δ in Dementia Clinical Trials (δND)

Novel Methods for Clinical Trials in Dementia and Cognitive Decline

The goal of this clinical trial is to demonstrate potential improvements in clinical trial methods relating to dementia and cognitive decline. The main questions it aims to answer are:

• Can an intervention's outcome be better assessed by a latent variable ("δ") integrating cognitive performance with functional status?
• Can latent biomarkers of δ guide the selection of an intervention that will modulate dementia severity?
• Can a latent variable, derived from information collected remotely from caregivers, preselect subjects most likely to respond to the intervention?
• Is the effect of the intervention in fact medicated by changes in the targeted biomarker?

In this case, the biomarker will be a latent variable derived from several proteins measured in blood (i.e., so-called "adipokines"). The intervention will be donepezil, a medication approved for the treatment of Alzheimer's Disease, but only recently associated with adipokine changes.

Participants with cognitive impairment and their caregivers will be interviewed by telephone and those with cognitive impairment will be treated for six-months with donepezil. On the basis of the caregiver's report, the cognitively impaired subjects will be assigned to two groups based on a prediction of their response to donepezil. Researchers will compare those groups to see if dementia severity, as measured by δ, improves in predicted responders, and whether the change in the d-score is mediated by changes in adipokines.

Study Overview

• Status: Not yet recruiting
• Conditions: Dementia; Alzheimer's Disease (AD); Cognitive Decline; Mild Cognitivie Impairment (MCI)
• Intervention / Treatment: Drug: Donepezil

Detailed Description

Title: "Novel Methods for Clinical rials in Dementia and Cognitive Decline"

Study Description: This is a double-blind assignment open label clinical trial to test novel approaches to clinical trial methods. 1) The study team will pre-select cases most likely to benefit from adipokine modulation by a telephone assessment. 2) The study team will pre-select subjects with clinical and preclinical dementia most likely to respond to therapy. 3) The study team will test the drug donepezil's effect on dementia severity, in predicted responders and non-responders, as measured by a latent dementia phenotype "δ' and 4) test a latent Adipokines biomarker construct as a mediator of their association in the predicted responders.

Objectives:

Primary Objective: To test novel clinical trial methods relevant to dementia.

Secondary Objectives:

1. To test donepezil's effect on dementia severity as measured by δ.
2. To test Adipokines as a mediator of donepezil's effect on δ.

Endpoints: Primary Endpoint: Dementia severity as measured by the latent phenotype "δ" using the "dTEL" homolog.

Secondary Endpoint: Change in Adipokines as a mediator of donepezil's effect on dTEL.

• Study Type: Interventional
• Enrollment (Estimated): 200
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Amy Saklad; Phone Number: 210 567-8229; Email: SAKLADA@uthscsa.edu

Study Locations

• United States
  • Texas
    • San Antonio, Texas, United States, 78229-3900
      • Univeristy of Texas Health Science Center at San Antonio (UTHSCSA)
      • Contact: Marsha J. Polk, MS; Phone Number: 210 450-8403; Email: polk@uthscsa.edu
      • Contact: Amy Saklad; Phone Number: 210-567-8229; Email: SAKLADA@uthscsa.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 63 years to 98 years (Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Ambulatory outpatient volunteers with competent informants. Competent informants are cognitively normal individual(s) who interacts with the person on a regular (at least 5 or more hours/week) basis and in the opinion of the PI can provide adequate collateral information on the participant's memory and cognitive status.
• Aged 65-100 years
• Clinical diagnosis of AD, or MCI. In Lieu of clinical diagnosis, the subject may proceed upon PI's review of cognitive testing done at pre-screening and baseline and their confirmation that the subject's scores are consistent with Mild Cognitive Impairment or Alzheimer's
• Capacity to give informed consent. If a patient is found to clinically decline during the course of the study and no longer able to provide consent, continued participation will be evaluated by the PI on a case-by-case basis.
• Geriatric Depression Scale (GDS) (15 item) score ≤ 6
• No significant visual or hearing impairments
• A standardized dECog score between 0.0 and -1.0 relative to ADNI's cohort
• Assignment to "Group 1" by a LOI assessment of Adipokine adjusted v. unadjusted dECog scores.

