Poster Presentations: P3P668

P3-301 CLINICAL DEMENTIA RATING MODELING AND

SIMULATION: MODELING AND SIMULATION OF

CDR PROGRESSION IN THE ADNI COHORT

BASED ON ITEM RESPONSE THEORY

Daniel Polhamus1, James Rogers1, Jonathan French1, William Gillespie2,1Metrum Research Group, Tariffville, Connecticut, United States; 2Metrum

Research Group, Tarrifville, Connecticut, United States.

Contact e-mail: danp@metrumrg.com

Background: Future clinical trials in prodromal AD are expected to

rely on CDR as an important efficacy endpoint. Sensitivity of the

CDR in the prodromal population is favorable compared to other com-

mon clinical endpoints. Statistical models for the longitudinal progres-

sion of CDR scores provide a basis for more insightful analysis of

clinical trial data, as well as a basis for better prospective understand-

ing of the operating characteristics of candidate trial designs through

simulating from the model. Models that describe CDR progression

as a function of demographic and biomarker covariates may be used

to evaluate the likely impact of various trial enrichment strategies

through simulation. Simulation-based trial design has already been

successfully applied in the context of mild-to-moderate AD, and our

current effort seeks to enable similar approaches for prodromal AD.

Methods: The CDR is comprised of 6 subscores, but analysis of the

CDR often focuses on an aggregate score, the sum of boxes, that

weights each item equally. Recent approaches improve upon this using

item response theory (IRT), and we extended the IRT approach to in-

clude longitudinal and covariate data. Patient subscores were modeled

using a graded-response IRT model, where progression was captured

as change in the latent disease status over time, controlled by baseline

covariates. Results: Modeling the joint progression of individual item re-

sponses allowed for better understanding of the item sensitivity in different

subpopulations, at different stages of the disease. To illustrate, Figure 1

shows the progression of the probability of a subscore being greater than

zero for a patient with baseline MMSE of 29 with (in order of increasing

sensitivity): personal care, community affairs, home and hobbies, orienta-

tion, judgement and problem solving, and memory. The longitudinal as-

pect of the model facilitated quantification of progression rates to later

stages of dementia, and the covariate model allowed further quantification

within subpopulations. Conclusions: Identification and enrichment of

populations identified by this approach in trials will lead to better signal

detection, smaller trials, and encourages innovation in development.

This work demonstrates a modeling approach that utilizes longitudinal

data with covariates, greatly expanding on the existing CDR IRTmodeling

methodology.

P3-302 RECRUITMENT OF PEOPLE WITH AMNESTIC

MILD COGNITIVE IMPAIRMENT FOR AN

EXERCISE STUDY

Candace Hill1, Niki Mirshams1, Kyle Armstrong2, Kristin Martin-Cook3,

Rong Zhang2, 1Institute for Exercise and Environmental Medicine, Dallas,

Texas, United States; 2Institute for Exercise and Environmental Medicine,

Texas Health Presbyterian Hospital Dallas, Dallas, Texas, United States;3Alzheimer’s Disease Center, University of Texas Southwestern Medical

Center, Dallas, Texas, United States. Contact e-mail: candacehill@

texashealth.org

Background: Recruitment of healthy controls and Amnestic Mild Cogni-

tive Impairment (aMCI) patients, a prodromal stage of Alzheimer’s disease

(AD), to participate in clinical trials is essential for research and testing the

efficacy of potential pharmacological or nonpharmacological interventions

for AD. However, significant challenges present in recruitment of subjects in

these studies.We reported herein our experience of recruiting aMCI patients

for a year-long exercise training study (ClinicalTrials.gov, CT01146717).

