Trial Outcomes & Findings for Evaluation of the Efficacy and Safety of Azeliragon (TTP488) in Patients With Mild Alzheimer's Disease (NCT NCT02080364)

NCT ID: NCT02080364

Last Updated: 2021-05-07

Results Overview

The ADAS-cog is a structured scale (approximately 40 minutes to complete) that evaluates memory, orientation, attention, reasoning, language and constructional praxis (Rosen, 1984). The ADAS-cog scoring range for the version used in this study is from 0 to 70, with higher scores indicating greater cognitive impairment.

Recruitment status

TERMINATED

Study phase

PHASE3

Target enrollment

880 participants

Primary outcome timeframe

Baseline and 18 months (A-Study); baseline and 12 months (B-Study)

Results posted on

2021-05-07

Participant Flow

The A-Study was conducted from April 2015 through April 2018 in the United States and Canada. The B-Study was conducted from September 2016 through June 2018 in the United States, Canada, United Kingdom, Ireland, South Africa, Australia and New Zealand.

A total of 1733 subjects underwent screening procedures for determination of eligibility for participation across the A- and B- Studies. 880 subjects were eligible and were randomized and assigned to treatment groups.

Participant milestones

Participant milestones
Measure	A-Study: Azeliragon Azeliragon 5 mg once daily	A-Study: Placebo Placebo once daily	B-Study: Azeliragon Azeliragon 5 mg once daily	B-Study: Placebo Placebo capsule once daily
Baseline Period STARTED	197	208	247	228
Baseline Period COMPLETED	195	206	246	228
Baseline Period NOT COMPLETED	2	2	1	0
Treatment Period STARTED	195	206	246	228
Treatment Period COMPLETED	148	157	9	4
Treatment Period NOT COMPLETED	47	49	237	224

Reasons for withdrawal

Reasons for withdrawal
Measure	A-Study: Azeliragon Azeliragon 5 mg once daily	A-Study: Placebo Placebo once daily	B-Study: Azeliragon Azeliragon 5 mg once daily	B-Study: Placebo Placebo capsule once daily
Baseline Period Protocol Violation	2	1	0	0
Baseline Period Other	0	1	1	0
Treatment Period Adverse Event	10	15	11	14
Treatment Period Lost to Follow-up	2	3	5	0
Treatment Period Protocol Violation	5	3	5	1
Treatment Period Withdrawal by Subject	16	16	15	10
Treatment Period Study Terminated by Sponsor	0	0	180	183
Treatment Period Other	14	12	21	16

