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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02080364
Recruitment Status : Terminated (Not due to safety but due to a lack of efficacy at the 5 mg azeliragon dose.)
First Posted : March 6, 2014
Results First Posted : May 7, 2021
Last Update Posted : May 7, 2021
Information provided by (Responsible Party):
vTv Therapeutics

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

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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

Resource links provided by the National Library of Medicine

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

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'.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02080364

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Sponsors and Collaborators
vTv Therapeutics
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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

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

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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
Additional relevant MeSH terms:
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Alzheimer Disease
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders