The ENRGISE (ENabling Reduction of Low-Grade Inflammation in SEniors) Pilot Study

Phase 2

Completed

Conditions: Inflammation

Interventions: Dietary Supplement: Omega-3 fish oil
Other: Corn Oil (Fish oil Placebo)
Other: Cellulose Based (Losartan Placebo)
Drug: Losartan

Registration Number: NCT02676466

Lead Sponsor: University of Florida

Brief Summary: ENRGISE Pilot Study will test the ability of anti-inflammatory interventions for preventing major mobility disability by improving or preserving walking ability.

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 289

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Fish oil Active	Omega-3 fish oil	This group will receive the Omega-3 fish oil which will be administered at a dose of 1.4 grams per day for the first six months. Based on tolerability and inflammation level, dose may either continue at 1.4 grams per day or be increased to 2.8 grams per day for the remaining six month.
Fish oil Placebo	Corn Oil (Fish oil Placebo)	This group will receive a placebo which will be matching to the Omega-3 fish oil. The placebo corn oil are obtained in gel caps and they have identical shape, color, taste and weight. The doses will be administered at doses corresponding to the Omega-3 fish oil.
Losartan Placebo	Cellulose Based (Losartan Placebo)	This group will receive a placebo which will be matching to the losartan. The placebo cellulose based capsule are obtained in 25 mg and 50 mg capsules. The shell capsules are cellulose based. Placebo and LO have identical shape, color, taste and weight. the doses will be administered at doses corresponding to the losartan.
Fish oil Active + Losartan Active	Omega-3 fish oil	This group will receive both the Losartan and Omega-3 fish oil. Losartan will be administered at a starting dose of 25 milligrams per day. Based on tolerability, losartan will continue at a dose of either 25 milligrams per day or 50 milligrams per day for the first six months. Based on continued tolerability and inflammation level, dose may either continue at 25 or 50 milligrams per day or be increased to 100 milligrams per day for the remaining six months. Omega-3 fish oil will be administered at a dose of 1.4 grams per day for the first six months. Based on tolerability and inflammation level, dose may either continue at 1.4 grams per day or be increased to 2.8 grams per day for the remaining six month.
Fish oil Active + Losartan Placebo	Omega-3 fish oil	This group will receive the Omega-3 fish oil which will be administered at a dose of 1.4 grams per day for the first six months. Based on tolerability and inflammation level, dose may either continue at 1.4 grams per day or be increased to 2.8 grams per day for the remaining six month. In addition, this group will receive a placebo which will be matching to the losartan. The placebo cellulose based capsule are obtained in 25 mg and 50 mg capsules. The shell capsules are cellulose based. Placebo and LO have identical shape, color, taste and weight. the doses will be administered at doses corresponding to the losartan.
Fish oil Active + Losartan Placebo	Cellulose Based (Losartan Placebo)	This group will receive the Omega-3 fish oil which will be administered at a dose of 1.4 grams per day for the first six months. Based on tolerability and inflammation level, dose may either continue at 1.4 grams per day or be increased to 2.8 grams per day for the remaining six month. In addition, this group will receive a placebo which will be matching to the losartan. The placebo cellulose based capsule are obtained in 25 mg and 50 mg capsules. The shell capsules are cellulose based. Placebo and LO have identical shape, color, taste and weight. the doses will be administered at doses corresponding to the losartan.
Fish oil Placebo + Losartan Active	Corn Oil (Fish oil Placebo)	This group will receive a placebo which will be matching to the Omega-3 fish oil. The placebo corn oil are obtained in gel caps and they have identical shape, color, taste and weight. The doses will be administered at doses corresponding to the Omega-3 fish oil. In addition, this group will receive the Losartan which will be administered at a starting dose of 25 milligrams per day. Based on tolerability, losartan will continue at a dose of either 25 milligrams per day or 50 milligrams per day for the first six months. Based on continued tolerability and inflammation level, dose may either continue at 25 or 50 milligrams per day or be increased to 100 milligrams per day for the remaining six months.
Fish oil Placebo + Losartan Placebo	Corn Oil (Fish oil Placebo)	This group will receive a placebo which will be matching to both the omega-3 fish oil and losartan which will be administered at doses corresponding to doses administered for omega-3 fish oil and losartan throughout the 12 month study.
Fish oil Placebo + Losartan Placebo	Cellulose Based (Losartan Placebo)	This group will receive a placebo which will be matching to both the omega-3 fish oil and losartan which will be administered at doses corresponding to doses administered for omega-3 fish oil and losartan throughout the 12 month study.
Losartan Active	Losartan	This group will receive the Losartan which will be administered at a starting dose of 25 milligrams per day. Based on tolerability, losartan will continue at a dose of either 25 milligrams per day or 50 milligrams per day for the first six months. Based on continued tolerability and inflammation level, dose may either continue at 25 or 50 milligrams per day or be increased to 100 milligrams per day for the remaining six months.
Fish oil Active + Losartan Active	Losartan	This group will receive both the Losartan and Omega-3 fish oil. Losartan will be administered at a starting dose of 25 milligrams per day. Based on tolerability, losartan will continue at a dose of either 25 milligrams per day or 50 milligrams per day for the first six months. Based on continued tolerability and inflammation level, dose may either continue at 25 or 50 milligrams per day or be increased to 100 milligrams per day for the remaining six months. Omega-3 fish oil will be administered at a dose of 1.4 grams per day for the first six months. Based on tolerability and inflammation level, dose may either continue at 1.4 grams per day or be increased to 2.8 grams per day for the remaining six month.
Fish oil Placebo + Losartan Active	Losartan	This group will receive a placebo which will be matching to the Omega-3 fish oil. The placebo corn oil are obtained in gel caps and they have identical shape, color, taste and weight. The doses will be administered at doses corresponding to the Omega-3 fish oil. In addition, this group will receive the Losartan which will be administered at a starting dose of 25 milligrams per day. Based on tolerability, losartan will continue at a dose of either 25 milligrams per day or 50 milligrams per day for the first six months. Based on continued tolerability and inflammation level, dose may either continue at 25 or 50 milligrams per day or be increased to 100 milligrams per day for the remaining six months.