Baseline Characteristics

Baseline MMSE was not reported / not valid for some subjects; therefore, the number analyzed is smaller than overall number.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	A-Study: Azeliragon n=195 Participants Azeliragon 5 mg once daily	A-Study: Placebo n=206 Participants Placebo once daily	B-Study: Azeliragon n=246 Participants Azeliragon 5 mg once daily	B-Study: Placebo n=228 Participants Placebo capsule once daily	Total n=875 Participants Total of all reporting groups
Age, Continuous	74.6 years STANDARD_DEVIATION 9.13 • n=195 Participants	74.9 years STANDARD_DEVIATION 7.96 • n=206 Participants	74.9 years STANDARD_DEVIATION 8.55 • n=246 Participants	74.4 years STANDARD_DEVIATION 8.64 • n=228 Participants	74.7 years STANDARD_DEVIATION 8.56 • n=875 Participants
Sex: Female, Male Female	97 Participants n=195 Participants	91 Participants n=206 Participants	107 Participants n=246 Participants	107 Participants n=228 Participants	402 Participants n=875 Participants
Sex: Female, Male Male	98 Participants n=195 Participants	115 Participants n=206 Participants	139 Participants n=246 Participants	121 Participants n=228 Participants	473 Participants n=875 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	27 Participants n=195 Participants	23 Participants n=206 Participants	8 Participants n=246 Participants	15 Participants n=228 Participants	73 Participants n=875 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	168 Participants n=195 Participants	183 Participants n=206 Participants	238 Participants n=246 Participants	213 Participants n=228 Participants	802 Participants n=875 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=195 Participants	0 Participants n=206 Participants	0 Participants n=246 Participants	0 Participants n=228 Participants	0 Participants n=875 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=195 Participants	1 Participants n=206 Participants	0 Participants n=246 Participants	0 Participants n=228 Participants	1 Participants n=875 Participants
Race (NIH/OMB) Asian	5 Participants n=195 Participants	2 Participants n=206 Participants	6 Participants n=246 Participants	3 Participants n=228 Participants	16 Participants n=875 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	2 Participants n=195 Participants	0 Participants n=206 Participants	1 Participants n=246 Participants	0 Participants n=228 Participants	3 Participants n=875 Participants
Race (NIH/OMB) Black or African American	8 Participants n=195 Participants	9 Participants n=206 Participants	8 Participants n=246 Participants	5 Participants n=228 Participants	30 Participants n=875 Participants
Race (NIH/OMB) White	179 Participants n=195 Participants	194 Participants n=206 Participants	231 Participants n=246 Participants	220 Participants n=228 Participants	824 Participants n=875 Participants
Race (NIH/OMB) More than one race	1 Participants n=195 Participants	0 Participants n=206 Participants	0 Participants n=246 Participants	0 Participants n=228 Participants	1 Participants n=875 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=195 Participants	0 Participants n=206 Participants	0 Participants n=246 Participants	0 Participants n=228 Participants	0 Participants n=875 Participants
Region of Enrollment New Zealand	0 participants n=195 Participants	0 participants n=206 Participants	6 participants n=246 Participants	3 participants n=228 Participants	9 participants n=875 Participants
Region of Enrollment Canada	25 participants n=195 Participants	25 participants n=206 Participants	16 participants n=246 Participants	18 participants n=228 Participants	84 participants n=875 Participants
Region of Enrollment United States	170 participants n=195 Participants	181 participants n=206 Participants	163 participants n=246 Participants	144 participants n=228 Participants	558 participants n=875 Participants
Region of Enrollment Ireland	0 participants n=195 Participants	0 participants n=206 Participants	9 participants n=246 Participants	7 participants n=228 Participants	16 participants n=875 Participants
Region of Enrollment South Africa	0 participants n=195 Participants	0 participants n=206 Participants	24 participants n=246 Participants	22 participants n=228 Participants	46 participants n=875 Participants
Region of Enrollment United Kingdom	0 participants n=195 Participants	0 participants n=206 Participants	20 participants n=246 Participants	27 participants n=228 Participants	47 participants n=875 Participants
Region of Enrollment Australia	0 participants n=195 Participants	0 participants n=206 Participants	8 participants n=246 Participants	7 participants n=228 Participants	15 participants n=875 Participants
Apo E4 status Heterozygous	83 Participants n=195 Participants	79 Participants n=206 Participants	115 Participants n=246 Participants	105 Participants n=228 Participants	382 Participants n=875 Participants
Apo E4 status Homozygous	15 Participants n=195 Participants	27 Participants n=206 Participants	31 Participants n=246 Participants	18 Participants n=228 Participants	91 Participants n=875 Participants
Apo E4 status Non-carrier	95 Participants n=195 Participants	98 Participants n=206 Participants	96 Participants n=246 Participants	99 Participants n=228 Participants	388 Participants n=875 Participants
Apo E4 status Not reported	2 Participants n=195 Participants	2 Participants n=206 Participants	4 Participants n=246 Participants	6 Participants n=228 Participants	14 Participants n=875 Participants
Education Level High School	61 Participants n=195 Participants	65 Participants n=206 Participants	86 Participants n=246 Participants	79 Participants n=228 Participants	291 Participants n=875 Participants
Education Level Other (trainings, certifications)	15 Participants n=195 Participants	14 Participants n=206 Participants	8 Participants n=246 Participants	6 Participants n=228 Participants	43 Participants n=875 Participants
Education Level Some college	32 Participants n=195 Participants	33 Participants n=206 Participants	34 Participants n=246 Participants	31 Participants n=228 Participants	130 Participants n=875 Participants
