Does Dietary Supplementation With Curcumin Maintain or Improve Physical and Cognitive Function in Aging Adults at Increased Risk for Disability?
Phase: PHASE2
Conditions: Older Adults, Physical Function, Cognitive Function
Sponsor: University of Florida

 
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Protocol 
1. Project Title 
Does dietary supplementation with curcumin maintain or improve physical and cognitive 
function in aging adults at increased risk for disability?  
 
Short Title 
Supporting Physical Independence and Cognition in Elders (SPICE) 
2. Investigator(s) 
Principal Investigator:  
Steve Anton, Ph.D. Department of Aging and Geriatric Research 
 
Co-Principal Investigator 
Robert Mankowski, Ph.D. Department of Aging and Geriatric Research 
 
3. Abstract 
 
Aging is associated with a progressive decline in cognitive and physical function leading to 
a loss of independence.  A growing body of evidence strongly implicates chronic low-grade 
systemic inflammation as having a significant role in contributing to sarcopenia1, functional 
decline2-4, and ultimately disability5. To date, few therapies have been identified to reduce 
chronic systemic inflammation and improve functional performance in seniors. Natural 
compounds represent important and underexplored sources of potential new therapies for 
improving physical function because of their anti-inflammatory properties.  In particular, the 
natural compound, curcumin, has been shown to have potent anti-inflammatory effects in 
recent clinical trials. The effect of these compounds on functional outcomes, particularly in 
older humans (age > 70 years) at risk of functional decline, is not well documented. This 
placebo-controlled RCT tests whether dietary supplementation with curcumin maintains or 
improves cognitive and physical function in older adults who are at high risk of functional decline 
due existing (mild) functional impairments and elevated biomarkers of inflammation and explore 
the association between functional changes and changes in biological indicators of active 
inflammation. 
 
4. Background 
 
a. General Overview. The life expectancy of older Americans continues to increase, with 
persons aged >70 years representing the fastest growing segment of the US population7. While 
prolongation of life remains an important public health goal, of even greater significance is that 
extended life should involve preservation of the capacity to live independently and to function 
well8. Therefore, identification of proven interventions to maintain physical function and prevent 
disability is a major public health challenge9. Mobility and activities of daily living represent tasks 
that are necessary for the maintenance of basic independent functioning10;11. The inability to 
perform these activities marks a serious decline in functional health, conferring increased risk of 
institutionalization and death12;13.  Many older adults are sedentary14;15.  Among this  population, 
many are mobile and free of disability but have elevated levels of pro-inflammatory markers and 
reductions in mobility marked by slower walking speed, which, in turn, is a key predictor of 
further decline and of increased risk of mortality16. These individuals represent the target 
population for the proposed intervention17-19.  

 
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b. Causes of Physical Disability in Older Persons. Although physical disability can be directly 
caused or aggravated by acute events (stroke and hip fracture) and severe chronic conditions 
(heart failure, coronary heart disease)20;21, a large proportion of mobility disability follows a 
progressive course over several years in older persons22.  Specifically, a large and growing 
number of older adults experience progressive declines in physical function culminating in age-
related physical disability with no clear connection to a single disease.  Sarcopenia, the 
progressive loss of muscle mass and strength, has been identified as a common pathway 
associated with initial onset and progression of physical disability among adults with a variety of 
disease conditions23;24. This is noteworthy as recent estimates suggest that sarcopenia is 
present in one quarter of persons aged 65 years or older25;26.  Chronic health conditions, such 
as diabetes and peripheral artery disease, and lifestyle factors, such as poor nutrition and 
physical inactivity, have strong potential to accelerate sarcopenia progression and ultimately 
physical disability23;24. This is particularly important as the number of older adults with chronic 
disease conditions associated with unhealthy lifestyle habits has increased dramatically over the 
past few decades27.   
 
