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

Inflammation Clinical Trial

— ENRGISE  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02676466
• Other study ID #: IRB201500894 - A-N
• Secondary ID: U01AG050499
• Status: Completed
• Phase: Phase 2
• Start date: April 26, 2016
• Est. completion date: June 22, 2018

Study information

• Verified date: December 2019
• Source: University of Florida
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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 information / eligibility

• Status: Completed
• Enrollment: 289
• Est. completion date: June 22, 2018
• Est. primary completion date: June 22, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 70 Years and older

Eligibility

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 ?-3:

• Intolerance or allergy to ?-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 (?-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 ?-3:

• Use of ?-3 within 2 months

Related Conditions & MeSH terms

• Inflammation

Intervention

Dietary Supplement:
• Omega-3 fish oil
The Omega-3 fish oil will be provided in 700 mg gelcaps. The starting dose will be 1.4 g/day of fish oil and continue until the 6 month visit. If the average of IL-6 measured at 3- and 6-month visits does not decrease by >40% vs. baseline (average of screening visits 1 and 2), we increase the dose to 2.8 g/day.

Drug:
• Losartan
The Losartan will be provided in 25 mg and 50 mg capsules. The starting dose will be 25 mg/day, if tolerated, then stepped up to 50 mg/day. If there are no safety concerns, a continuation of 50 mg/day will be provided until the 6 month visit. If the average of IL-6 measured at 3- and 6-month visits does not decrease by >40% vs. baseline (average of screening visits 1 and 2), an increase to the dose of 100 mg/day.

Other:
• Corn Oil (Fish oil Placebo)
The corn oil placebo gel caps will be identical in shape, color, taste and weight as the Omega-3 fish oil.
• Cellulose Based (Losartan Placebo)
The placebo cellulose based capsules will be identical in shape, color, taste and weight as the losartan capsules.

Locations

Country	Name	City	State
United States	Tufts University	Boston	Massachusetts
United States	Northwestern University	Chicago	Illinois
United States	University of Florida	Gainesville	Florida
United States	University of Pittsburgh	Pittsburgh	Pennsylvania
United States	Wake Forest University	Winston-Salem	North Carolina

Sponsors (3)

Lead Sponsor	Collaborator
University of Florida	Abbott, National Institute on Aging (NIA)

Country where clinical trial is conducted

United States, 

References & Publications (1)

Manini TM, Anton SD, Beavers DP, Cauley JA, Espeland MA, Fielding RA, Kritchevsky SB, Leeuwenburgh C, Lewis KH, Liu C, McDermott MM, Miller ME, Tracy RP, Walston JD, Radziszewska B, Lu J, Stowe C, Wu S, Newman AB, Ambrosius WT, Pahor M; ENRGISE Pilot study investigators. ENabling Reduction of Low-grade Inflammation in SEniors Pilot Study: Concept, Rationale, and Design. J Am Geriatr Soc. 2017 Sep;65(9):1961-1968. doi: 10.1111/jgs.14965. Epub 2017 Jul 22. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Changes in the Interleukin-6 Level Between Groups	Changes in the Interleukin-6 Level Between the Groups	Changes from baseline to month 12
Primary	Number of Participants Experiencing Major Mobility Disability	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.	12 months
Secondary	Short Physical Performance Battery (SPPB)	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.	12 months
Secondary	Number of Participants Exhibiting Frailty	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.	12 months
Secondary	Isometric Hand Grip Strength	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.	12 months
Secondary	Peak Torque of the Knee Extensor and Flexor Muscles	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.	month 12
Secondary	Short Form Health Survey (SF-36) - Physical Component Score	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.	month 12