Education Level Associates Degree	17 Participants n=195 Participants	14 Participants n=206 Participants	14 Participants n=246 Participants	21 Participants n=228 Participants	66 Participants n=875 Participants
Education Level Bachelor's Degree	44 Participants n=195 Participants	39 Participants n=206 Participants	64 Participants n=246 Participants	55 Participants n=228 Participants	202 Participants n=875 Participants
Education Level Master's Degree	21 Participants n=195 Participants	26 Participants n=206 Participants	29 Participants n=246 Participants	25 Participants n=228 Participants	101 Participants n=875 Participants
Education Level Doctoral Degree	5 Participants n=195 Participants	15 Participants n=206 Participants	11 Participants n=246 Participants	11 Participants n=228 Participants	42 Participants n=875 Participants
Background AD Medication Memantine	12 Participants n=195 Participants	16 Participants n=206 Participants	19 Participants n=246 Participants	22 Participants n=228 Participants	69 Participants n=875 Participants
Background AD Medication Acetylcholinesterase inhibitor	117 Participants n=195 Participants	124 Participants n=206 Participants	156 Participants n=246 Participants	145 Participants n=228 Participants	542 Participants n=875 Participants
Background AD Medication Both Memantine and Acetylcholinesterase inhibitor	65 Participants n=195 Participants	66 Participants n=206 Participants	71 Participants n=246 Participants	60 Participants n=228 Participants	262 Participants n=875 Participants
Background AD Medication Not recorded	1 Participants n=195 Participants	0 Participants n=206 Participants	0 Participants n=246 Participants	1 Participants n=228 Participants	2 Participants n=875 Participants
Years since AD diagnosis	2.41 years STANDARD_DEVIATION 2.389 • n=195 Participants	2.32 years STANDARD_DEVIATION 2.414 • n=206 Participants	2.05 years STANDARD_DEVIATION 1.932 • n=246 Participants	1.86 years STANDARD_DEVIATION 1.871 • n=228 Participants	2.14 years STANDARD_DEVIATION 2.153 • n=875 Participants
Baseline MMSE	23.42 units on a scale STANDARD_DEVIATION 2.733 • n=189 Participants • Baseline MMSE was not reported / not valid for some subjects; therefore, the number analyzed is smaller than overall number.	23.22 units on a scale STANDARD_DEVIATION 2.522 • n=202 Participants • Baseline MMSE was not reported / not valid for some subjects; therefore, the number analyzed is smaller than overall number.	23.29 units on a scale STANDARD_DEVIATION 2.513 • n=244 Participants • Baseline MMSE was not reported / not valid for some subjects; therefore, the number analyzed is smaller than overall number.	23.41 units on a scale STANDARD_DEVIATION 2.701 • n=225 Participants • Baseline MMSE was not reported / not valid for some subjects; therefore, the number analyzed is smaller than overall number.	23.33 units on a scale STANDARD_DEVIATION 2.611 • n=860 Participants • Baseline MMSE was not reported / not valid for some subjects; therefore, the number analyzed is smaller than overall number.
Baseline ADAS-cog	15.42 units on a scale STANDARD_DEVIATION 5.186 • n=188 Participants • Baseline ADAScog was not reported / not valid for some subjects; therefore, the number analyzed is smaller than overall number.	15.51 units on a scale STANDARD_DEVIATION 5.427 • n=202 Participants • Baseline ADAScog was not reported / not valid for some subjects; therefore, the number analyzed is smaller than overall number.	16.94 units on a scale STANDARD_DEVIATION 5.623 • n=243 Participants • Baseline ADAScog was not reported / not valid for some subjects; therefore, the number analyzed is smaller than overall number.	16.08 units on a scale STANDARD_DEVIATION 5.295 • n=225 Participants • Baseline ADAScog was not reported / not valid for some subjects; therefore, the number analyzed is smaller than overall number.	16.05 units on a scale STANDARD_DEVIATION 5.424 • n=858 Participants • Baseline ADAScog was not reported / not valid for some subjects; therefore, the number analyzed is smaller than overall number.
Baseline CDR-Sum of Boxes	4.06 units on a scale STANDARD_DEVIATION 1.747 • n=189 Participants • Baseline CDR-sb was not reported / not valid for some subjects; therefore, the number analyzed is smaller than overall number.	4.07 units on a scale STANDARD_DEVIATION 1.623 • n=202 Participants • Baseline CDR-sb was not reported / not valid for some subjects; therefore, the number analyzed is smaller than overall number.	4.64 units on a scale STANDARD_DEVIATION 1.585 • n=244 Participants • Baseline CDR-sb was not reported / not valid for some subjects; therefore, the number analyzed is smaller than overall number.	4.5 units on a scale STANDARD_DEVIATION 1.570 • n=225 Participants • Baseline CDR-sb was not reported / not valid for some subjects; therefore, the number analyzed is smaller than overall number.	4.34 units on a scale STANDARD_DEVIATION 1.645 • n=860 Participants • Baseline CDR-sb was not reported / not valid for some subjects; therefore, the number analyzed is smaller than overall number.
Baseline ADCS-ADL	67.62 units on a scale STANDARD_DEVIATION 7.67 • n=189 Participants • Baseline ADCS-ADL was not reported / not valid for some subjects; therefore, the number analyzed is smaller than overall number.	67.37 units on a scale STANDARD_DEVIATION 8.56 • n=202 Participants • Baseline ADCS-ADL was not reported / not valid for some subjects; therefore, the number analyzed is smaller than overall number.	66.25 units on a scale STANDARD_DEVIATION 8.142 • n=244 Participants • Baseline ADCS-ADL was not reported / not valid for some subjects; therefore, the number analyzed is smaller than overall number.	67.25 units on a scale STANDARD_DEVIATION 7.568 • n=225 Participants • Baseline ADCS-ADL was not reported / not valid for some subjects; therefore, the number analyzed is smaller than overall number.	67.08 units on a scale STANDARD_DEVIATION 8.001 • n=860 Participants • Baseline ADCS-ADL was not reported / not valid for some subjects; therefore, the number analyzed is smaller than overall number.

