The Effect of Exercise and Alagebrium on the Diastolic Function of the Heart (AGE)

August 4, 2020 updated by: Benjamin Levine, University of Texas Southwestern Medical Center
The purpose of this study is to determine whether an investigational drug (Alagebrium (generic: ALT-711), a type of medication referred to as an advanced glycaton end-product clever) can be combined with exercise training to reverse the stiffening of the heart that takes place naturally with aging.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Objectives: Chronic physical inactivity contributes to the deaths of nearly 1 in 10 Americans. In seniors, the single most common life-threatening disease is congestive heart failure and for these patients, abnormalities of diastolic function play a critical role in the pathophysiology of their disease. The sponsor's research has demonstrated that healthy but sedentary aging leads to atrophy and stiffening of the heart with reduced myocardial and chamber compliance. In contrast, highly competitive senior runners had cardiac compliance that was indistinguishable from healthy young individuals suggesting that lifelong exercise training prevented this stiffening. However, prolonged and intense exercise training (4-6 hrs/wk for 1 yr) failed to restore cardiac compliance in healthy seniors despite other health benefits.

Why did this year of training fail to restore cardiac compliance? New evidence suggests that the structural plasticity of myocardial cells in the elderly may be functionally constrained by the accumulation of toxic metabolites called advanced glycation end-products (AGEs). AGEs are arrays of protein which have been non-enzymatically cross-linked by sugars; these arrays increase the stiffness of arterial walls and the myocardium. Investigators have recently developed a drug capable of cleaving AGE cross-links. Termed ALT-711, this drug has been shown to be safe in human studies with varying degrees of efficacy on endpoints such as blood pressure and non-invasive indices of diastolic function. Based on animal studies, we hypothesize that AGE cross-links must be broken before a meaningful improvement in cardiac compliance can occur with exercise training in sedentary seniors.

Hypothesis: We hypothesize that AGE cross-links must be broken before a meaningful improvement in cardiac compliance can occur with exercise training in previously sedentary seniors; the combination of the AGE cross-link breaker, ALT-711, with exercise training will be superior to either intervention alone in improving cardiac compliance in these subjects.

Specific Aim: To test this hypothesis, we will study four groups of previously sedentary senior subjects for one year with the following interventions: A) sedentary controls taking placebo; B) sedentary subjects taking ALT-711; C) subjects undergoing moderate intensity exercise training while taking placebo and D) subjects undergoing moderate intensity exercise training while taking ALT-711.

A comprehensive set of "Baseline Testing" (prior to the one year intervention) and "Follow-up Testing" (after the one year intervention) will take place to assess the effects of the intervention. This testing will include submaximal and maximal exercise testing as well as comprehensive invasive (right heart catheterization) and non-invasive (ultrasound, MRI) measures of cardiac mechanics, relaxation and morphology. From these data, the following indices of diastolic and systolic function will be generated: Starling and pressure/volume curves; calculations of LV wall stress and strain; and measurements of flow propagation velocity, ejection fraction and relaxation velocity.

In assessing the risk benefit ratio for our study, the major benefits include: 1) obtaining meaningful information for society regarding the effects of ALT-711 and moderate intensity exercise training on the compliance of the left ventricular chamber; 2) obtaining important information for the subject regarding ambulatory blood pressure, exercise performance, cardiac morphology and cardiac function; and 3) providing the subject one year of supervised moderate intensity exercise training or yoga training, each with associated health benefits. The risks of the study are primarily imposed by the dosing of our investigational drug, which has a favorable side effect profile, and the placement of a peripherally inserted right heart catheter, which carries minimal risk when placed by an experienced cardiovascular specialist in a catheterization lab. Hence, in the final analysis, we feel the benefits to both the enrolled individual and to society far outweigh the risks of participation.

Study Type

Interventional

Enrollment (Actual)

62

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Texas
      • Dallas, Texas, United States, 75231
        • The Institute for Exercise and Environmental Medicine

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

65 years to 80 years (Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Healthy senior status (age > 64)
  • Body mass index < 30
  • Sedentary status (not exercising > 2/wk)

Exclusion Criteria:

  • Hypertension
  • Diabetes
  • Heart Failure
  • Asthma
  • Chronic obstructive pulmonary disease
  • Coronary artery disease (as evidenced by angina or prior myocardial infarction)
  • Cerebrovascular disease (as evidenced by prior transient ischemic attack or stroke)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Aerobic Exercise Training + Placebo
Behavioral: Aerobic Exercise Training
Aerobic exercise training consisting of exercise of choice (walking, eliptical machine, stairstepper, stationary bike, etc.) 4 times per week for 40 minutes at a base pace, and two higher intensity steady state sessions per month.
Experimental: Tai Chi and/or Yoga Training + Placebo
Behavioral: Tai Chi and/or Yoga Training
Tai Chi or Yoga training includes a series of exercises that improve flexibility, balance and coordination. Training will be supervised by trained instructors. This training will occur 3 times per week.
Experimental: Aerobic Exercise Training + Alagebrium
Behavioral: Aerobic Exercise Training
Aerobic exercise training consisting of exercise of choice (walking, eliptical machine, stairstepper, stationary bike, etc.) 4 times per week for 40 minutes at a base pace, and two higher intensity steady state sessions per month.
Drug: Alagebrium (generic: ALT-711)
The dosage of our drug, ALT-711, will be one 100 mg caplet by mouth twice per day for 12 months. Total dose per day 200 mg.
Experimental: Tai Chi and/or Yoga Training + Alagebrium
Behavioral: Tai Chi and/or Yoga Training
Tai Chi or Yoga training includes a series of exercises that improve flexibility, balance and coordination. Training will be supervised by trained instructors. This training will occur 3 times per week.
Drug: Alagebrium (generic: ALT-711)
The dosage of our drug, ALT-711, will be one 100 mg caplet by mouth twice per day for 12 months. Total dose per day 200 mg.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Left ventricular compliance and distensibility.
Time Frame: One year after enrollment in the study.
One year after enrollment in the study.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Texas Southwestern Medical Center

Collaborators

National Institute on Aging (NIA)

Investigators

  • Principal Investigator: Benjamin D Levine, M.D., University of Texas Southwestern Medical Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

July 1, 2008

Primary Completion (Actual)

June 1, 2012

Study Completion (Actual)

December 1, 2013

Study Registration Dates

First Submitted

November 13, 2009

First Submitted That Met QC Criteria

November 16, 2009

First Posted (Estimate)

November 17, 2009

Study Record Updates

Last Update Posted (Actual)

August 7, 2020

Last Update Submitted That Met QC Criteria

August 4, 2020

Last Verified

August 1, 2020

More Information

Terms related to this study

Keywords

Other Study ID Numbers

  • STU 122010-189
  • R01AG017479 (NIH)
  • IRB#032008-012
  • IND72,382

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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