As diverse as the etiologies of physical disability are, a growing body of evidence strongly 
implicates chronic low-grade systemic inflammation as playing a significant role in contributing 
to sarcopenia and associated functional decline.1 In present study, systemic inflammation is 
defined based on elevations in key pro-inflammatory cytokines, specifically plasma C-reactive 
protein (CRP), tumor necrosis factor Alpha (TNF-ά), and particularly interleukin-6 (IL-6). 
Increased levels of systemic inflammation have been shown to be detrimental to skeletal muscle 
in humans28 as well as in animal models29 through direct catabolic effects or through indirect 
mechanisms (i.e., decreases in GH and IGF-1 concentrations, induction of anorexia)24.  Chronic 
low-grade systemic inflammation has been found to be inversely associated with IGF-131, and 
reductions in IGF-1, a main messenger of growth hormone, and is associated with sarcopenia, 
frailty, and mortality in older adults32.  Elevated levels of systemic pro-inflammatory cytokines 
have also been found to be positively associated with cachexia, which suggests inflammation 
may be involved in the process responsible for the anorexia of aging33.   
 
Apoptosis (i.e., programmed cell death) may play a key role in the development of sarcopenia, 
with cell loss occurring in post-mitotic tissues (such as skeletal muscle)34.  An enhanced 
apoptotic process has been shown in several clinical conditions negatively affecting muscle 
mass and function34-37.  A major mechanism leading to cellular apoptosis is promoted by the 
activation of specific signaling pathways, including the death receptor binding of TNF-α38. This 
receptor-mediated pathway promotes the activation of a cascade of caspases (e.g., caspase-8 
activates capsase-3 and -7) leading to the proteolysis and cellular breakdown. Moreover, 
cytokines and reactive oxygen species (ROS) can stimulate cytosolic transcription factor nuclear 
factor-kappa B (NF-kB) to translocate to the nucleus.  Translocation of this protein to the 
nucleus regulates various pro-oxidant enzymes, such as inducible nitric oxide synthase (iNOS), 
cyclooxygenase-2 (COX), vascular cell adhesion molecule-1 (VCAM-1), and intercellular 
adhesion molecule-1 (ICAM-1).  Hence, pro-inflammatory cytokine production in various tissues 
is known to be redox-sensitive and can be activated through an altered redox environment.  
Below, we review the biological mechanisms through which chronic low-grade systemic 
inflammation may contribute to functional decline.  
 
c. Strategies to Reduce Inflammation and Improve Function in Seniors. Few therapies have 
been identified to reduce chronic low-grade systemic inflammation and improve functional 
performance in the elderly.  There are currently no FDA-approved medications for the treatment 
of functional impairment in older adults.  Given the increasing number of older adults with 
elevated levels of systemic inflammation who are at risk for functional decline, new therapies 
are urgently needed to reduce systemic inflammation levels and improve functional ability in 

 
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older adults, particularly among adults 70 years and older. In view of recent evidence from both 
basic and clinical research which identified chronic, low-grade inflammation as the major risk 
factor underpinning many diseases, a better understanding of the mechanisms of both natural 
and pharmaceutical anti-inflammatory agents is essential and beneficial beyond academic 
curiosity. 
 
Natural agents that can modulate the inflammation process have the potential to improve both 
cognitive and physical function through a number of biological pathways.  Long term treatment 
of inflammatory disorders with NSAIDs (non-steroidal anti-inflammatory drugs) has the potential 
of serious side effects such as increased risk of gastrointestinal and cardiovascular disease, 
increased susceptibility to fracture, opportunistic infections, and peptic ulcers. Given the 
increasing use of anti-inflammatory agents among older individuals, studies are needed to 
examine their safety and efficacy.   
 
Some natural compounds, such as curcumin, may have multiple physiological effects due to 
their anti-inflammatory and anti-oxidant properties39;40. These findings are not unexpected given 
that curcumin has been found to activate a wide variety of targets, and produces broad, 
systemic effects that are very similar to caloric restriction, the only method to date that has been 
found to increase healthy lifespan in multiple species. Below we describe studies supporting the 
potential use of both of these compounds.  
 
d. Curcumin. Curcumin is the bioactive polyphenolic extract of Turmeric, which has been used 
to treat inflammatory conditions in India for centuries. Findings over the past few decades 
indicate that curcumin has a broad range of biological properties, including anti-inflammatory 
and anti-oxidative properties, directly relevant to human health. In past clinical trials, doses 
ranging from 1000-2500 mg of curcumin per day have been found to be safe and well 
tolerated41.  The anti-inflammatory role of curcumin is supported by both in vitro and in vivo 
evidence.  For example, curcumin has been found to inhibit TNFα -activated NF- κ B signaling in 
adipocytes; thereby reducing cytokine expression42. Curcumin’s anti-inflammatory effects may 
be due in part to its ability to upregulate expression of peroxisome proliferator-activated receptor 
gamma (PPAR-γ)43.   Small scale pilot trials have found supplementation with low doses of 
curcumin (i.e., 20 mg per day) was effective in reducing plasma fibrinogen levels and 
apolipoprotein B in patients with elevated cardiovascular risk factors44;45. Most recently, 
supplementation with curcumin at a dose of 500 mg per day over an eight week period was 
found to significantly lower CRP levels in patients with rheumatoid arthritis46. 
 