PRIMARY outcome

Timeframe: Baseline and 18 months (A-Study); baseline and 12 months (B-Study)

Population: Full Analysis Set (all randomized subjects who receive study medication and have at least one post-baseline efficacy assessment) with Month 18 (A-Study) or Month 12 (B-Study) data. B-Study excludes data from visits occurring after A-Study results announcement on 09 Apr 2018. ADAS-cog was not reported / not valid for some subject visits; therefore, the number analyzed is smaller than overall number.

Outcome measures

Outcome measures
Measure	A-Study: Azeliragon n=138 Participants Azeliragon 5 mg once daily	A-Study: Placebo n=151 Participants Placebo once daily	B-Study: Azeliragon n=118 Participants Azeliragon 5 mg once daily	B-Study: Placebo n=121 Participants Placebo capsule once daily
Change From Baseline in Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Total Score	3.8 score on a scale Standard Error 0.51	3.1 score on a scale Standard Error 0.49	3.4 score on a scale Standard Error 0.46	2.5 score on a scale Standard Error 0.46

PRIMARY outcome

Timeframe: Baseline and 18 months (A-Study); baseline and 12 months (B-Study)

Population: Full Analysis Set (all randomized subjects who receive study medication and have at least one post-baseline efficacy assessment) with Month 18 (A-Study) or Month 12 (B-Study) data. B-Study excludes data from visits occurring after A-Study results announcement on 09 Apr 2018. CDR-sb was not reported / not valid for some subject visits; therefore, the number analyzed is smaller than overall number.

The CDR scale is used as a global measure of dementia and is completed by a clinician in the setting of detailed knowledge of the individual patient collected from interviews with the patient and caregiver (Berg, 1988). The CDR describes 5 degrees of impairment in performance on each of 6 categories including memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. CDR ratings are 0 for healthy individuals, 0.5 for questionable dementia and 1, 2 and 3 for mild, moderate and severe dementia as defined in the CDR scale. The scores for each category can also be summed and this is known as the sum of box score (CSR-SB). Sum of box scores range from 0 to 18 with higher scores indicating greater cognitive impairment.

Outcome measures

Outcome measures
Measure	A-Study: Azeliragon n=140 Participants Azeliragon 5 mg once daily	A-Study: Placebo n=150 Participants Placebo once daily	B-Study: Azeliragon n=117 Participants Azeliragon 5 mg once daily	B-Study: Placebo n=120 Participants Placebo capsule once daily
Change From Baseline in Clinical Dementia Rating Scale Sum of Boxes (CDR-sb)	1.4 score on a scale Standard Deviation 2.23	1.4 score on a scale Standard Deviation 1.85	1.3 score on a scale Standard Deviation 1.87	0.7 score on a scale Standard Deviation 1.4

SECONDARY outcome

Timeframe: Baseline and 18 months

Population: Number of subjects with paired Baseline and Month 18 MRIs

Percent of Total Hippocampus Atrophy to Intracranial Volume

Outcome measures

Outcome measures
Measure	A-Study: Azeliragon n=112 Participants Azeliragon 5 mg once daily	A-Study: Placebo n=116 Participants Placebo once daily	B-Study: Azeliragon Azeliragon 5 mg once daily	B-Study: Placebo Placebo capsule once daily
Change From Baseline in Magnetic Resonance Imaging (MRI) Brain Volumetric Measures	-0.016 percentage of Total Hippocampus Atrophy Standard Error 0.001	-0.014 percentage of Total Hippocampus Atrophy Standard Error 0.001	—	—

SECONDARY outcome

Timeframe: Baseline to 18 months

Population: Analyzed as part of an optional FDG-PET substudy

Extent and severity of brain hypometabolism was assessed centrally at Baseline and Month 18. SUVR PET was designed to make use of FreeSurfer-based segmentations of the brain obtained using the 3DT1 MRI. Following the methods published by Landau and Jagust (Landau SM, Annals of Neurology 2012) and described on the ADNI website (http://adni.loni.usc.edu/methods/pet-analysis-method/), regions were defined in native patient space on the 3DT1 MRI acquired at the Baseline visit and at Month 18 visit. An SUVR measure was computed regionally over five sub-regions (anterior/posterior cingulate, temporal, parietal, frontal and hippocampal areas), normalized to activity in the cerebral white matter. These sub-regions were selected to optimize sensitivity in longitudinal studies. This outcome measure presents the change from baseline in the normalized mean composite SUVR of the 5 regions. A negative change from baseline indicates a decrease (worsening) in brain glucose metabolism/utilization.

