Evaluation of the Efficacy and Safety of Azeliragon (TTP488) in Patients With Mild Alzheimer's Disease (STEADFAST)

• ClinicalTrials.gov Identifier: NCT02080364
• Recruitment Status: Terminated
• First Posted: March 6, 2014
• Results First Posted: May 7, 2021
• Last Update Posted: May 7, 2021
• Sponsor: vTv Therapeutics
• Information provided by (Responsible Party): vTv Therapeutics

Study Description

Brief Summary:

This is a study to evaluate the efficacy and safety of azeliragon in patients with mild Alzheimer's disease. Patients will receive either azeliragon or placebo with a patient's participation lasting approximately 18 months.

Condition or disease	Intervention/treatment	Phase
Alzheimer's Disease	Drug: Azeliragon; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 880 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Randomized, Double-blind, Placebo Controlled, Multi-center Registration Trial to Evaluate the Efficacy and Safety of Azeliragon (TTP488) in Patients With Mild Alzheimer's Disease Receiving Acetylcholinesterase Inhibitors and/or Memantine
• Actual Study Start Date: April 2015
• Actual Primary Completion Date: June 1, 2018
• Actual Study Completion Date: June 1, 2018

Arms and Interventions

Arm	Intervention/treatment
Experimental: Azeliragon 5mg; Azeliragon (TTP488) 5mg orally once daily for 18 months	Drug: Azeliragon; Azeliragon 5mg administered orally, once daily for 18 months; Other Name: TTP488
Placebo Comparator: Placebo; Placebo orally once daily for 18 months	Drug: Placebo; Placebo administered orally, once daily for 18 months

Outcome Measures

Primary Outcome Measures :

1. Change From Baseline in Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Total Score [ Time Frame: Baseline and 18 months (A-Study); baseline and 12 months (B-Study) ]
   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.
2. Change From Baseline in Clinical Dementia Rating Scale Sum of Boxes (CDR-sb) [ Time Frame: Baseline and 18 months (A-Study); baseline and 12 months (B-Study) ]
   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.

Secondary Outcome Measures :

1. Change From Baseline in Magnetic Resonance Imaging (MRI) Brain Volumetric Measures [ Time Frame: Baseline and 18 months ]
   Percent of Total Hippocampus Atrophy to Intracranial Volume
2. Change From Baseline in the Normalized Mean Composite SUVR of the 5 Regions [ Time Frame: Baseline to 18 months ]
   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.
3. Change From Baseline in Alzheimer's Disease Cooperative Study- Activities of Daily Living Inventory (ADCS-ADL) [ Time Frame: Baseline and 18 months (A-Study); baseline and 12 months (B-Study) ]
   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.
4. Change From Baseline in Mini-Mental State Examination (MMSE) [ Time Frame: Baseline and 18 months (A-Study); baseline and 12 months (B-Study) ]
   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.
5. Change From Baseline in Neuropsychiatric Inventory (NPI) [ Time Frame: Baseline and 18 months (A-Study); baseline and 12 months (B-Study) ]

   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.

6. Change From Baseline in Dementia Quality of Life (DEMQOL) [ Time Frame: Baseline and 18 months (A-Study); baseline and 12 months (B-Study) ]
   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.
7. Change From Baseline in Continuous Oral Word Association Task (COWAT) [ Time Frame: Baseline and 18 months (A-Study); baseline and 12 months (B-Study) ]
   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.
8. Change From Baseline in Category Fluency Test (CFT) [ Time Frame: Baseline and 18 months (A-Study); baseline and 12 months (B-Study) ]
   Study participants are given one minute to provide exemplars of the category 'animals'.

