The Effect of Exercise and Alagebrium on the Diastolic Function of the Heart

NCT ID: NCT01014572

Last Updated: 2020-08-07

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 62 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-07-31
• Study Completion Date: 2013-12-31

Brief Summary

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.

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.

Conditions

Ventricular Function

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Aerobic Exercise Training + Placebo

Group Type: EXPERIMENTAL

Aerobic Exercise Training

Intervention Type: BEHAVIORAL

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.

Tai Chi and/or Yoga Training + Placebo

Group Type: EXPERIMENTAL

Tai Chi and/or Yoga Training

Intervention Type: BEHAVIORAL

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.

Aerobic Exercise Training + Alagebrium

Group Type: EXPERIMENTAL

Aerobic Exercise Training

Intervention Type: BEHAVIORAL

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.

Alagebrium (generic: ALT-711)

Intervention Type: DRUG

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.

Tai Chi and/or Yoga Training + Alagebrium

Group Type: EXPERIMENTAL

Alagebrium (generic: ALT-711)

Intervention Type: DRUG

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.

Tai Chi and/or Yoga Training

Intervention Type: BEHAVIORAL

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.

Interventions

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.

Intervention Type: BEHAVIORAL

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.

Intervention Type: DRUG

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.

Intervention Type: BEHAVIORAL

Eligibility Criteria

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)

• Minimum Eligible Age: 65 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

National Institute on Aging (NIA)

NIH

Sponsor Role: collaborator

University of Texas Southwestern Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Benjamin Levine

Professor of Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Benjamin D Levine, M.D.

Role: PRINCIPAL_INVESTIGATOR

University of Texas Southwestern Medical Center

Locations

The Institute for Exercise and Environmental Medicine

Dallas, Texas, United States

Countries

United States

References

Fujimoto N, Hastings JL, Carrick-Ranson G, Shafer KM, Shibata S, Bhella PS, Abdullah SM, Barkley KW, Adams-Huet B, Boyd KN, Livingston SA, Palmer D, Levine BD. Cardiovascular effects of 1 year of alagebrium and endurance exercise training in healthy older individuals. Circ Heart Fail. 2013 Nov;6(6):1155-64. doi: 10.1161/CIRCHEARTFAILURE.113.000440. Epub 2013 Oct 15.

Reference Type: DERIVED

PMID: 24130005 (View on PubMed)

Other Identifiers

R01AG017479

Identifier Type: NIH

Identifier Source: secondary_id

View Link

IRB#032008-012

Identifier Type: -

Identifier Source: secondary_id

IND72,382

Identifier Type: -

Identifier Source: secondary_id

STU 122010-189

Identifier Type: -

Identifier Source: org_study_id