Outcome measures

Outcome measures
Measure	A-Study: Azeliragon n=38 Participants Azeliragon 5 mg once daily	A-Study: Placebo n=36 Participants Placebo once daily	B-Study: Azeliragon Azeliragon 5 mg once daily	B-Study: Placebo Placebo capsule once daily
Change From Baseline in the Normalized Mean Composite SUVR of the 5 Regions	-0.0304 SUVR ratio Standard Error 0.0039	-0.0342 SUVR ratio Standard Error 0.0039	—	—

SECONDARY outcome

Timeframe: Baseline and 18 months (A-Study); baseline and 12 months (B-Study)

Population: Full Analysis Set (all randomized subjects who receive study medication and have at least one post-baseline efficacy assessment) with Month 18 (A-Study) or Month 12 (B-Study) data. B-Study excludes data from visits occurring after A-Study results announcement on 09 Apr 2018. ADCS-ADL was not reported / not valid for some subject visits; therefore, the number analyzed is smaller than overall number.

The ADCS-ADL is an activity of daily living inventory developed by the ADCS to assess functional performance in participants with AD (Galasko et al., 1997). Informants are queried via a structured interview format as to whether participants attempted each item in the inventory during the preceding 4 weeks, as well as their level of performance. Scores range from 0-78 with lower scores indicating greater functional impairment.

Outcome measures

Outcome measures
Measure	A-Study: Azeliragon n=141 Participants Azeliragon 5 mg once daily	A-Study: Placebo n=152 Participants Placebo once daily	B-Study: Azeliragon n=121 Participants Azeliragon 5 mg once daily	B-Study: Placebo n=122 Participants Placebo capsule once daily
Change From Baseline in Alzheimer's Disease Cooperative Study- Activities of Daily Living Inventory (ADCS-ADL)	-5.1 score on a scale Standard Deviation 8.63	-3.2 score on a scale Standard Deviation 8.92	-5.4 score on a scale Standard Deviation 8.85	-2.8 score on a scale Standard Deviation 7.83

SECONDARY outcome

Timeframe: Baseline and 18 months (A-Study); baseline and 12 months (B-Study)

Population: Full Analysis Set (all randomized subjects who receive study medication and have at least one post-baseline efficacy assessment) with Month 18 (A-Study) or Month 12 (B-Study) data. B-Study excludes data from visits occurring after A-Study results announcement on 09 Apr 2018. MMSE was not reported / not valid for some subject visits; therefore, the number analyzed is smaller than overall number.

The MMSE is a brief 30-point test that is used to assess cognition (Folstein, 1975). It is commonly used to screen for dementia. In the time span of about 10 minutes, it samples various functions, including arithmetic, memory and orientation. Scores range from 0-30 with lower scores indicating greater cognitive impairment.

Outcome measures

Outcome measures
Measure	A-Study: Azeliragon n=142 Participants Azeliragon 5 mg once daily	A-Study: Placebo n=153 Participants Placebo once daily	B-Study: Azeliragon n=121 Participants Azeliragon 5 mg once daily	B-Study: Placebo n=121 Participants Placebo capsule once daily
Change From Baseline in Mini-Mental State Examination (MMSE)	-2.1 score on a scale Standard Deviation 3.55	-2.0 score on a scale Standard Deviation 3.25	-2.1 score on a scale Standard Deviation 3.25	-1.8 score on a scale Standard Deviation 3.29

SECONDARY outcome

Timeframe: Baseline and 18 months (A-Study); baseline and 12 months (B-Study)

Population: Full Analysis Set (all randomized subjects who receive study medication and have at least one post-baseline efficacy assessment) with Month 18 (A-Study) or Month 12 (B-Study) data. B-Study excludes data from visits occurring after A-Study results announcement on 09 Apr 2018. NPI was not reported / not valid for some subject visits; therefore, the number analyzed is smaller than overall number.

The NPI is a well-validated, reliable, multi-item instrument to assess psychopathology in AD based on an interview with the caregiver (Cummings et al, 1994). It evaluates both the frequency and severity of 12 behavioral areas including delusions, hallucinations, dysphoria (depression) anxiety, agitation/aggression, euphoria, disinhibition, irritability, lability, apathy, aberrant motor behavior, appetite and eating changes and night-time behaviors. Frequency assessments range from 1 (occasionally, less than once per week) to 4 (very frequently, once or more per day or continuously) as well as severity (1= mild, 2 = moderate, 3 = severe). Distress is rated by the study partner or caregiver and ranges from 0 (no distress) to 5 (very severe or extreme). The overall score and the score for each subscale are the product of severity and frequency. Scores range from 0-144 with higher scores indicating a greater presence of neuropsychiatric symptoms.

