ENRGISE a RCT of anti-inflammatory therapy in older persons Marco - - PowerPoint PPT Presentation

ENRGISE – a RCT of anti-inflammatory therapy in older persons

Marco Pahor, MD University of Florida Institute on Aging

www.aging.ufl.edu

Inflammation & cytokinemia are associated with:

• Alzheimer’s Disease
• Anemia
• Atherosclerosis
• Autoimmune Dis.
• Cancer
• Cerebrovascular Dis.
• Coronary Heart Dis.
• Congestive Heart Fail.
• COPD
• Dementias
• Depression
• Diabetes
• Disability, impaired

physical function

• Frailty
• Gastrointestinal dis.
• Infection
• Obesity, adiposity
• Osteoarthritis
• Osteoporosis
• Periodontal disease
• Renal disease
• Sarcopenia
• Sedentary lifestyle
• Smoking

5 1 1 5 I L 6 I L 6 2 4 6 8 C R P C R P 5 1 1 5 2 2 5 T N F T N F

Mean: 2.40 pg/ml Median: 1.83 IQR: 1.27 – 2.77 Mean: 3.00 mg/L Median: 1.68 IQR: 0.99 – 3.14 Mean: 3.48 pg/ml Median: 3.16 IQR: 2.44 – 4.11

l

Distribution of 3 Inflammatory Markers

HABC - Spearman Correlations Among Markers (N=3037)

Y1,Y2 (n=411) CRP IL-6 TNF Chol Glucose CRP 0.66 0.46 0.12 0.03 0.10 IL-6 0.63 0.27

• 0.12

0.15 TNF 0.41

• 0.03

0.11 Chol 0.72 0.01 Gluc 0.74

2 4 6 8

Years of Follow-Up

0.96 0.97 0.98 0.99 1.00

Quintiles of LDL

2 4 6 8

Years of Follow-Up

0.96 0.97 0.98 0.99 1.00

CVD Event-Free Survival Probability

Quintiles of hsCRP Ridker et al N Engl J Med. 2002;347:1157-1165.

5 4 3 2 1 5 4 3 2 1

Event-Free Survival According to Baseline Quintiles of hs-CRP and LDL Cholesterol

CHD Events (n= 188; RR, 95%CI)

IL-6 in highest tertile 1.71 (1.27-2.29) CRP in highest tertile 1.33 (0.98-1.80) TNF-α in highest tertile 1.67 (1.23-2.26) Current smoking 1.32 (0.98-1.77) Total cholesterol > 240 mg/dl 1.13 (0.76-1.70) LDL cholesterol ≥ 130 mg/dl 1.07 (0.80-1.44) HDL cholesterol ≤ 40 mg/dl 1.19 (0.84-1.70) Hypertension 1.28 (0.95-1.22) Diabetes 1.90 (1.33-2.70) BMI> 30 kg/m2 1.51 (1.10-2.07)

Adjusted for age, gender and race

Cesari et al Circulation 2003; 108:2317

CHD (n=188) Stroke (n=60) CHF (n=92) 1 2 3 4 5 p = 0.02 p = 0.12 p < 0.001

HABC – Inflammation and CVD events

Cesari et al Circulation 2003; 108:2317

RR 1 2 3 4 0.5 Number of markers in the upper tertile 1 2 3

HABC - Inflammatory markers and cognition

Yaffe et al. Neurology 61:76-80, 2003

Buford et al. Ageing Research Reviews 2010

Sarcopenia in the context of the International Classification of Function (ICF) model

Biology

neural transmission, hormones, proteolysis, autophagy, apoptosis, satellite cells, inflammation, oxidative stress, energy production, blood flow

Body (physiological) functions & Body structure

Aging

Disease

metabolic, pulmonary, vascular, immune,

• rgan-specific

Activity limitations

Difficulties in executing tasks

Dynapenia

Loss of muscle strength

Environmental Personal factors

Participation In life situations

Sarcopenia

Muscle atrophy &

intramuscular adipose

↓ Independence ↑ Healthcare cost ↑ Caretaker Stress

Buford et al. Ageing Research Reviews 2010

Inflammation and Prevalence of Frailty in Older Women Enrolled in WHAS

Leng et al. JAGS 55:864–871, 2007

EPESE - IL-6 and 4 year incident mobility disability

0.2 0.4 0.6 0.8 1

• 0.5 0 0.5 1 1.5 2 2.5 3

Ln (IL-6)

Probability 2.5 pg/ml

Adjusted probability 95% CI

n=633

95% CI

Ferrucci et al JAGS 1999;47:639

no yes

incident disability

no yes

incident disability

HABC - Inflammation markers by mobility disability

9 8 7 6 5 4 3 2 1

CRP (mg/L) IL-6 (pg/mL)

7 6 5 4 3 2 1

p<.001 p<.001

Penninx et al JAGS 2004;52:1105

HABC - Inflammation markers by mobility disability

TNF-α (pg/mL) no yes

incident disability

8 7 6 5 4 3 2 1

p<.001

Penninx et al JAGS 2004;52:1105

HABC - Inflammation & incidence of mobility disability

CRP IL-6

tertile incidence RR* 95% CI I 22.2% 1 II 26.9% 1.05 0.88-1.26 III 41.4% 1.40 1.18-1.68 I 19.8% 1 II 30.6% 1.34 1.11-1.62 III 40.2% 1.65 1.37-1.98

TNF-α

I 25.0% 1 II 28.7% 1.09 0.91-1.30 III 36.1% 1.18 0.99-1.41

*adjusted for age, gender, race, education, fat mass, smoking, CVD, COPD, diabetes, cancer, arthritis, NSAIDs, corticosteroids albumin, creatinine, EPESE perf.

Penninx et al JAGS 2004;52:1105

HABC - Composite measure of inflammation and RR of mobility disability

1 2 3

1 2 3

number of high inflammatory markers (upper tertile)

RR

P-trend <.001

Penninx et al JAGS 2004;52:1105

1.5 2 2.5 3

Adjusted Physical Performance Score CRP (mg/dl) IL-6 (pg/dl)

<0.59

* * *

0.59 0.60 >0.60 <0.86 0.86-1.46 1.46-2.28 >2.28

*

InChianti – Inflammation and physical performance in older persons

Cesari et al J Gerontol 2004; 59A:242 p=<0.05 p=<0.05 p=<0.01

Brinkley et al. J Gerontol; 2008;64A:455

Changes in physical function measures per 1 SD increment in log(CRP) and log(IL-6)

ADAPT – Diet, exercise and IL-6

• 0.25
• 0.2
• 0.15
• 0.1
• 0.05

0.05 0.1

Control (n=70) Exercise (n=74) Diet (n=74) Diet+Exe. (n=71)

∆ log IL-6

treatment effect for weight loss (P=0.009) adjusted for age, race, gender, BMI, baseline IL-6

Baseline 6 mo 18 mo

Nicklas et al Am J Clin Nutr 2004;79:544

Nicklas et al. JAGS; 2008;56:2045

LIFE-P – Physical activity and IL-6

Nicklas et al. JAGS; 2008;56:2045

LIFE-P – Physical activity and IL-6 According to SPPB at baseline

Nicklas et al. JAGS; 2008;56:2045

LIFE-P – Physical activity and IL-6 According to IL-6 at baseline

ENabling Reduction of low- Grade Inflammation in Seniors - Pilot Study

Funding: NIA U01AG050499

Abbott grant for study drug – the company has no other involvement with the study

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• Double-blinded, 2x2 factorial randomized pilot trial
• 5 field centers
• Coordinating Center: University of Florida
• Data Management Quality Control: Wake Forest University
• n=300 – follow-up duration 12 months

Florida Northwestern Wake Forest Pittsburgh Tufts ClinicalsTrials.gov NCT02676466

Specific Aims 1

Conduct a pilot RCT in 300 older persons at risk of mobility decline to assess: – Compared with placebo, the effects of losartan, ω-3, and losartan+ω-3 on IL-6 and walking speed; – The recruitment yields, the target population, adherence, retention, tolerability of the interventions – The primary outcome, sample-size, design, and cost for the main trial; – The intra-subject variability of IL-6, – The dosage and safety of the interventions

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Specific Aims 2

Measure novel and established inflammatory markers

• Characterize the effect of losartan and ω-3 on these

biomarkers and determine:

– Are these cytokines/pathways impacted by the interventions? – Are the changes in these markers pre- vs. post-intervention less than, equivalent to, or greater than that of IL-6?

• Assess if these biomarkers yield independent

information from IL-6 with respect to change in walking speed and/or provide benefit for screening participants for the main trial

26

Background

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Genetic & Epigenetic Factors Exogenous Factors

Smoking, Air pollution, Alcohol, Infectious burden, diet*

Endogenous Factors

Adiposity , Subclinical disease burden*, Oxidative stress status*, Innate and adaptive immune response capacity, hypertension

SOURCES MOLECULAR AND BIOCHEMICAL CONSEQUENCES PHYSIOLOGICAL CONSEQUENCES Directly related :

Loss of muscle mass/function: sarcopenia*

MOBILITY LIMITATION and ultimately Major Mobility Disability Directly related:

NF-kB activation & cytokine production*&, loss

• f mitochondrial function*, myocyte

apoptosis*&, loss of muscle regeneration*, proinflammatory lipid signaling*, etc.

Indirectly related:

Chronic diseases*& such as cardiovascular disease, diabetes, osteoporosis, etc

Indirectly related:

Monocyte & platelet activation  atherosclerosis Loss of insulin signaling*  diabetes Increased osteoclast bone resorption  osteoporosis, etc.

* Potential effect of ω-3

& Potential effect of ARB

Figure 5.1. The relation of inflammation to loss of physical function. The three main sources of inflammation in the elderly (genetic and epigenetic

factors, exogenous factors and endogenous factors) combine to cause molecular and biochemical changes with important consequences, which in turn lead to physiological consequences, and ultimately to mobility limitation and mortality. These changes are complex with thousands of genes and

• ther macromolecules involved; some examples of important pathways are listed. The potential impact of the chosen interventions are shown.

Criteria for prioritizing the interventions

1.Safety, tolerability and acceptability are key criteria. Vulnerable older persons use

multiple drugs and have multiple comorbidities, and thus, are at high risk of adverse drug reactions. Newer drugs are often tested in younger or middle age adults for the treatment of a single condition and therefore, their safety and tolerability in older persons is not fully known.73 Furthermore, for the prevention of mobility limitations, vulnerable or frail older persons may not be willing to take, and their providers may not be willing to prescribe drugs that bear a risk of severe adverse events. Finally, we exclude interventions that may negatively affect skeletal muscle or neuromuscular metabolism.

2.Reduction of IL-6 and possibly CRP in clinical trials is our primary criterion.

• 3. Benefit on physical performance and/or skeletal muscle is a relevant, but not

necessary criterion.

4.Innovation. We have prioritized interventions that have not been, or are not being tested in RCTs for

preventing mobility limitations.

5.Biological mechanisms are considered to prioritize interventions that target different

inflammatory mechanisms or may have synergistic effects. We exclude interventions that may negatively affect skeletal muscle metabolism.

6.Practical and affordable for implementation in the US health care system. Cost is a major

factor for this criterion to maximize the public health impact of the trial

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Selection of the Interventions

Criteria Interventions

• 1. Safe,

tolerable, acceptable

• 2. IL-6

redu-ction

• 3. Physical

performance

• 4. Inno-

vation

• 5. Mecha-

nism

• 6. Practical,

affordable

ACEIs, ARBs

+ + + + + +

ω-3

+ + + + + +

Mediterranean diet

+ + + + +

• Physical activity, weight loss

+ + +

• +

+?

Vitamin D

+ + +

• +

+

Anti-TNF-α, -IL6,-IL1; methotrexate thiazolidinediones

• +

? + + ?

Statins, chloroquine, colchicine

• +
• ?

+

• +

Corticosteroids, aspirin, NSAIDs, cox-2 inhibitors

• +

? + + +

Metformin, fosinopril, ghrelin, lactoferrin, oxytocin, salsalate, curcuma, creatine, probiotics, resveratrol

+

• ?
• ?

+ + ? +

+ positive evidence, - negative evidence, ? evidence lacking

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Potential Pharmacological Interventions

• ACEIs and ARBs have shown excellent safety in large

hypertension and heart failure trials in older persons

• ARBs are prioritized over ACEIs due to tolerability
• Losartan is prioritized among ARBs due to low cost

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Potential Nutritional Interventions

• ω-3 and lipoic acid reduce IL-6 and CRP
• ω-3 shows anti-inflammatory effects, improves

walking speed in women, improves strength as a supplement to exercise, and is widely available and affordable in the form of fish oil

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Potential Behavioral Interventions

• Mediterranean diet (MED) reduces IL-6 and CRP

compared to Western diet

• MED is promising, but after consulting experts in the

field, it was determined to be too complex and resource intensive for this pilot study

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Design

• Double-blind, placebo controlled RCT to test

losartan, ω-3, and their combination in a 2 x 2 factorial design

• Recruitment to last 1 year
• Each participant will be followed for 1 year

33

ω-3 Intervention

• ω-3 and placebo

–Start with 1.4g/day (two 0.7g gel caps) fish

• il

–Increase to 2.8g/day after 6 month visit if average IL-6 (measured at 3 and 6 month visit) does not decrease by 40% compared to baseline

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Losartan Intervention

• Losartan and placebo

– Start with 25mg/day, and if tolerated, – Step up to 50mg/day – Increase to 100mg/day if average of IL-6 measured at 3 and 6 month visits does not decrease by 40% compared to baseline

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Main inclusion criteria

• Men and women aged 70 years and older
• Self-reported difficulty walking ¼ mile or climbing a

flight of stairs

• Usual walking speed <1 m/sec, but greater than 0.44

m/sec

• Able to walk 400 m
• IL-6 >2.5 pg/ml and <10 pg/ml

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Outcomes

• Primary Outcomes

– IL-6 – Walking speed during 400 m walk test

• Secondary outcomes

– SPPB – Frailty – Grip strength – Isokinetic knee extension strength – Inability to walk 400m (planned primary outcome for the main trial) – Biomarkers of inflammation

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Innovation

• Targeting chronic low grade inflammation to achieve reduced

inflammation and reduced mobility limitations

• Targeting an older population at high risk of mobility disability,

which is often excluded from large RCTs

• Repurposing widely available inexpensive interventions

(losartan and ω-3)

• Testing losartan and ω-3 in combination to maximize their

effects on inflammation and mobility

• The use of several adaptive features in design and stratified

screening

• The assessment of novel inflammatory markers

38

The ENRGISE Pilot Study will provide preliminary data to design a definitive clinical trial to assess whether the reduction of chronic low-grade inflammation may prevent of major mobility disability

39