Conditions: Alzheimer's Disease
Keywords: Alzheimer's Disease Alzheimer's
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 482
Healthy volunteers: no

Brief summary:
The primary objective is to evaluate the efficacy of T-817MA as measured by ADAS-cog and ADCS-CGIC.

The secondary objectives are:

* To evaluate the safety and tolerability of T-817MA measured by clinical safety laboratories, physical examinations, ECGs and solicitation of adverse events.
* To evaluate the efficacy of T-817MA as measured by ADCS-ADL, FAQ, Neuropsychiatric Inventory (NPI) and Mini-mental State Examination (MMSE).

Detailed description:

Arms:
arm 1: 224 mg T-817MA once daily for first 4 weeks and 448 mg T-817MA once daily for the following weeks. arm 2: 224 mg T-817MA once daily arm 3: Placebo once daily

Interventions: intervention 1: T-817MA-H intervention 2: T-817MA-L intervention 3: Placebo
Intervention descriptions: intervention 1: 224 mg or 448 mg T-817 MA once daily intervention 2: 224 mg T-817 MA once daily intervention 3: Placebo

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
A Phase 2 multi-center, randomized, double blind, 
placebo-controlled, parallel group study to evaluate 
the efficacy and safety of T-817MA in patients with 
mild to moderate Alzheimer’s Disease (US202) 
 
 
Protocol & SAP Synopsis 
 
2018.7.12 
 
NCT02079909 
 
 


PROTOCOL TITLE 
A 
Phase 
2 
multi-center, 
randomized, 
double 
blind, 
placebo-controlled, parallel group study to evaluate the efficacy 
and safety of T-817MA in patients with mild to moderate 
Alzheimer’s Disease (US202) 
STUDY SPONSOR 
Toyama Chemical Co., Ltd. 
COORDINATING CENTER 
Alzheimer’s Disease Cooperative Study (ADCS) 
STUDY PHASE 
 
 
2 
INDICATION 
 
 
For the treatment of mild to moderate Alzheimer's disease. 
OBJECTIVES 
The primary objective is to evaluate the efficacy of T-817MA 
as measured by ADAS-cog and ADCS-CGIC. 
The secondary objectives are: 
• To evaluate the safety and tolerability of T-817MA 
measured 
by 
clinical 
safety 
laboratories, 
physical 
examinations, ECGs and solicitation of adverse events. 
• To evaluate the efficacy of T-817MA as measured by 
ADCS-ADL, FAQ, Neuropsychiatric Inventory (NPI) and 
Mini-mental State Examination (MMSE).   
ADDITIONAL OBJECTIVES 
Population pharmacokinetics of T-817 will be analyzed. 
Volumetric MRI (vMRI) scans will be evaluated. CSF 
biomarkers will be evaluated in a subset of the study 
population. 
PRIMARY ENDPOINTS 
The change in the ADAS-cog and ADCS-CGIC from Baseline 
to Week 52 between each T-817MA treatment group (high or 
low dose) and the placebo group. 
SECONDARY ENDPOINTS 
• The change in the ADAS-cog from Baseline to Weeks 12, 
24, 36, 44 and 56. 
• The change in the ADCS-CGIC from Baseline to Weeks 
12, 24, 36 and 44. 
• The change in the MMSE from Baseline to Weeks 12, 24, 