Exclusion Criteria:

• A current self-reported diagnosis of "Major Depression" (treatment with "antidepressants" not exclusionary);
• A history of psychosis, including visual hallucinations;
• History or treatment for Parkinson's, or tremor, or Rapid Eye Movement (REM) behavior disorder;
• History or treatment for atrial fibrillation;
• History of bradycardia or syncopal events;
• Chronic diarrhea, h/o colonic resection or irritable bowel syndrome;
• Treatment for cancer in the last 5 years (excluding skin cancers);
• Major surgery in the last year;
• Treatment with anti-convulsants, mood stabilizers, neuroleptics, opiates, muscle relaxants, or systemic steroids.
• Current treatment with any AChEI or past treatment within the last year.
• Co-current treatment with any pharmacological intervention for dementia administered as either on or off label. Non-pharmacological interventions (e.g. Behavior Therapy) will be evaluated on a case by cases basis by the PI.
• In the opinion of the PI, treatment with AChEI is not appropriate due to a possible negative risk/benefit ratio based on past medical history or endorsement of symptoms during the screening interview.
• Co-participation in another study that the PI feels would pose a safety risk or adversely affect data integrity of this study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Predicted Responders; Group assignment determined by a response predictor algorithm derived from remotely acquired caregiver reports of cognitive performance.	Drug: Donepezil; 6 months of open label treatment at 10mg PO QD (maximum); Other Names: Aricept ®
Active Comparator: Predicted Non-Responders; Group assignment determined by a response predictor algorithm derived from remotely acquired caregiver reports of cognitive performance.	Drug: Donepezil; 6 months of open label treatment at 10mg PO QD (maximum); Other Names: Aricept ®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
dTEL change	Change in a latent dementia-specific phenotype derived from cognitive assessment.	At baseline, and weeks 4, 12 and 24.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ADIPOKINES change	Change in a latent construct derived from eight "Adipokine" proteins measured in blood.	Baseline and week 24.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dementia "Reversion"	The frequency of dementia "reversion" defined as a final dTEL score > -0.40, i.e., the optimal d-score that discriminates subjects with AD from those with MCI in the Alzheimer's Disease Neuroimaging Initiative (ADNI).	Week 24

Collaborators and Investigators

• Sponsor: The University of Texas Health Science Center at San Antonio
• Collaborators: National Institute on Aging (NIA)
• Investigators: Principal Investigator: Donald R. Royall, MD, University of Texas

Study record dates

Study Major Dates

• Study Start (Estimated): March 1, 2024
• Primary Completion (Estimated): November 1, 2028
• Study Completion (Estimated): November 1, 2028

Study Registration Dates

• First Submitted: October 13, 2022
• First Submitted That Met QC Criteria: October 19, 2022
• First Posted (Actual): October 25, 2022

Study Record Updates

• Last Update Posted (Estimated): January 8, 2024
• Last Update Submitted That Met QC Criteria: January 4, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: dementia; cognition; functional status; intelligence; adipokines
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Tauopathies; Cognition Disorders; Dementia; Alzheimer Disease; Cognitive Dysfunction; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Cholinergic Agents; Enzyme Inhibitors; Nootropic Agents; Cholinesterase Inhibitors; Donepezil
• Other Study ID Numbers: HSC20220551H; R01AG080548 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. As such, this trial will be registered at ClinicalTrials.gov, and results information from this trial will be submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-reviewed journals. Data from this study may be requested from other researchers 5 years after the completion of the primary endpoint by contacting royall@uthscsa.edu
• IPD Sharing Time Frame: Data from this study may be requested from other researchers 5 years after the completion of the primary endpoint by contacting royall@uthscsa.edu
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No