Eligibility Criteria

• Ages Eligible for Study: 50 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Diagnosis of probable Alzheimer Disease (AD) with documented evidence of progression of disease
• Mini Mental State Examination (MMSE) score of 21-26, inclusive
• Clinical Dementia Rating global score of 0.5 or 1
• Rosen-Modified Hachinski Ischemia Score less than or equal to 4
• Brain magnetic resonance imaging (MRI) consistent with the diagnosis of probable AD
• Concurrent use of cholinesterase inhibitor or memantine with stable dose for at least 3 months prior to randomization
• Caregiver willing to participate and be able to attend clinic visits with patient
• Ability to ingest oral medications

Exclusion Criteria:

• Significant neurological or psychiatric disease other than Alzheimer's disease
• Participants with evidence or history of severe drug allergies (resulting in dyspnea or severe rash).
• Any contraindications to MRI (e.g., clinically significant claustrophobia, non-removable ferromagnetic implants). Patients with contraindications to MRI may undergo computed tomography (CT) on approval by sponsor.
• Any contraindications to the FDG-PET study (e.g. allergy to any component of the FDG dose) in the cohort undergoing a PET scan.
• Previous exposure to investigational or non-investigational therapies for Alzheimer's disease within 6 months of screening
• History of cancer within the last 5 years except adequately treated cervical carcinoma in-situ, cutaneous basal cell or squamous cell cancer, or non-progressive prostate cancer not requiring treatment
• Women of childbearing potential
• Uncontrolled blood pressure and/or blood pressure above 160/100
• Prescription medical food intended for dietary management of the metabolic processes associated with Alzheimer's disease.
• Diagnosis or history of cerebrovascular stroke, severe carotid stenosis, cerebral hemorrhage, intracranial tumor, subarachnoid hemorrhage.
• Patients with unstable, uncontrolled diabetes (HbA1c > 7.7%) and those requiring insulin.