36, 44, 52 and 56. 
• The change in the ADCS-ADL, FAQ and NPI from 
Baseline to Weeks 12, 24, 36 and 52. 
• Safety as measured by occurrence of adverse events, 
clinical laboratory tests, vital signs, physical examinations, 
ECGs, use of concomitant medications, and the C-SSRS 
Pediatric. 
STUDY DESIGN 
This is a Phase 2 multi-center, randomized, double blind, 
placebo-controlled, parallel group study. 
Patients will be screened at the investigative site in order to 
determine their eligibility for the study. A central review of 
screening results will then be conducted and, if appropriate, 
permission will be granted to randomize the patient. 
At Baseline, patients will be randomized to one of three 
treatment groups: placebo, 224 mg T-817MA, or 448 mg 
T-817MA in a 1:1:1 allocation. Donepezil or rivastigmine 
transdermal system, concomitant treatment for Alzheimer’s 
disease, will be required to be taken as prescribed by the PI or 
other prescribing physician, and will be encouraged to be 
maintained throughout the study. Memantine will be allowed 
only when prescribed in combination with donepezil or 
rivastigmine transdermal system.  
Patients will be seen every four weeks for the first 12 weeks of 
the study, and then will be seen every 6 weeks thereafter until 
Week 36, then at Week 44 and Week 52. A final follow-up visit 
will be conducted at Week 56. 
Safety evaluations will be carried out at each visit. Efficacy will 
be assessed every 12 weeks beginning at Baseline through 
Week 36 then at Week 44 and 52 and finally during the follow 
up visit at Week 56. Volumetric MRI scans of the brain will be 
done at Screening and Week 52.  Blood collection for 
population pharmacokinetic (PPK) assessments will be done at 
Baseline and Weeks 12, 24, 36, 44 and 52. A subset of patients 
will undergo lumbar puncture at Weeks 0 and 52 to evaluate 


CSF biomarkers.  
SAMPLE SIZE 
 
In order to arrive at 110 evaluable patients in each study group, 
it is necessary to randomize at least 450 patients (at least 150 
per group), assuming a 26% dropout rate during the treatment 
period. 
KEY ELIGIBILITY CRITERIA 
 
 
• Ages 55 to 85 years (inclusive), with probable AD 
• MMSE 12-22 (inclusive) at screening 
• Receiving donepezil or rivastigmine transdermal system 
treatment for at least 4 months prior to Baseline and on a 
stable dose for 3 months prior to Baseline  
• Brain MRI or CT consistent with Alzheimer’s disease 
• Residing in the community with a designated study partner 
who will accompany the patient to all clinic visits and 
participate in the evaluations (see protocol details) 
• Informed consent or Legally Authorized Representative 
(LAR) proxy informed consent with patient’s assent 
DRUG DOSAGE AND 
FORMULATION 
Two dosing levels of T-817MA (224 and 448 mg/day) or 
placebo. The 448 mg dose arm will be started at 224 mg for 4 
weeks, and then increased to 448 mg.  
Film-coated tablets are 112 mg T-817MA or placebo and 
dispensed in blister packs. 
The study medication will be taken once daily after breakfast.   
ROUTE OF ADMINISTRATION Oral 
TREATMENT DURATION 
Duration of treatment is 52 weeks.  There is also a screening 
period of up to 6 weeks; and a 4-week post-treatment 
observation period.  Each patient may participate in the study 
for up to 62 weeks. 
PROCEDURES 
 
Physical examinations, cognitive and functional test batteries, 
clinical and research venipunctures, volumetric MRIs, and 
lumbar puncture in a subset of patients. 
Visits: Screening (within 42 days prior to randomization), 


Baseline (Week 0), Weeks 4, 8, 12, 18, 24, 30, 36, 44, 52, and 
56 (follow-up) 
 
 
STATISTICAL METHODS 
1.1 Sample Size Determination 
The change in the ADAS-cog score in the placebo group is expected to be 3.5 points in 
one year.  Assuming that the difference in the ADAS-cog scale between each 
T-817MA treatment group and the placebo group is 2.5 points after one year, with a 
Standard Deviation of 6.5, the required number of cases to show a significant difference 
in the ADAS-cog is estimated at 110 per group.  This calculation has 80% statistical 
power at the 5% significance level. 
The power calculation of 80% as shown above corresponds to achieving significance on 
the ADAS-cog alone, which would be considered a successful outcome for a proof of 
concept study. Achieving significance on both co-primary endpoints is not fully 
powered, but would be considered a successful outcome for a pivotal study. 
In order to have 110 evaluable patients in each group, it is necessary to randomize at 
least 450 patients (at least 150 per group) to double-blind treatment, assuming a 26% 
dropout rate during the treatment period. 
1.2 Randomization and Stratification 
Each patient will be randomly allocated in a 1:1:1 ratio into one of the 3 groups: 
treatment with 448 mg or 224 mg of T-817 or placebo.  A randomization schedule will 
be generated and incorporated into the Electronic Data Capture system (EDC) and the 
treatment group will be assigned as the site activates the patient.  A centralized 
eligibility evaluation procedure will be applied for each patient.  A stratified permuted 
block randomization procedure will be used.  Site and baseline MMSE will be 
stratification factors. 
1.3 Protocol Deviations, Data Blind Review, and Unblinding 
Classification of deviations from the protocol as minor or major, and decisions 
regarding exclusion of patients and/or patient data from the statistical analyses, will be 
decided on a case-by-case basis without knowledge of the treatment assigned and before 


