The Effect of Exercise and Alagebrium on the Diastolic Function of the Heart
Condition: Ventricular Function
Study type: Interventional
Phase: Phase 2

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.
    

Intervention name(s): Aerobic Exercise Training; Alagebrium (generic: ALT-711); Tai Chi and/or Yoga Training
Intervention type(s): Behavioral; Drug; Behavioral
Intervention description(s): 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.; 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 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.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: Clinical Trials, Phase II; Exercise; Exercise Tolerance; Aging