutation positive
participants are randomized to drug or placebo in a 3:1 ratio (A). 80 participants will be enrolled in each of
three two-year biomarker trials; 40 mutation carriers and up to 40 non-carriers will be enrolled in each trial.
Biomarker outcomes through week 96 will be assessed before the start of Year 3. In B, one trial is successful
and continues while enrolling a total of 240 participants in the three-year cognitive endpoint trial. In C, none
of the three original trials is successful, and three new two-year biomarker trials are begun.

14. Clinical Trial Design
• Study visits:
– Monthly infusions or injections
– Safety MRI every 3 months
– Length of commitment is 2 years for first part of
study, 3 additional years if a treatment is
successful

15. Schedule of Events
VISIT SITE DIAN DIAN Sat Sat Sat Sat Sat Sat Sat Sat Sat Sat Sat DIAN
PROCEDURE: Visit No V1 V2 V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 V13 V14
Timing (wks.) -4 to 0 0 4 8 12 16 20 24 28 32 36 40 44 48
Informed consent X
Medical/Treatment History X X X X X X X X X X X X X X
Clinical Assessment X X
Physical/Neurological Exam X X
Vital signs X X X X X X X X X X X X X X
12- lead ECG X X X
Questionnaire(s) X X X X X
Hematology/Chemistry/LFTs/UA X X X X X X
Pregnancy testing (dipstick) X X X X X X X X X X X X X X
Study Therapy Administration X X X X X X X X X X X X X
Cognitive Testing X ? X
PET-PIB X X
F-18 PET X X
Safety MRI X X X
Volumetric MRI X X
Lumbar Puncture (CSF) X X
FDG-PET X X
DIAN = DIAN observational study site location
Sat = Satellite site

16. Inclusion/Exclusion
• -15 before to +10 years after parental age of
onset
• Possible symptomatic or mild dementia
eligible
• Greater than 18 years of age
• Non-carriers who know their mutation status
are not eligible

17. Genetic Testing
• DIAN can pay for discovery testing for
appropriate families or DIAN participants.
• DIAN can pay for Genetic Counseling and
Testing.
• DIAN Coordinators will assist in finding a
genetic counselor in participant’s own area.
• DIAN Coordinator will arrange payment with
the associated billing office.

18. Trial Design Key Points
• Run-in design using DIAN data – Need consistent
DIAN follow-up visits
• DIAN participants will have the first opportunity to
enroll in the trials. DIAN participants will be taken
first as they have baseline data collected
– Others will be welcomed but may need to do DIAN
baseline measurements
• 75% chance of receiving active drug (25% chance of
placebo)

19. Patient Randomization Chart
Brief review and consenting to hear
more details about the study and
possible drug you may receive
Full, detailed review of the study
procedures, office visits, drug therapies
(sign consent)
Assigned to drug treatment or placebo
(blinded to you and the physician).
Begin 22 months of drug therapy.

20. DIAN Trials Grant Resubmission
Reviewers’ concern: Ability to recruit
sufficient numbers of participants
Actions to address concerns
• Show proof of participant numbers and interest
in trials
– Expanded registry
– Site Expansion
– Input from participants (letters of support, survey)

21. DIAN Trials Participant Status
242*
Total Participants Enrolled
(N=estimated based on %)
% Mutation Carriers 63% (N=152)
% eligible for trials
69% (N=105)
Age-range: 15 years before - 10 years after
Note: Goal is 120
the Parental Age at Onset
CDR = 0 46% (N=48)
CDR = 0.5 (prodromal) 36% (N=38)
CDR => 1.0 (dementia) 18% (N=19)
 Numbers in parentheses are estimated based on percentage enrolled in DIAN

22. DIAN Trials Next Steps
• DIAN Trials Start-Up: now through end of year
– Grant resubmission: July 5th , 2012
– Protocol design (currently underway): statistical analysis;
participant procedure/assessments selection; final therapy
selection
– FDA Meeting (late summer): meet with the FDA for their
input and approval to proceed with the planned trial
protocol
– Site identification (currently underway): identification of
sites with capabilities, experience, and training in
performing trials in this patient population (neurologists)
– Training of all sites (physicians and nurse coordinators) for
the trial

23. DIAN Trials Next Steps
• DIAN Trials Start-Up: continued
– Ethics / IRB approval at each location (several
months): review board to ensure trial is ethical
and there are no patient safety issues; review
informed consent document
– Participant enrollment into the trial: end of year
through next year
– Participants undergo therapy administration and
procedures to measure the effect of the therapy

24. Q & A Session

25. Questions from Participants
1. Will an individual’s stage of disease (mildly
vs. greatly symptomatic) affect their eligibility
or response to treatment.
2. Do you know what drugs will be used?
3. Do you know what the possible side effects
are?
4. How will the study be administered?

26. Questions continued…
5. How frequent are the study visits?
6. Are we able to have weekend treatments?
7. How long would a person be in a trial?
8. If you know you have the mutation, would
you be able to tell if the drug is working?
9. When will the trials begin?

27. Questions continued…
10.Will the participant continue taking their
current medications (Namenda, Aricept, etc.)
while on the trial drug?
11.If not, how long before the trial drug is
administered should the participant stop
taking their medication?
12.How is it decided which trial drug the
participant is to receive?

28. Questions continued…
13.What side effects of the trial drug should we
(caretakers) be aware of and expect?
14.Due to DIAN site locations vs. participant
locations, have you been able to work out a
system to have participant’s doctor
administer the trial drug?