the database lock (Data Blind Review).  After database lock, the responsible 
statistician will request the treatment codes, the study will be unblinded, and the 
statistical analysis will be conducted. 
1.4 Analysis Populations 
Analysis populations are defined as follows: 
• The Safety population will include all randomized patients who took at least one 
dose of the study medication. 
• The modified Intent-to-Treat (mITT) population will include all randomized 
patients who took at least one dose of the study medication and who have at least 
one efficacy evaluation following baseline. 
• The Per Protocol (PP) population will include all mITT patients who: 
- took the assigned medication during the 52 weeks of treatment, and 
- did not have any major protocol deviations. 
The primary population for efficacy analysis is the mITT population.  Analysis of 
primary and secondary efficacy endpoints will be performed in the mITT and PP 
populations.  The safety population will be used for analyses of safety endpoints. 
1.5 Efficacy Endpoints  
1.5.1 
Primary Efficacy Endpoints 
The co-primary efficacy endpoints are the change in the ADAS-cog and ADCS-CGIC 
from Baseline to Week 52 between each T-817MA treatment group (high dose or low 
dose) and the placebo group in the mITT population.  A Mixed-effects Model Repeated 
Measure will be used to calculate the differences in change of ADAS-cog at 52 weeks, 
with baseline ADAS-cog score as covariate. A Mixed-effects Model Repeated Measure 
will be used to calculate the differences in change of ADCS-CGIC at 52 weeks. 
1.5.2 
Secondary Efficacy Endpoints 
1. The change in the following assessments from Baseline to Week 52 between 
each T-817MA treatment group (high dose and low dose) and the placebo 
treatment group in the mITT population: 
a. ADCS-ADL 
b. FAQ 
c. NPI  


d. MMSE 
A Mixed-effects Model Repeated Measure will be used to calculate differences 
at 52 weeks, using baseline assessment as a covariate. 
2. The following will also be analyzed in the mITT population: 
a. The change in ADAS-cog, ADCS-CGIC, ADCS-ADL, FAQ, NPI and 
MMSE from Baseline to Weeks 12, 24 and 36 
b. The change in ADAS-cog, ADCS-CGIC and MMSE from Baseline to 
Week 44 
c. The change in ADAS-cog and MMSE from Baseline to Week 56 
3.  Primary and secondary endpoints will similarly be assessed in the per-protocol 
population. 
1.6 vMRI 
Observed Case analysis for differences in change of vMRI over 52 weeks with mITT 
and PP.  
1.7 CSF Substudy 
Observed Case analysis for differences in change of CSF biomarkers over 52 weeks 
with mITT and PP.  
1.8 Safety Endpoints 
• Occurrence of adverse events (AEs) 
• Clinical laboratory tests 
• Vital signs 
• Physical examinations 
• ECGs 
• Use of concomitant medications 
• C-SSRS Pediatric 
1.9 Statistical Methods 
Complete details of efficacy and safety analyses will be provided in a separate 
Statistical Analysis Plan (SAP). 