5. Specific Aims: 
 
Overall objectives: 
 
(1) to demonstrate the feasibility, acceptability, and efficacy of the proposed intervention 
in older adults;  
 
(2) to examine the biological effects of the intervention on functional performance and 
inflammatory processes  (Specific Aims); and  
(3) to determine the effect size of intervention on key outcomes for sample size 
calculations for future RCTs. 
Specific Aims: 
  
Specific Aim 1 - To examine the effects of dietary supplementation with curcumin on 
changes in physical function (walking speed, muscle fatigue, and grip strength) and in 

 
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self-reported physical activity  
 
Hypothesis 1 – Dietary supplementation with curcumin will maintain or improve walking 
speed, muscle fatigue, strength, and physical activity compared to controls. 
Specific Aim 2 – To examine the effects of dietary supplementation with curcumin on 
cognitive performance (attention, memory), and pain symptoms. 
 
Hypothesis 2 - Dietary supplementation with curcumin will maintain or improve attention 
and memory and reduce pain symptoms.  
 
Specific Aim 3 – To examine the effects of dietary supplementation with curcumin on 
markers of systemic inflammation  
 
Hypothesis 3 - Dietary supplementation with curcumin will decrease levels of IL-6 and of 
other systemic and cellular biomarkers of inflammation  
 
6. Research Plan 
 
Design 
 
The study will be a randomized, placebo-controlled, repeated measures clinical trial  to examine 
whether supplementation with curcumin is associated with the following outcomes in 24 
moderately functioning older adults (age > 70 years) with elevated levels of inflammation (defined 
as IL-6 > 2.0 pg/mL):  
 
(1) Improvement  in physical function and increase in physical activity,  
(2) Improvement  in cognitive performance, 
(3) Improvement in pain symptoms, and  
(4)  Reductions in systemic inflammatory biomarkers. 
Study Population 
The RCT will include 24 moderately functioning, sedentary adults age 70 years or older with 
elevated levels of systemic inflammation but without overt disease conditions. We estimate that up 
to 324 potential participants will undergo screening procedures to identify 24 persons eligible for 
enrollment in the RCT.   
Based on our previous studies47-49, we anticipate that the average age of participants will be 
approximately 77.0 years, and that approximately 20% will be African Americans.  In general, 
participants will have a relative low prevalence of comorbid diseases. 
 
The key inclusion criteria are the following:  
 
 
(1) Age ≥ 70 years; 
(2) Mild to moderate physical impairment (Short Physical Performance Battery score < 10); 
(3) Sedentary lifestyle (< 120 min per week of moderate intensity physical activity); 
(4) Chronic low-grade inflammation measured by IL-6 >2.5 pg/ml.  To minimize within 
person variability,150, 156 IL-6 is the average of 2 measures taken 1-3 weeks apart at 
screening visits 
 
See Table 1 for a complete list of eligibility criteria. 

 
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Table 1.  Inclusion and Exclusion Criteria 
 
Inclusion Criteria  
• 
Age  
• 
Mild to moderate physical impairment (Short Physical Performance Battery score < 10); 
• 
Sedentary lifestyle (< 120 min per week of moderate intensity physical activity); 
• 
IL-6 > 2.5 pg/mL;  
• 
Willingness and ability to give informed consent 
• 
Willingness to be randomized to the intervention groups 
• 
Availability for participation through duration of study 
 
 
Exclusion Criteria (General) 
• 
Failure or inability to provide informed consent  
• 
Residence in a Skilled Nursing Facility (SNF); residence in an Assisted Living Facility (ALF) or 
independent housing is allowed 
• 
Self-reported inability to walk one block; 
• 
Unable to communicate because of severe hearing loss or speech disorder 
• 
Clinically significant depression (CES-D score > 20) 
• 
Severe cardiac disease, including NYHA Class III or IV congestive heart failure, clinically significant 
aortic stenosis, history of cardiac arrest, use of a cardiac defibrillator, or uncontrolled angina;  
• 
Severe pulmonary disease, pneumonitis or interstitial lung disease; 
• 
Severe rheumatologic or orthopedic diseases (e.g., awaiting joint replacement, active inflammatory 
disease); 
• 
Neurological conditions that cause impaired muscle function or mobility (e.g., Parkinson’s Disease, 
multiple sclerosis, ALS) 
• 
Other significant co-morbid medical disease (e.g. renal failure with eGFR < 24 ml/minute or on 
hemodialysis) or severe psychiatric disorder (e.g. bipolar, schizophrenia);  
• 
Terminal illness with life expectancy less than 12 months, as determined by a physician; 
• 
Excessive alcohol use, defined as more than 5 drinks/day for males or more than 4 drinks/day for 
females, or more than 14 drinks per week; 
• 
Current smoker or less than 3 years smoking cessation 
• 
Participating in another clinical trial or receiving an investigational product within 3 months prior to 
screening/enrollment. 
 
Exclusion Criteria (Curcumin-related) 
• 
Diabetes mellitus currently taking medications to lower blood glucose (oral or by injection) 
• 
Current use of anticoagulant or anti-platelet medications (aspirin 81 mg daily is allowed) 
• 
Congenital or acquired bleeding disorders 
• 
Cholelithiasis or other gall bladder or biliary tract disease 
• 
Chronic gastrointestinal blood loss or iron deficiency (serum ferritin < 12 ng/mL, with or without 
anemia)   
• 
History of estrogen-sensitive conditions including breast, uterine, and ovarian cancers; endometriosis; 
and uterine fibroids  
• 
History of Tuberculosis (TB), HIV, Hepatitis B or C, or other disease potentially compromising immune 
function 

 
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• 
Current use of: 
- 
medications targeting immune or inflammatory function (e.g., sulfasalazine, systemic 
corticosteroids 
- 
anabolic medications (e.g., growth hormone, testosterone)  
- 
monoamine oxidase inhibitors (e.g., phenelzine, selegiline, tranylcypromine) 
- 
anticholinesterase inhibitors (e.g., donepezil, rivastigmine, galantamine 
 
Temporary Exclusion Criteria  
• 
Acute infection (urinary, respiratory, other) or hospitalization within 1 month 
• 
Myocardial infarction, CABG, or valve replacement within past 6 months 
• 
Pulmonary embolism or deep venous thrombosis within past 6 months 
• 
Stroke, hip fracture, hip or knee replacement, or spinal surgery within past 4 months 
• 
Receiving physical therapy for gait, balance, or other lower extremity training 
 
Recruitment and Initial (Telephone) Pre-Screening 
Potential participants will be recruited from the general population in the North/Central Florida 
region through: 
(1) IRB-approved advertisements providing basic information about the study and inviting 
potential participants to call for additional information;  
(2) Contact of potential participants who are enrolled in the Claude D. Pepper Recruitment 
Registry (IRB#417-2007) by Registry staff;  
(3) Contact of potential participants who are enrolled in Community Engagement and 
Research Program – Health Street (IRB #265-2011) by Health Street staff; and  
(4) Contact of participants in previous IOA studies who have given consent for re-contact 
about future studies by Study Coordinators. 
Those who express interest will participate in a telephone pre-screening interview to assure basic 
eligibility criteria are met and exclusion criteria are identified. The interview is designed in a 
manner that does not collect specific PHI and is conducted by an IRB-approved script. Those who 
remain eligible after completing the telephone interview are invited to attend in-person screening 
visit prior to enrollment. 
In-Person Screening (Screening Visits 1 and 2) 
At Screening Visit 1, participants will be asked to give written informed consent for in-person 
screening tests and will then be evaluated for cardiovascular and other major diseases by a health 
review.  The health review consists of a review of criteria in the telephone screen, medical and 
hospital admission history, medication inventory, and physical exam including blood pressure, 
pulse, weight, and waist circumference.  
Short Physical Performance Battery (SPPB) will be performed and the Physical Activity 
Questionnaire will be administered. 
Mini Mental Status Exam (MMSE) and Center for Epidemiological Studies – Depression Scale 
(CES-D) will be administered to identify potential participants with cognitive dysfunction or 

 
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clinically significant depression that would preclude participation.  Participants will also provide a 
blood sample for additional eligibility requirements and participant safety measures. 
Approximately 60 ml of blood will be drawn for laboratory tests to assure eligibility (complete 
metabolic panel, CBC with differential, serum ferritin, and IL-6). 
Results of Screening Visit 1 will be reviewed by the PI or his designee.  .  At this time a copy of the 
Informed Consent document for the main study will be provided, to allow adequate opportunity for 
review and consideration before the baseline visit when consent for the main study is obtained.  
Ineligibles will be contacted by the Study Coordinator for an explanation of ineligibility and will 
receive a copy of abnormal laboratory results. 
Enrollment and Randomization 
24 eligible participants will be enrolled and randomized to allow for 6 participant failures or 
withdrawals  
At the baseline visit, the Informed Consent document for the RCT will be reviewed with the 
potential participant and written consent obtained.  Participants will undergo a battery of physical 
performance tests (400-meter walk; short physical performance battery, grip strength and 
endurance), formal tests of cognitive function, and a blood draw of about 60 ml (See Table 1).  
Quality of Life and pain will be assessed with the AM-PAC, the SF-36, and the Brief Pain 
Inventory (BPI). Self-report of physical activity and dietary fat intake will be obtained through brief 
questionnaires (RAPA and Block High Fat screen). 
Participants will then be randomized to receive either curcumin (1000 mg/day; n = 15) or placebo 
(microcrystalline cellulose; n=15) for a three-month period.  The study drug will be provided for the 
first month according to randomization. 
Participants in both groups will be instructed to return to the research center every month for the 
duration of the three-month trial.  At the monthly visits, compliance with the supplementation 
regimen for the previous month will be assessed by pill count and participants will be provided 
with another month’s supply of study medication according to initial randomization. Participants 
will be queried about any adverse events they experienced since their previous visit and any 
medical history updates they may need to provide.  Additionally, blood samples will be obtained 
(chemistry 15 panel and complete blood count) to ensure that no adverse changes have occurred 
since their previous visit.  
To enhance retention and to ensure participant safety, participants will receive bi-weekly 
telephone calls throughout the intervention period to ascertain adverse events and express 
appreciation for participation.  
Following the three month supplementation period (Month 3 visit), participants will complete a 
post-treatment assessment including the battery of physical performance tests (400-meter walk, 
short physical performance battery, grip strength and endurance); cognitive function tests; 
questionnaires for quality of life, pain symptoms, and physical activity; and a blood draw of 
approximately 60 ml (See Table 2).   
Approximately 3-4 weeks after the Month 3 visit (at Week 15 – 16), participants will receive a final 
telephone call to ascertain any late adverse events, discuss any abnormalities from the final 
safety lab results, and express appreciation for participation.  

 
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Table 2.  Study Visit Schedule 
Visit Type 
Phone screen 
(pre-screening)
Screening visit  1 
 
Baseline visit 
Week 2 
1-Month Visit 
Week 6 
2-Month Visit 
Week 10 
3-Month visit 
Week 15-16 
Basic eligibility screening 
X 
X 
 
  
  
  
  
  
  
  
  
Informed Consent  (Screening) 
  
X 
 
  
  
  
  
  
  
  
  
Health review and physical examination (including BP, 
pulse, weight, height, waist circumference) 
  
X 
 
  
  
  
  
  
  
  
  
Medical History and Concomitant Medication  
  
X 
 
  
  
  
  
  
  
  
  
Update Medical History and Concomitant Medication Info 
  
  
 
X 
  
X 
  
X 
  
X 
  
BP, pulse, height and weight, waist circumference 
  
X 
 
X 
  
X 
  
X 
  
X 
  
MMSE, CES-D 
  
X 
 
  
  
  
  
  
  
  
  
Physical Activity Questionnaire (RAPA) 
  
  
 
X 
  
  
  
  
  
X 
  
SPPB (including 4 m walk test) 
  
X 
 
X 
  
  
  
  
  
X 
  
Phlebotomy 
 
X 
 
X 
 
X 
 
X 
 
X 
 
   IL-6  
  
X 
 
  
  
  
  
  
  