Contacts and Locations

Locations

United States, Arizona

Phoenix, Arizona, United States, 85004

Phoenix, Arizona, United States, 85013

Phoenix, Arizona, United States, 85018

Tucson, Arizona, United States, 85724

Tucson, Arizona, United States, 85741

United States, California

Bellflower, California, United States, 90706

Costa Mesa, California, United States, 92626

Fullerton, California, United States, 92835

Glendale, California, United States, 91206

Imperial, California, United States, 92251

Irvine, California, United States, 92614

Laguna Hills, California, United States, 92653

Long Beach, California, United States, 90806

Long Beach, California, United States, 90807

Orange, California, United States, 92868

Riverside, California, United States, 92506

San Bernardino, California, United States, 92408

San Francisco, California, United States, 94114

Santa Ana, California, United States, 92705

United States, Florida

Atlantis, Florida, United States, 33462

Brooksville, Florida, United States, 34601

Delray Beach, Florida, United States, 33445

Hallandale Beach, Florida, United States, 33009

Hialeah, Florida, United States, 33016

Jacksonville, Florida, United States, 32216

Lake Worth, Florida, United States, 33449

Leesburg, Florida, United States, 34748

Miami Beach, Florida, United States, 33140

Miami Lakes, Florida, United States, 33014

Miami Lakes, Florida, United States, 33016

Miami, Florida, United States, 33122

Miami, Florida, United States, 33137

Orlando, Florida, United States, 32806

Pensacola, Florida, United States, 32503

Sarasota, Florida, United States, 34243

Sunrise, Florida, United States, 33351

United States, Georgia

Atlanta, Georgia, United States, 30331

Columbus, Georgia, United States, 31909

United States, Illinois

Chicago, Illinois, United States, 60640

United States, Kansas

Fairway, Kansas, United States, 66205

Prairie Village, Kansas, United States, 66201

United States, Kentucky

Lexington, Kentucky, United States, 40504

United States, Maryland

Baltimore, Maryland, United States, 21208

United States, Massachusetts

Newton, Massachusetts, United States, 02459

Plymouth, Massachusetts, United States, 02360

Quincy, Massachusetts, United States, 01269

United States, Mississippi

Hattiesburg, Mississippi, United States, 39401

United States, Missouri

Creve Coeur, Missouri, United States, 63141

United States, New Jersey

Princeton, New Jersey, United States, 08540

United States, New Mexico

Albuquerque, New Mexico, United States, 87109

United States, New York

Albany, New York, United States, 12208

Lake Success, New York, United States, 11042

New York, New York, United States, 10032

Staten Island, New York, United States, 10312

United States, North Carolina

Charlotte, North Carolina, United States, 28270

Raleigh, North Carolina, United States, 27607

Wilmington, North Carolina, United States, 28401

Winston-Salem, North Carolina, United States, 27157

United States, Ohio

Canton, Ohio, United States, 44718

Shaker Heights, Ohio, United States, 44122

United States, Oklahoma

Oklahoma City, Oklahoma, United States, 73103

Oklahoma City, Oklahoma, United States, 73118

United States, Oregon

Portland, Oregon, United States, 97210

Portland, Oregon, United States, 97225

United States, Pennsylvania

Media, Pennsylvania, United States, 19063

Norristown, Pennsylvania, United States, 19403

Plains, Pennsylvania, United States, 18705

United States, Rhode Island

East Providence, Rhode Island, United States, 02914

East Providence, Rhode Island, United States, 02916

United States, South Carolina

Charleston, South Carolina, United States, 24901

Mount Pleasant, South Carolina, United States, 29464

United States, Tennessee

Cordova, Tennessee, United States, 38018

Nashville, Tennessee, United States, 37203

United States, Texas

Dallas, Texas, United States, 75231

San Antonio, Texas, United States, 78229

San Antonio, Texas, United States, 78232

Wichita Falls, Texas, United States, 76309

United States, Utah

Murray, Utah, United States, 84123

United States, Washington

Kirkland, Washington, United States, 98201

Richland, Washington, United States, 99352

Australia, Queensland

Southport, Queensland, Australia, 4222

Australia, Victoria

Caulfield, Victoria, Australia, 3162

Geelong, Victoria, Australia, 3220

Heidelberg West, Victoria, Australia, 3081

Australia, Western Australia

Nedlands, Western Australia, Australia, 6009

West Perth, Western Australia, Australia, 6005

Canada, Alberta

Calgary, Alberta, Canada, T2N 4Z6

Medicine Hat, Alberta, Canada, T1B 4E7

Canada, Nova Scotia

Kentville, Nova Scotia, Canada, B4N4K9

Canada, Ontario

Chatham, Ontario, Canada, N7L 1C1

London, Ontario, Canada, N6C 5J1

Toronto, Ontario, Canada, M3B 257

Canada, Quebec

Gatineau, Quebec, Canada, J8T 8J1

Greenfield Park, Quebec, Canada, J4V2J2

Ireland

Cork, Ireland

Dublin 8, Ireland

Galway, Ireland

New Zealand

Christchurch, Canterbury, New Zealand, 8011

Christchurch, Canterbury, New Zealand, 8022

South Africa

Cape Town, South Africa, 7405

Cape Town, South Africa, 7530

Johannesburg, South Africa, 2196

St. George, South Africa, 6529

United Kingdom

Glasgow, United Kingdom, G20 OAXA

London, United Kingdom, W1G 9RU

London, United Kingdom, WC1X 8QD

Manchester, United Kingdom, M8 5RB

Northampton, United Kingdom, NN5 6UD

Oxford, United Kingdom, OX3 7JX

Penarth, United Kingdom, CF64 2XX

Preston, United Kingdom, PR2 9HT

Sheffield, United Kingdom, S5 7JT

Southhampton, United Kingdom, SO30 3JB

Swindon, United Kingdom, SN3 6BW

Warrington, United Kingdom, WA2 8WA

Sponsors and Collaborators

vTv Therapeutics

Investigators

• Study Director: Aaron H Burstein, PharmD; vTv Therapeutics

  Study Documents (Full-Text)

Documents provided by vTv Therapeutics:

Study Protocol  [PDF] November 28, 2017

Statistical Analysis Plan  [PDF] March 23, 2018

More Information

Additional Information:

Related Info 

• Responsible Party: vTv Therapeutics
• ClinicalTrials.gov Identifier: NCT02080364
• Other Study ID Numbers: TTP488-301
• First Posted: March 6, 2014
• Results First Posted: May 7, 2021
• Last Update Posted: May 7, 2021
• Last Verified: May 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by vTv Therapeutics:

Alzheimer's disease; RAGE; ADAS-cog; CDR-sb

Additional relevant MeSH terms:

Alzheimer Disease; Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders