The ENRGISE Pilot Study

Growing evidence shows that low-grade chronic inflammation, characterized by elevations in
plasma C-reactive protein, tumor necrosis factor alpha, and particularly Interleukin-6
(IL-6), is an independent risk factor of disability, impaired mobility, and lower walking
speed. Low-grade chronic inflammation is a modifiable risk factor. However, it is unknown
whether interventions that reduce the levels of inflammatory markers per se improve mobility,
or avert decline in mobility in older persons.

To address this gap in evidence the investigators are conducting the randomized clinical
trial ENRGISE (ENabling Reduction of low-Grade Inflammation in SEniors) Pilot Study to test
the ability of anti-inflammatory interventions for preventing major mobility disability by
improving or preserving walking ability. We have maximized the public health impact by
selecting interventions that are safe, tolerable, acceptable, and affordable for vulnerable
older persons. Specifically, in this trial the investigators test the efficacy verus placebo
of the angiotensin receptor blocker losartan and omega-3 polyunsaturated fatty acids in the
form of fish oil, alone and in combination. Both angiotensin receptor blockers and omega-3
polyunsaturated fatty acids have shown to reduce IL-6 in clinical trials and preliminary data
suggest that they may improve physical function.

Recruitment will include the older persons who are at risk for, or with, mobility impairment,
as measured by slow gait speed and self-reported mobility difficulty, and who have elevated
levels of IL-6, the marker most consistently associated with mobility limitations.
Preliminary data regarding feasibility need to be gathered before such a trial can be
effectively designed and implemented. We conduct The ENRGISE Pilot Study to assess the
effects of the interventions on several inflammatory markers, walking speed, physical
function and strength. This allows us to refine the design, recruitment yields, target
population, adherence, retention, tolerability, sample-size, and cost for the main ENRGISE
trial.

Inclusion Criteria:

- Men and women age >70 years

- Self-reported difficulty walking ¼ of a mile or climbing a flight of stairs

- Walking speed <1 meters per second and >0.44 meters per second on the 4 meter walk at
usual pace. A walking speed of <0.44 meters per second would not be compatible with
completing the 400 meter walk in 15 minutes. (In the pilot phase we explore the
feasibility of recruiting at least 50% of participants who have a baseline walking
speed of <0.80 meters per second and >0.44 meters per second)

- Able to complete the 400 meter walk test within 15 minutes without sitting or the help
of another person and without a walker, a cane is allowed

- Blood level IL-6 >2.5 pg/ml and <30 pg/ml.

- Willingness to be randomized to the intervention groups

Exclusion Criteria:

- Failure or inability to provide informed consent

- Lives in a nursing home; persons living in assisted or independent housing are not
excluded

- Self-reported inability to walk one block

- Significant cognitive impairment, defined as a known diagnosis of dementia, or a
Mini-Mental State Exam (MMSE) score <24 (<23 for racial/ethnic minorities or
participants with less than 9 years of education)

- Unable to communicate because of severe hearing loss or speech disorder

- Neurological conditions that are causing impaired muscle function or mobility (may
include stroke with residual paresis, paralysis, neuropathy, Parkinson disease, or
multiple sclerosis)

- Severe rheumatologic or orthopedic diseases, e.g., awaiting joint replacement, known
active inflammatory or autoimmune disease (e.g. rheumatoid arthritis, lupus, Crohn's
disease, HIV)

- Terminal illness with life expectancy less than 12 months

- Severe pulmonary disease, requiring either steroid pills or injections

- Other significant co-morbid disease that in the opinion of the field center PI would
impair ability to participate in the trial, e.g. renal failure on hemodialysis, severe
psychiatric disorder (e.g. bipolar, schizophrenia), excessive alcohol use (>14 drinks
per week); drug addiction; treatment for cancer (radiation or chemotherapy) within the
past 1 year; or other conditions

- Lives outside of the study site or is planning to move out of the area in next 1 year
or leave the area for >3 months during the next year

- Exclusion criteria that apply only to those who receive losartan:

- Intolerance or allergy to Angiotensin II Receptor Blockers (ARBs)

- Known bilateral renal artery stenosis or liver cirrhosis

- Hypotension Systolic Blood Pressure<110 or Diastolic Blood Pressure<60 mmHg

- Serum potassium ≥5.0 mEq/L

- Use of lithium salts

- eGFR <15

- Congestive heart failure with ejection fraction < 40%

- Exclusion criteria that apply only to those who receive ω-3:

- Intolerance or allergy to ω-3 or fish/shellfish

- Fatty fish intake >2 servings per week on average

- History of paroxysmal or persistent atrial fibrillation

- To maintain blinding, those who are not eligible to receive any active treatment (ω-3
or losartan) are excluded

Temporary exclusion criteria

- Myocardial infarction, coronary artery bypass grafting (CABG), or valve replacement
within past 6 months;

- Pulmonary embolism or deep venous thrombosis within past 6 months;

- Uncontrolled diabetes with recent weight loss, diabetic coma, or frequent insulin
reactions;

- Stroke, hip fracture, hip or knee replacement, or spinal surgery within past 4 months;

- Physical therapy for gait, balance, or other lower extremity training within the past
2 months;

- Severe hypertension, e.g., Systolic Blood Pressure > 200, or Diastolic Blood Pressure>
110 mmHg;

- Hemoglobin <10 g/dL

- Participation in another intervention trial within 3 months; participation in an
observational study may be permitted;

- Current smoking (within 6 months),

- Acute infection (urinary, respiratory, other) or hospitalization within 1 month

- Exclusion criteria that apply only to those who receive losartan:

- Use of Angiotensin-Converting Enzyme Inhibitor (ACEI), Angiotensin II Receptor
Blocker (ARB) within 2 months

- Use of aliskiren within 2 months in patients with type 2 diabetes or renal
impairment with Estimated Glomerular Filtration Rate (eGFR)<60

- Use of potassium sparing diuretics, other medications with potassium sparing
properties (such as but not limited to spironolactone or eplerenone) potassium
supplements, and salt substitutes containing potassium within 1 week

- Transaminases >twice upper limit of normal to exclude participants with impaired
liver function

- Exclusion criteria that apply only to those who receive ω-3:

- Use of ω-3 within 2 months