X 
  
   Additional exploratory inflammatory markers (TBD) 
 
 
 
X 
 
 
 
 
 
X 
 
   CBC and Comprehensive Metabolic Panel (CMP) 
(Safety blood tests) 
  
X 
 
X 
  
X 
  
X 
  
X 
  
Informed Consent (Main Study), enrollment, and 
randomization 
  
  
 
X 
  
  
  
  
  
  
  
400 m walk test 
  
  
 
X 
  
  
  
  
  
X 
  
Isokinetic dynamometry of knee flexors and extensors 
  
  
 
X 
  
  
  
  
  
X 
  
Isometric hand grip strength 
  
  
 
X 
  
  
  
  
  
X 
  
Cognitive Function Tests (NIH Toolbox) 
  
  
 
X 
  
  
  
  
  
X 
  
Quality of Life (AM-PAC, SF-36) 
  
  
 
X 
  
  
  
  
  
X 
  
Brief Pain Inventory 
  
  
 
X 
  
  
  
  
  
X 
  
Dietary Fat questionnaire (Block) 
  
  
 
X 
  
  
  
  
  
  
  
Dispense study drug 
  
  
 
X 
  
X 
  
X 
  
  
  
Scheduled phone call 
  
  
 
  
X 
  
X 
  
X 
  
X 
Assess compliance, query adverse effects and events 
  
  
 
  
  
X 
  
X 
  
X X 
 
Dietary Supplement Intervention 
Participants will be given identical capsules containing either: (1) curcumin (1000 mg/day), or (2) 
placebo (microcrystalline cellulose) and will be instructed to consume two 500 mg capsules prior 
to breakfast every morning with a glass of water.  Participants will be instructed to follow this 
dosing regimen throughout the entire three-month treatment period. Compliance with the dosing 
regimen will be monitored both through interview and by counting capsules left at monthly clinic 
visits. 

 
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Curcumin – C3 Complex (Sabinsa Corporation, Piscataway NJ) will be used as the curcumin 
preparation. Each 500 mg capsule of C3 Complex contains 450 mg of curcumin, 40 mg of 
desmethoxycurcumin, and 10 mg of bisdemethoxycurcumin. Based on findings from recent 
studies demonstrating supplementation with curcumin reduced systemic inflammation in middle-
age adults39, the selected dose will be 1000 milligrams per day in 2 divided doses. In safety 
studies, this dosage level has been determined to be safe for human consumption41.   
Placebo – Participants will consume microcrystalline cellulose in capsules identical to C3 
Complex.  There are no active ingredients in the placebo capsules. 
Outcome Measures 
a. Physical Function Measures.  
 400-meter walk test will assess gait speed. Participants will be asked to walk at their usual 
pace, without over-exerting.  They can stop for up to 1 min for fatigue or other symptoms.  
Participants will be allowed to use a cane, but not a walker, to complete this test. The results 
from this test are directly related to whole body aerobic capacity, which has been found to be 
strongly associated (r > 0.70) with mitochondrial function in both younger and older adults54-56.   
Short physical performance battery (SPPB)57will  assess functional performance on different 
tasks including timed short distance walk, repeated chair stands and a balance test. The battery 
will be administered by a trained and certified examiner.   
We will conduct additional tests of isolated muscle function by performing unilateral knee 
extension and flexion maximal strength and endurance testing.  This test involves using an 
isokinetic dynamometer set at 90 degrees per second.  Methods similar to that previously 
described by our group will be used58-61.  We have reported the reliability of strength testing to 
be very high (ICC=0.97; coefficient of variation=4.1%) when the testing sessions are separated 
by 4-weeks62.  Participants will perform 50 maximal knee extension and flexion concentric 
repetitions, which will be administered by trained and certified research assistants.  Maximal 
muscle strength will be summarized as peak torque achieved in Newton-meters.  A muscle 
endurance index will be calculated as the decline in peak torque over the 50 repetitions.  This 
will be calculated as a slope and be used to evaluate the effect of curcumin on muscle 
endurance.  
Grip strength will be measured with a hand-held dynamometer as the average of three readings  
b. Cognitive Function Assessments   
Cognitive tasks.  A valid cognitive battery (NIH Toolbox) will be used in this study to assess 
various aspects of cognitive performance including executive functioning, memory, language, 
and processing speed.  
c. Self-Reported Function and Quality of Life. The Activity Measure for Post-Acute Care (AM-
PAC) will be used to assess participants’ level of perceived functioning. The total score on the 
AM-PAC is an excellent composite measure of disability or difficulty in performing basic and 
instrumental ADLs63;64, especially those related to lower extremity function, and inability to move 
around (mobility limitations) which contribute the most to dependency, need for assistance from 
another person or a device, placement in an assisted care facility or a nursing home. It 
examines a set of functional activities that are likely to be encountered by most adults during 
daily routines during inpatient care, with outpatient post-acute services, or in the community 