Outcome measures

Outcome measures
Measure	A-Study: Azeliragon n=142 Participants Azeliragon 5 mg once daily	A-Study: Placebo n=152 Participants Placebo once daily	B-Study: Azeliragon n=121 Participants Azeliragon 5 mg once daily	B-Study: Placebo n=122 Participants Placebo capsule once daily
Change From Baseline in Neuropsychiatric Inventory (NPI)	-0.2 score on a scale Standard Deviation 9.77	1.3 score on a scale Standard Deviation 11.53	2.3 score on a scale Standard Deviation 11.24	0.0 score on a scale Standard Deviation 10.67

SECONDARY outcome

Timeframe: Baseline and 18 months (A-Study); baseline and 12 months (B-Study)

Population: Full Analysis Set (all randomized subjects who receive study medication and have at least one post-baseline efficacy assessment) with Month 18 (A-Study) or Month 12 (B-Study) data. DEMQOL was not reported / not valid for some subject visits; therefore, the number analyzed is smaller than overall number.

The DEMQOL-Proxy questionnaire is a validated and reliable questionnaire that is interview administered and completed by the caregiver about the patient's health related quality of life (Smith et al, 2005). It consists of 31 items representing 5 domains (daily activities and looking after yourself, health and well-being, cognitive functioning, social relationships, and self-concept) and takes approximately 20 minutes to complete. Scores range 31-124 with higher scores indicate better health related quality of life.

Outcome measures

Outcome measures
Measure	A-Study: Azeliragon n=142 Participants Azeliragon 5 mg once daily	A-Study: Placebo n=152 Participants Placebo once daily	B-Study: Azeliragon n=179 Participants Azeliragon 5 mg once daily	B-Study: Placebo n=187 Participants Placebo capsule once daily
Change From Baseline in Dementia Quality of Life (DEMQOL)	0.0 score on a scale Standard Deviation 10.2	-1.2 score on a scale Standard Deviation 9.38	-0.1 score on a scale Standard Deviation 10.55	-0.8 score on a scale Standard Deviation 11.70

SECONDARY outcome

Timeframe: Baseline and 18 months (A-Study); baseline and 12 months (B-Study)

Population: Full Analysis Set (all randomized subjects who receive study medication and have at least one post-baseline efficacy assessment) with Month 18 (A-Study) or Month 12 (B-Study) data. NPI was not reported / not valid for some subject visits; therefore, the number analyzed is smaller than overall number.

The COWAT is a measure of verbal fluency in which the participant is asked to generate orally as many words as possible that begin with the letters "F", "A", and "S", excluding proper names and different forms of the same word. (Borkowski, 1967, Loonstra 2001) For each letter, the participant is allowed one minute to generate the words. Performance is measured by the total number of correct words produced summed across the three letters. Perseverations (i.e., repetitions of a correct word) and intrusions (i.e., words not beginning with the designated letter) are noted.

Outcome measures

Outcome measures
Measure	A-Study: Azeliragon n=142 Participants Azeliragon 5 mg once daily	A-Study: Placebo n=153 Participants Placebo once daily	B-Study: Azeliragon n=180 Participants Azeliragon 5 mg once daily	B-Study: Placebo n=188 Participants Placebo capsule once daily
Change From Baseline in Continuous Oral Word Association Task (COWAT)	-2.0 Total acceptable Words Standard Deviation 9.61	-0.1 Total acceptable Words Standard Deviation 8.92	-1.8 Total acceptable Words Standard Deviation 8.12	-0.8 Total acceptable Words Standard Deviation 8.71

SECONDARY outcome

Timeframe: Baseline and 18 months (A-Study); baseline and 12 months (B-Study)

Population: Full Analysis Set (all randomized subjects who receive study medication and have at least one post-baseline efficacy assessment) with Month 18 (A-Study) or Month 12 (B-Study) data. NPI was not reported / not valid for some subject visits; therefore, the number analyzed is smaller than overall number.

Study participants are given one minute to provide exemplars of the category 'animals'.

Outcome measures

Outcome measures
Measure	A-Study: Azeliragon n=142 Participants Azeliragon 5 mg once daily	A-Study: Placebo n=152 Participants Placebo once daily	B-Study: Azeliragon n=180 Participants Azeliragon 5 mg once daily	B-Study: Placebo n=188 Participants Placebo capsule once daily
Change From Baseline in Category Fluency Test (CFT)	-1.7 Total Acceptable Words Standard Deviation 4.45	-1.3 Total Acceptable Words Standard Deviation 4.26	-1.5 Total Acceptable Words Standard Deviation 3.80	9.7 Total Acceptable Words Standard Deviation 146.20

