The ENRGISE (ENabling Reduction of Low-Grade Inflammation... | NCT02676466

ID	Type	Description	Link
U01AG050499	U.S. NIH Grant/Contract		View source

Name	Class
National Institute on Aging (NIA)	NIH
Abbott	INDUSTRY

Description Module

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.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Fish oil Active	Experimental	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.	Dietary Supplement: Omega-3 fish oil
Fish oil Placebo	Placebo Comparator	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.	Other: Corn Oil (Fish oil Placebo)
Losartan Active	Active Comparator	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.	Drug: Losartan
Losartan Placebo	Placebo Comparator	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.

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Omega-3 fish oil	Dietary Supplement	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.

Measure	Description	Time Frame
Changes in the Interleukin-6 Level Between Groups	Changes in the Interleukin-6 Level Between the Groups	Changes from baseline to month 12
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

Measure	Description	Time Frame
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

Eligibility Module

Eligibility Criteria

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

Name	Affiliation	Role
Marco Pahor, MD	University of Florida	Principal Investigator
Walter Ambrosius, PhD	Wake Forest University	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
University of Florida		Gainesville	Florida	32611	United States
Northwestern University

PubMed Identifier	Type	Citation	Retractions
28734043	Background	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.
30541065

Arm/Group Information

ID	Title	Description
FG000	Fish Oil Active	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. 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.
FG001	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. 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.
FG002	Losartan Active	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. 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.
FG003	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. Cellulose Based (Losartan Placebo): The placebo cellulose based capsules will be identical in shape, color, taste and weight as the losartan capsules.
FG004	Fish Oil Active + Losartan Active	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 months.
FG005	Fish Oil Active + 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.
FG006	Fish Oil Placebo + Losartan Active	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.
FG007	Fish Oil Placebo + 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.

Baseline Characteristics Module

Arm/Group Information

ID	Title	Description
BG000	Fish Oil Active	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. 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.

Units	Counts
Participants	BG000

Baseline Measures

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Categorical			Count of Participants

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Fish Oil Active	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. 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.

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot_SAP	Yes	Yes	No	Study Protocol and Statistical Analysis Plan	Oct 18, 2016	Jun 6, 2019	Prot_SAP_000.pdf
ICF	No	No	Yes	Informed Consent Form	Jan 6, 2017	Apr 15, 2024	ICF_001.pdf

ID	Term
D010335	Pathologic Processes
D013568	Pathological Conditions, Signs and Symptoms

ID	Term
D009821	Oils
D008055	Lipids
D001713	Biphenyl Compounds
D001555	Benzene Derivatives