 
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setting outside rehabilitation. Because functional activity is multidimensional, AM-PAC assesses 
multiple aspects (i.e., difficulty, assistance, limitations) of an individual's ability to perform 
specific daily activities in three functional areas: Basic Mobility (131 items), Daily Activity (88 
items), and Applied Cognitive (50 items). AM-PAC is administered on a computer using 
software licensed by PAC-Metrix. 
The Medical Outcomes Study Short-Form Health Survey (SF-36) will be used to provide a 
psychometrically valid measure of health-related quality of life (HRQOL)65;66.  The SF-36 
comprises a single multi-item self-report questionnaire that assesses 8 health concepts, yielding 
an overall score and individual scores for the eight subscales.  Subscales assessing limitations 
in physical activities; limitations in usual role activities due to physical problems; bodily pain; 
vitality (energy and fatigue); and general health perceptions are particularly relevant to this 
study.  The SF-36 has been utilized in many studies of HRQOL associated with a variety of 
medical conditions and it has often been used to measure changes in HRQOL associated with a 
variety of treatment interventions67-69.  
e. Pain Assessments. The Brief Pain Inventory (BPI)70 will be used to assess the presence and 
location of daily pains, as well as pain severity and pain-related interference.  The BPI 
measures pain severity using a series of 0 (no pain) to 10 (worst possible pain) scales, which 
assess average pain, worst pain, and least pain in the past week, as well as current pain at the 
time of testing. There are seven BPI interference questions, each ranging from 0 (does not 
interfere) to 10 (completely interferes), assessing the extent to which pain has interfered over 
the past 24 hours with general activity, mood, walking ability, normal work, relations with other 
people, sleep, and enjoyment of life.  This instrument has been validated for assessing 
outcomes in participants with non-cancer pain and has been used to quantify treatment 
outcomes.   
f. Systemic Inflammatory biomarkers. Standard inflammatory biomarkers (i.e., IL-6, TNFa, and 
novel markers of inflammation) will be measured by ELISA at Baseline and the 3-month visit. All 
samples will be measured in duplicate and the average of the two measures will be used for 
data analyses.  
g. Other measures  
Dietary Fat (Block) questionnaire. Poor absorption of curcumin has been reported for various 
preparations, with enhanced absorption in high fat diets. This brief (13 item) “fat screen” 
identifies individuals with “high” fat intake, a potential confounder due to enhanced curcumin 
absorption.71. 
Self-reported physical activity.  The Rapid Assessment of Physical Activity (RAPA) is a 9-item 
questionnaire developed to assess strength, flexibility, and level and intensity of physical activity 
among older adults72. 
Safety.  As a safety check to ensure no adverse biological changes have occurred, the following 
measures will be completed at screening, baseline, and each monthly visit: 
• 
Study Coordinator will review any changes in medication, ED visits or hospitalizations, 
or side effects since previous visit with the participant 
 
• 
At monthly visits, 30 cc of blood will be drawn and analyzed for a CHEM-15 metabolic 
profile (Albumin, Albumin/Globulin Ratio (calculated), Alkaline Phosphatase, ALT, AST, 