Adverse Events

Azeliragon 5mg

Serious events: 70 serious events

Other events: 320 other events

Deaths: 4 deaths

Placebo

Serious events: 67 serious events

Other events: 324 other events

Deaths: 5 deaths

Serious adverse events

Other adverse events

Additional Information

Ann Gooch PhD,RAC,CCRP; Vice President Clinical Development & Regulatory Operations

vTv Therapeutics LLC

Phone: 336-841-0300

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Where PI requires the use of the Study Results for publication, the PI shall seek the Sponsor's written approval which shall not be unreasonably withheld; provided, however, that (i) Sponsor may require removal of any Confidential Information of Sponsor or may delay publication for a reasonable period of time in order to secure protection any IP Rights; and, (ii) as the Study is designed as a multi-center Study, no publication shall be made until after the first multi-center publication.
Publication restrictions are in place

Restriction type: OTHER

Measure	Azeliragon 5mg n=441 participants at risk Azeliragon (TTP488) 5mg orally once daily for 18 months Parts A and B Combined	Placebo n=434 participants at risk Placebo orally once daily for 18 months Parts A and B Combined
Infections and infestations Urinary tract infection	10.2% 45/441 • Number of events 47 • Adverse event reporting commenced when the subject received their first dose and ended at the final study visit (21 months).	7.6% 33/434 • Number of events 33 • Adverse event reporting commenced when the subject received their first dose and ended at the final study visit (21 months).
Infections and infestations Nasopharyngitis	4.3% 19/441 • Number of events 19 • Adverse event reporting commenced when the subject received their first dose and ended at the final study visit (21 months).	5.3% 23/434 • Number of events 24 • Adverse event reporting commenced when the subject received their first dose and ended at the final study visit (21 months).
Infections and infestations Upper Respiratory Tract Infection	4.5% 20/441 • Number of events 23 • Adverse event reporting commenced when the subject received their first dose and ended at the final study visit (21 months).	3.7% 16/434 • Number of events 17 • Adverse event reporting commenced when the subject received their first dose and ended at the final study visit (21 months).
Infections and infestations Bronchitis	2.0% 9/441 • Number of events 9 • Adverse event reporting commenced when the subject received their first dose and ended at the final study visit (21 months).	3.2% 14/434 • Number of events 14 • Adverse event reporting commenced when the subject received their first dose and ended at the final study visit (21 months).
Infections and infestations Sinusitis	2.0% 9/441 • Number of events 9 • Adverse event reporting commenced when the subject received their first dose and ended at the final study visit (21 months).	2.1% 9/434 • Number of events 9 • Adverse event reporting commenced when the subject received their first dose and ended at the final study visit (21 months).
Infections and infestations Influenza	1.6% 7/441 • Number of events 7 • Adverse event reporting commenced when the subject received their first dose and ended at the final study visit (21 months).	2.5% 11/434 • Number of events 11 • Adverse event reporting commenced when the subject received their first dose and ended at the final study visit (21 months).
Gastrointestinal disorders Diarrhoea	3.9% 17/441 • Number of events 18 • Adverse event reporting commenced when the subject received their first dose and ended at the final study visit (21 months).	4.6% 20/434 • Number of events 22 • Adverse event reporting commenced when the subject received their first dose and ended at the final study visit (21 months).
Gastrointestinal disorders Nausea	3.2% 14/441 • Number of events 14 • Adverse event reporting commenced when the subject received their first dose and ended at the final study visit (21 months).	2.3% 10/434 • Number of events 10 • Adverse event reporting commenced when the subject received their first dose and ended at the final study visit (21 months).
Gastrointestinal disorders Constipation	2.3% 10/441 • Number of events 10 • Adverse event reporting commenced when the subject received their first dose and ended at the final study visit (21 months).	1.8% 8/434 • Number of events 8 • Adverse event reporting commenced when the subject received their first dose and ended at the final study visit (21 months).
Nervous system disorders Dizziness	4.1% 18/441 • Number of events 19 • Adverse event reporting commenced when the subject received their first dose and ended at the final study visit (21 months).	3.5% 15/434 • Number of events 15 • Adverse event reporting commenced when the subject received their first dose and ended at the final study visit (21 months).
Nervous system disorders Headache	3.4% 15/441 • Number of events 16 • Adverse event reporting commenced when the subject received their first dose and ended at the final study visit (21 months).	4.4% 19/434 • Number of events 19 • Adverse event reporting commenced when the subject received their first dose and ended at the final study visit (21 months).
Nervous system disorders Syncope	1.6% 7/441 • Number of events 8 • Adverse event reporting commenced when the subject received their first dose and ended at the final study visit (21 months).	1.2% 5/434 • Number of events 5 • Adverse event reporting commenced when the subject received their first dose and ended at the final study visit (21 months).