Methods: Participantswere recruited from theDallas-FortWorthMetroplex,

the fourth-largest metropolitan area in the US. Recruitment materials adver-

tised for men and women between the ages of 55-80 with subjective memory

complaintswho did nomore than 90minutes of aerobic exercise perweek and

were without uncontrolled hypertension, diabetes, obesity and any other ma-

jormedical problems. Screening for aMCI is basedon the revisedPetersen cri-

teria. Potential subjects must be willing and able to commit to a 12-month

exercise or stretchingprogram.A recruiter gave talks, passed out fliers and ad-

vertised in well-known local newspapers. Two symposiums were conducted

aimed at informing the local community on the aging brain and AD.Results:

The presentation showed results between 02/2010 and 02/2013. A total of 976

people were screened by telephone. 810 were excluded based on the inclusion/

exclusion criteria. An additional 91 subjects were excluded after a clinical visit

for further screening. The 3 top reasons for exclusion by telephone are: 1) med-

ical issues commonly seen in the aging population (256); 2) not interested/avail-

able after learning more about the study (203); 3) exercise history (158). The 3

top reasons for exclusion after a clinical visit are: 1) memory screen fail using

revised Petersen criteria (44); 2) not interested/available (21); 3) medical issues

(16). Only 8% of the contacted population (30 controls and 45 aMCI) were en-

rolled in the study.Conclusions: The age-related comorbidities were the main

reason for the exclusion of potential subjects in this exercise study in sedentary

but otherwise healthy aMCI patients. Future interventional studies need to con-

sider the age-related comorbidities in aMCI patients.

P3-303 A RANDOMIZED, DOUBLE-BLIND, PLACEBO-

CONTROLLED, MULTIPLE ASCENDING DOSE

STUDY TO EVALUATE THE SAFETY,

TOLERABILITYAND PHARMACOKINETICS OF

A MICROTUBULE STABILIZER (BMS-241027) IN

HEALTHY FEMALES

Richard Malamut, Jun-Sheng Wang, Ishani Savant, Hong Xiao,

Oleksandr Sverdlov, Amol V. Tendolkar, Sanjay C. Keswani, Bristol-Myers

Squibb R&D, Princeton, New Jersey, United States.

Contact e-mail: Richard.Malamut@bms.com

Background: In Alzheimer’s disease (AD), tau loss of function is hypoth-

esized to cause microtubule (MT) destabilization and intraneuronal tau ac-

cumulation within neurofibrillary tangles. BMS-241027 is a brain-penetrant

MT stabilizer which normalizes tau binding at low doses. BMS-241027 has

been previously evaluated in solid tumor oncology trials with a high fre-

quency of adverse events (AEs). Study CN167-002 assessed the safety

and tolerability of multiple ascending doses of BMS-241027 in healthy fe-

male subjects at exposures>150 -fold lower than used in the oncology stud-

ies.Methods: BMS-241027 (0.002 mg/kg-0.2 mg/kg IV) was administered

as multiple once-weekly doses up to 0.06 mg/kg for 4 weeks, and single

doses up to 0.2 mg/kg. Safety assessments were based on AE reports,

Poster Presentations: P3 P669

ECGs, vital sign measurements, and laboratory parameters. PK parameters

were derived from plasma concentrations versus time data in young and el-

derly female subjects. Results: Among 304 enrolled subjects, 60 were ran-

domized and treated with BMS-241027 (n¼45) or placebo (n¼15). There

were no deaths or discontinuations due to AEs and most AEs were mild.

One patient experienced a Grade 3 hypersensitivity reaction w2.5 hours

after the fourth and final dose of 0.002 mg/kg BMS-241027 (5-minute IV

infusion), that responded to treatment without residual symptoms. Infusion

time was lengthened to 60 minutes for remaining dose panels without

additional hypersensitivity reactions. Overall, AEs occurred in 44 (73.3%)

subjects: BMS-241027, 35 (77.8%); placebo, 9 (60%). The most common

AEs were constipation (33.3%) and headache (30%) without cognitive or

peripheral nervous system AEs. No clinically significant abnormalities

were observed in ECG parameters, vital signs, or laboratory parameters.