1.9.1 
Efficacy Analysis 
Analysis of primary and secondary efficacy endpoints will be performed on the mITT, 
and PP populations. 
The primary efficacy hypothesis is that treatment with one or both of the T-817MA 
doses will result in a statistically significant reduction in total ADAS-cog score relative 
to the placebo group at Week 52 in the mITT population.  The first stage in the 
hierarchical analysis will test the statistical hypothesis of no difference between the 
three treatment groups.  
A hierarchical strategy will be used to preserve alpha:  the primary analysis will first 
compare the high dose arm to placebo at an alpha level of 0.05, and if this is positive the 
low dose group will be compared to placebo again at an alpha level of 0.05. 
The first stage in the hierarchical analysis will test the statistical hypothesis of no 
difference between the three treatment groups.  
Categorical variables will be summarized by treatment group using frequency 
distribution: number of non-missing observations (N) and percentages (%).  
Percentages will be calculated within each treatment group on the number of 
non-missing observations.  Continuous variables will be summarized using standard 
quantitative statistics: number of non-missing observations (N), mean, standard 
deviation (SD), median and range (minimum and maximum observed values).  
OC and Imputation analysis of primary and secondary efficacy endpoints (the change in 
ADAS-cog and MMSE from Baseline to Weeks 12, 24, 36, 44, 52 and 56, the change in 
ADCS-ADL, FAQ and NPI from Baseline to Weeks 12, 24, 36 and 52 and the change 
in ADCS-CGIC from Baseline to Weeks 12, 24, 36, 44 and 52) will be performed in the 
mITT and PP populations. 
Subgroup analysis (e.g. gender, age, baseline MMSE score) will be performed in the 
mITT and PP populations.   
1.9.2 
Safety Analysis 
The Safety population will be used for analyses of each of the safety endpoints.  All 
concomitant medications will be tabulated according to drug class and preferred term 
using the WHO dictionary.  Clinical laboratory tests, vital signs, physical examinations 
and ECG will be summarized by number of patients, frequency rates and number of 
events by adverse events and by treatment group.  The time point of each event will 


also be summarized.  C-SSRS results will be summarized by mean values and changes 
from baseline at each visit. 
1.9.2.1 Adverse Events 
Adverse events (AE) occurring after the start of study drug dosing at Baseline (Week 0) 
will be summarized descriptively for the safety population.  All AEs will be coded 
according to system organ class (SOC) and preferred term (PT) using a Medical 
Dictionary for Regulatory Activities (MedDRA) dictionary.  Summary tables showing 
the number of patients and percent within each category will be generated for each of 
the following types of adverse events and its relationship to study treatment (related to 
study treatment):  
• All events 
• Serious events 
• Deaths 
• Events leading to withdrawal 
• Severe events 
1.9.2.2 Laboratory parameters 
Laboratory parameters will be summarized by visit.  Frequencies of high and low 
values with respect to the normal range will be displayed, as will shift tables comparing 
each treatment visit (Weeks 4, 8, 12, 18, 24, 30, 36, 44, 52 and 56) and Baseline visit by 
time point and treatment group.  Urinalysis values will be cross-summarized at 
pre-dose and post-dose. 
1.9.2.3 Other Safety Parameters 
Vital signs and ECG parameters will be summarized across groups by visit using 
descriptive statistics, and at each outcome visit and at end of study. 
Physical examination findings and ECG abnormalities and number of patients will be 
summarized as the count and percentage of patients by eCRF pre-defined categories at 
last visit.  Change from baseline at last visit will be summarized in a shift table 
crossing baseline and last visit results.  Concomitant medications will be summarized 
by treatment group, drug class and preferred term.  Vital signs will be summarized by 
visit using descriptive statistics.  


The change in the C-SSRS Ped score from Baseline to Weeks 12, 24, 36 and 52 will be 
summarized between each T-817MA treatment group (high dose and low dose) and the 
placebo treatment group. 
1.10 Population Pharmacokinetic Analysis 
Population pharmacokinetic analysis will be performed as outlined in a separate PPK 
statistical analysis plan. 
1.11 Interim Analyses 
An interim analysis is not currently planned, but may be added at a later time if it is 
deemed necessary.  If so, an amendment to the protocol will be filed at that time.