Primary Outcome Measures

Name	Time	Method
Changes in the Interleukin-6 Level Between Groups	Changes from baseline to month 12	Changes in the Interleukin-6 Level Between the Groups
Number of Participants Experiencing Major Mobility Disability	12 months	The 400 meter walk test at usual pace is used to evaluate major mobility disability (MMD), defined as the inability to walk ¼ mile or 400 meters.

Secondary Outcome Measures

Name	Time	Method
Short Physical Performance Battery (SPPB)	12 months	A low score on the SPPB based on 4 m walk, balance \& chair stands tests is a risk factor for disability, institutionalization, morbidity and mortality in initially non-disabled older persons. The summary score and components of the SPPB have good reliability (ICCs range from 0.88 to 0.92). Higher scores are better. Range 0-12.
Number of Participants Exhibiting Frailty	12 months	Frailty will be characterized with Fried criteria developed by Fried et al. that employ self-reported exhaustion, unintentional weight loss, low energy expenditure, slow gait speed, and weak grip strength. Those with \>3 of the 5 factors are judged to be frail, those with 1 or 2 factors as pre-frail, and those with no factors as non-frail.
Isometric Hand Grip Strength	12 months	The purpose of this test is to measure the maximum isometric strength of the hand and forearm muscles. Scoring will be taken from the best results of 3 trials. Males scores range from 88 pounds as very poor to 141 pounds as excellent with an average of 105-113 pounds. Females scores range from 44 pounds as very poor to 84 pounds as excellent with an average of 57-65 pounds.
Peak Torque of the Knee Extensor and Flexor Muscles	month 12	Peak torque was measured at a rotational speed of 60 degrees per second using a commercially-available Isokinetic Dynamometer (Biodex). Torque was measured during maximal knee extension and flexion reported in Newton Meters.
Short Form Health Survey (SF-36) - Physical Component Score	month 12	The Short Form (36) Health Survey is a 36-item, patient-reported survey of patient health. The SF-36 consists of eight scaled scores, which are the weighted sums of the questions in their section. Range: 0-100. A lower score indicates more disability, i.e., a score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability.

Trial Locations

Locations (5): Wake Forest University
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Winston-Salem, North Carolina, United States
University of Florida
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Gainesville, Florida, United States
Northwestern University
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Chicago, Illinois, United States
Tufts University
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Boston, Massachusetts, United States
University of Pittsburgh
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Pittsburgh, Pennsylvania, United States