Clinical trial NCT02676466: The ENRGISE (ENabling Reduction of Low-Grade Inflammation in SEniors) Pilot Study
Official title: The ENRGISE (ENabling Reduction of Low-Grade Inflammation in SEniors) Pilot Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Inflammation
Keywords: Mobility
Lead sponsor: University of Florida
Sponsor class: OTHER
Collaborators: name: National Institute on Aging (NIA)
name: Abbott
First posted: 2016-02-08
Enrollment: 289
Sex: ALL
Minimum age (years): 70
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

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

Primary outcomes:
measure: Changes in the Interleukin-6 Level Between Groups
timeFrame: Changes from baseline to month 12
measure: Number of Participants Experiencing Major Mobility Disability
timeFrame: 12 months
Secondary outcomes:
measure: Short Physical Performance Battery (SPPB)
timeFrame: 12 months
measure: Number of Participants Exhibiting Frailty
timeFrame: 12 months
measure: Isometric Hand Grip Strength
timeFrame: 12 months
measure: Peak Torque of the Knee Extensor and Flexor Muscles
timeFrame: month 12
measure: Short Form Health Survey (SF-36) - Physical Component Score
timeFrame: month 12
Other outcomes:
Locations:
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Boston
country: United States
facility: Tufts University
state: Massachusetts
city: Winston-Salem
country: United States
facility: Wake Forest University
state: North Carolina
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
Study officials:
affiliation: University of Florida
name: Marco Pahor, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Wake Forest University
name: Walter Ambrosius, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: Pahor M, Anton SD, Beavers DP, Cauley JA, Fielding RA, Kritchevsky SB, Leeuwenburgh C, Lewis KH, Liu CK, Lovato LC, Lu J, Manini TM, McDermott MM, Miller ME, Newman AB, Radziszewska B, Stowe CL, Tracy RP, Walkup MP, Wu SS, Ambrosius WT. Effect of Losartan and Fish Oil on Plasma IL-6 and Mobility in Older Persons. The ENRGISE Pilot Randomized Clinical Trial. J Gerontol A Biol Sci Med Sci. 2019 Sep 15;74(10):1612-1619. doi: 10.1093/gerona/gly277.