BMS-241027 exposure (Cmax and AUC) increased dose proportionately

with negligible accumulation after once-weekly administration, without ev-

idence of time-dependent PK.Elderly subjects at 0.02 mg/kg had 2-6 fold

higher exposures than young subjects. Conclusions: BMS-241027 was

well-tolerated at multiple once-weekly doses up to 0.06 mg/kg, and single

doses up to 0.2 mg/kg; the MTD was not achieved. Overall, healthy female

subjects given lower doses with prolonged infusion times showed better

safety than subjects dosed in oncology trials. These data support future in-

vestigation of BMS-241027 in the treatment of AD and other tauopathies.

P3-304 LONGITUDINAL CHANGES OF MRI MARKER IN

ALZHEIMER’S DISEASE AND

FRONTOTEMPORAL DEMENTIA

Lars Frings1, Irina Mader2, Stefan Kl€oppel3, Volkmar Glauche4,

Cornelius Weiller5, Michael H€ull6, 1University of Freiburg, Freiburg,

Germany; 2University of Freiburg, Medical School, Freiburg, Germany;3University Medical Center Freiburg, Freiburg, Germany; 4Freiburger

Brain Imaging Centre, Freiburg, Germany; 5University Freiburg, Medical

Centre, Freiburg, Germany; 6University of Freiburg Medical School,

Freiburg, Germany. Contact e-mail: michael.huell@uniklinik-freiburg.de

Background:Clinical trialswith patientswith frontotemporal dementia (FTD)

may benefit from surrogat parameter which may suggest a modification of pro-

gressive loss of brain structure. Cross sectional imaging studies with Magnetic

Resonance Imaging (MRI) or postmortem investigations showed a huge loss of

frontal brain tissue in later stages of FTD. However the dynamic of brain struc-

ture damage in early stages of FTD is unknown.Methods: Patients diagnosed

with two variants of FTD, primary progressive aphasia (PPA), or behavioral-

variant frontotemporal dementia (bvFTD) and also patientswith early dementia

in Alzheimer’s disease (AD) were investigated longitudinally with MRI. Gray

matter (GM) and white matter (WM) atrophy as well as altered fractional an-

isotropy and mean diffusivity (MD) were measured. Changes over 14 months

were evaluated for each group, and effect sizes were used to compute sample

size estimations for clinical trials. Results:While at baseline the most promi-

nent feature of PPAwas left anterior temporal GM reduction, the most signif-

icant longitudinal change was a decrease of WMwithin the left temporal lobe.

In bvFTD an increase of MD of the right frontal cortex was the most striking

finding. In AD, the largest longitudinal change was a reduction of temporopar-

ietal GM. DTI provided complementary information to structural MRI about

present lesions and ongoing pathological processes. Conclusions: For patients

with early bvFTD, DTI changes in topographically predefined region in the

frontal cortex may provide a valuable biomarker for studies with disease-mod-

ifying drugs. Using a Region of Interest approach studies may gain significant

results within an acceptable study size.

P3-305 AN OVERVIEW OF THE MEDICAL FOOD

SOUVENAID CLINICALTRIAL PROGRAM

R. L.Wieggers1, P. Kamphuis2, Cornelis Stam3, Raj Shah4, David Bennett5,

T. Hartmann6, Hilkka Soininen7, Olde Rikkert Marcel8, Philip Scheltens3,1Nutricia Advanced Medical Nutrition, Danone Research Centre for

Specialised Nutrition, Wageningen, Netherlands; 2Nutricia Advanced

Medical Nutrition, Danone Research, Centre for Specialised Nutrition,

Wageningen, Netherlands; 3VU University Medical Center, Amsterdam,

Netherlands; 4Rush Alzheimer’s Disease Center, Rush University Medical

Center, Chicago, Illinois, United States; 5Rush University Medical Center,

Chicago, Illinois, United States; 6Deutsches Institut f€ur DemenzPr€avention(DIDP), Homburg, Germany; 7Kuopio University and University Hospital,

Kuopio, Finland; 8Radboud Alzheimer Centre, Radboud University

Hospital, Nijmegen, Nijmegen, Netherlands. Contact e-mail: rico.

wieggers@nutricia.com

Background: Synaptic dysfunction is an important characteristic in early

Alzheimer’s disease (AD), when memory impairment is a key symptom.