Injury, poisoning and procedural complications Fall	10.9% 48/441 • Number of events 59 • Adverse event reporting commenced when the subject received their first dose and ended at the final study visit (21 months).	12.7% 55/434 • Number of events 59 • Adverse event reporting commenced when the subject received their first dose and ended at the final study visit (21 months).
Injury, poisoning and procedural complications Laceration	2.3% 10/441 • Number of events 10 • Adverse event reporting commenced when the subject received their first dose and ended at the final study visit (21 months).	2.5% 11/434 • Number of events 13 • Adverse event reporting commenced when the subject received their first dose and ended at the final study visit (21 months).
Injury, poisoning and procedural complications Contusion	1.8% 8/441 • Number of events 9 • Adverse event reporting commenced when the subject received their first dose and ended at the final study visit (21 months).	1.8% 8/434 • Number of events 12 • Adverse event reporting commenced when the subject received their first dose and ended at the final study visit (21 months).
Psychiatric disorders Depression	4.8% 21/441 • Number of events 21 • Adverse event reporting commenced when the subject received their first dose and ended at the final study visit (21 months).	4.6% 20/434 • Number of events 20 • Adverse event reporting commenced when the subject received their first dose and ended at the final study visit (21 months).
Psychiatric disorders Agitation	3.2% 14/441 • Number of events 16 • Adverse event reporting commenced when the subject received their first dose and ended at the final study visit (21 months).	3.9% 17/434 • Number of events 18 • Adverse event reporting commenced when the subject received their first dose and ended at the final study visit (21 months).
Psychiatric disorders Anxiety	2.3% 10/441 • Number of events 11 • Adverse event reporting commenced when the subject received their first dose and ended at the final study visit (21 months).	3.5% 15/434 • Number of events 15 • Adverse event reporting commenced when the subject received their first dose and ended at the final study visit (21 months).
Psychiatric disorders Insomnia	2.5% 11/441 • Number of events 11 • Adverse event reporting commenced when the subject received their first dose and ended at the final study visit (21 months).	1.6% 7/434 • Number of events 7 • Adverse event reporting commenced when the subject received their first dose and ended at the final study visit (21 months).
Musculoskeletal and connective tissue disorders Back pain	2.3% 10/441 • Number of events 11 • Adverse event reporting commenced when the subject received their first dose and ended at the final study visit (21 months).	3.2% 14/434 • Number of events 14 • Adverse event reporting commenced when the subject received their first dose and ended at the final study visit (21 months).
Musculoskeletal and connective tissue disorders Musculoskeletal Pain	2.3% 10/441 • Number of events 10 • Adverse event reporting commenced when the subject received their first dose and ended at the final study visit (21 months).	1.2% 5/434 • Number of events 5 • Adverse event reporting commenced when the subject received their first dose and ended at the final study visit (21 months).
Musculoskeletal and connective tissue disorders Arthralgia	2.0% 9/441 • Number of events 9 • Adverse event reporting commenced when the subject received their first dose and ended at the final study visit (21 months).	3.2% 14/434 • Number of events 16 • Adverse event reporting commenced when the subject received their first dose and ended at the final study visit (21 months).
General disorders Fatigue	2.9% 13/441 • Number of events 16 • Adverse event reporting commenced when the subject received their first dose and ended at the final study visit (21 months).	3.2% 14/434 • Number of events 15 • Adverse event reporting commenced when the subject received their first dose and ended at the final study visit (21 months).
Respiratory, thoracic and mediastinal disorders Cough	2.9% 13/441 • Number of events 13 • Adverse event reporting commenced when the subject received their first dose and ended at the final study visit (21 months).	2.1% 9/434 • Number of events 9 • Adverse event reporting commenced when the subject received their first dose and ended at the final study visit (21 months).
Investigations Weight Decreased	3.9% 17/441 • Number of events 17 • Adverse event reporting commenced when the subject received their first dose and ended at the final study visit (21 months).	3.0% 13/434 • Number of events 13 • Adverse event reporting commenced when the subject received their first dose and ended at the final study visit (21 months).
Metabolism and nutrition disorders Decreased Appetite	1.1% 5/441 • Number of events 5 • Adverse event reporting commenced when the subject received their first dose and ended at the final study visit (21 months).	2.1% 9/434 • Number of events 9 • Adverse event reporting commenced when the subject received their first dose and ended at the final study visit (21 months).
Cardiac disorders Atrial Fibrillation	1.1% 5/441 • Number of events 7 • Adverse event reporting commenced when the subject received their first dose and ended at the final study visit (21 months).	1.6% 7/434 • Number of events 8 • Adverse event reporting commenced when the subject received their first dose and ended at the final study visit (21 months).
Vascular disorders Hypertension	2.3% 10/441 • Number of events 10 • Adverse event reporting commenced when the subject received their first dose and ended at the final study visit (21 months).	3.2% 14/434 • Number of events 14 • Adverse event reporting commenced when the subject received their first dose and ended at the final study visit (21 months).