Souvenaid�1 is a medical food containing the nutrient combination Forta-

syn � Connect 1, designed to improve synapse formation and function in

AD. Fortasyn Connect contains precursors and cofactors for the formation

of neuronal membranes, needed for the synthesis of new synapses.

Methods: The efficacy and mode of action of Souvenaid is investigated

in the global clinical trial programme. Results: Two double-blind rando-

mised controlled trials (RCT) of 12- and 24-week duration demonstrated

that Souvenaid improved memory performance in drug-na€ıve patients

with mild AD (’Souvenir I’ and ’Souvenir II’). The 24-week open-label ex-

tension following Souvenir II showed continued memory improvement on

a Neuropsychological Test Battery. Furthermore, Souvenaid is well-toler-

ated (compliance�95%) throughout 48 weeks of use and has a good safety

profile. A double-blind RCT (’ S-Connect’) inmoremoderate AD patients

(average MMSE score of 19.4)using AD medication also showed a good

safety profile of Souvenaid in combination with AD medication, but did

not show an effect on cognition.Electroencephalograpy (EEG) measures

in the Souvenir II 2 studymeasuredneuronal activity. Significant EEG effects

suggested that Souvenaid preserves functional connectivity and brain net-

work organisation in mild AD, supporting the hypothesis of changed synap-

tic activity. The current results suggest that Souvenaid is efficacious in early

AD and warrant long-term trials in very early AD phases. Such data will

come from the ongoing 24-month LipiDiDiet study 3 in prodromal AD

and from a new long-term RCT in subjects with mild cognitive impairment.

Souvenaid’s working mechanism is further studied using 18-f luorodeoxy-

glucose positron emission tomography, magnetoencephalography 2 and

magnetic resonance spectroscopy. Main and recent findings will be pre-

sented. Conclusions: Souvenaid is safe, well-tolerated, and has shown to

improve memory performance in mild AD. The longer-term clinical effi-

cacy of Souvenaid in the early stages of AD and the mechanisms of action

continue to be evaluated in the Souvenaid clinical trial programme.

P3-306 A RANDOMIZED CONTROLLED TRIAL

INVESTIGATING THE EFFECTS OF SOUVENAID

IN PRODROMAL ALZHEIMER’S DISEASE:

BASELINE CHARACTERISTICS OF THE

LIPIDIDIET STUDY

Pieter Jelle Visser1, Hilkka Soininen2, Miia Kivipelto3, Y. Freund-Levi4,

P. Kamphuis5, R. L. Wieggers6, T. Hartmann7, 1Alzheimer Centre VUMC,

Amsterdam, Netherlands; 2Institute of Clinical Medicine, University of

Eastern Finland, and Kuopio University Hospital, Kuopio, Finland;3Karolinska Institutet Alzheimer Disease Research Center, Aging Research

Center, and Karolinska University Hospital, Stockholm, Sweden;4Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden;5Nutricia Advanced Medical Nutrition, Danone Research, Centre for

Specialised Nutrition, Wageningen, Netherlands; 6Nutricia Advanced

Medical Nutrition, Danone Research Centre for Specialised Nutrition,

Wageningen, Netherlands; 7Deutsches Institut f€ur DemenzPr€avention

(DIDP), Homburg, Germany. Contact e-mail: pj.visser@vumc.nl

Background: Souvenaid �, containing the specific nutrient combination

Fortasyn � Connect 1, is designed to support synapse formation and func-

tion in patients with Alzheimer’s disease (AD). The nutrients in Fortasyn

Connect are precursors and cofactors for the formation of neuronal mem-

branes, and increasing their intake can promote synaptogenesis. Two earlier

randomized controlled trials (RCTs) have shown that Souvenaid improves