 
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BUN/Creatinine Ratio (calculated), Calcium, Carbon Dioxide, Chloride, Creatinine with 
GFR Estimated, Globulin (calculated), Glucose, Potassium, Sodium, Total Bilirubin, 
Total Protein, Urea Nitrogen) as well as for a complete blood count (WBC, RBC, 
Hemoglobin, Hematocrit, MCV, MCH, MCHC, RDW, Platelet Count, MPV and 
Differential (Absolute and Percent - Neutrophils, Lymphocytes, Monocytes, Eosinophils, 
and Basophils). 
Statistical Analyses   
Sample size estimates for pilot studies are inherently difficult because by intent, a pilot study is 
meant to include a smaller sample than a fully powered study. The enrollment sample of 15 
participants in the intervention group and 15 participants in the placebo group (allowing for at 
least 12 evaluable participants in each group after the expected 20% loss due to attrition) is 
intended to provide sufficient data to indicate feasibility of a larger study and to provide 
descriptive estimates of effects.  Additionally, it will provide for nominal estimation (using a 95% 
confidence interval) of the mean changes in the inflammatory marker, IL-6, the primary outcome 
of this pilot.  
Feasibility and acceptability of the proposed intervention in older adults will be evaluated by 
process variables including number of participants completing the study; medication 
compliance, number and severity of adverse events, and changes in Quality of Life attributable 
to study participation.  
Efficacy will be assessed as effects of the intervention on functional performance (physical and 
cognitive measures; pain perception, and inflammatory processes (Specific Aims). The following 
outcomes will be evaluated: physical function (walking speed, muscle fatigue); cognitive function 
(attention, executive, and memory function); pain (self-report); and systemic inflammation (IL-6, 
CRP, TNFα, and novel markers) 
For each outcome, we will take the value of that outcome after the 3-month supplementation 
period minus the value at baseline for each participant. Summary statistics and 95% confidence 
intervals will be provided for within group changes as well as between group differences.  
Effect size of intervention on key outcomes for sample size calculations in the planning of a 
larger RCT Based on a sample size of 15 per group and 20% attrition, we have 80% power to 
detect a between group difference of effect size 1.2. Specifically, if we use the root mean 
squared error from LIFE-P (adjusted for baseline log(IL-6) and treatment) of 0.52 for log(IL-6), 
then we can detect a mean difference of 0.62 (on the log scale) or equivalently the difference 
between 4.20 and 2.26 pg/ml (or a 46% difference). And for selection based on walking speed 
change, we used a within group standard deviation of 0.25, which leads to a detectable mean 
difference of 0.3 m/s. 
Compensation 
Participants enrolled in the main study (RCT) will receive compensation of $50 for completion of 
the Baseline and 3-month visits, and $25 for the 1- and 2-month visits. Thus the maximum 
compensation for completing the main study is $150.  Compensation will be provided at the 
completion of each visit. 
Data Safety and Monitoring 

 
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Study Monitor:  The study physician will serve as a Study Monitor to review all laboratory 
results, abnormal test scores (MMSE and CESD), and adverse events for individual 
participants.  
Data Safety and Monitoring Board (DSMB):  This project is funded as a Pilot Study through the 
UF Claude D. Pepper Older Americans Independence Center (OAIC) grant (NIH P24 
AG028740 ) and thus uses the OAIC Data Safety Monitoring Board (DSMB).  
The DSMB is an established board which has reviewed all studies conducted within the UF 
OAIC during for the past seven years. This board meets semi-annually.  Membership comprises 
(1) Stephen Kritchevsky, Ph.D., Chair, an epidemiologist who has been involved in research for 
many years; (2) Jing Cheng, Ph.D., a biostatistician who has been involved with many clinical 
trials; and (3) John Meuleman, M.D., a physician who has been involved in the conduct of 
clinical research for many years.  DSMB Reports will be provided to the UF IRB-01 with annual 
Continuing Review submissions. 
7.  Possible Discomforts and Risks: 
General Approach.   
All assessment visits will be conducted at a central location fully equipped with a semi-
automated ECG and defibrillator. 
All sessions are conducted by research staff trained to monitor potential adverse experiences 
and symptoms during the testing sessions.  All personnel associated with the study have 
completed Basic Life Support (BLS) training and education on management of acute events 
including syncope, chest pain, acute dyspnea, focal neurological symptoms and abnormal vital 
signs. Contact numbers for emergency services are posted, and community EMS services will 
be activated if needed.   
Participants will be instructed to talk with the investigators about any discomforts that occur 
during the study.  If a participant reports an injury, chest pain, leg swelling, excessive shortness 
of breath, palpitations, or dizziness, he/she will be referred to medical attention (his/her doctor, 
or Emergency Department).  
All research staff complete protection of human research subjects training required by the 
University of Florida institutional review board (IRB) and National Institutes of Health (NIH).  
This training includes education about the importance of maintaining confidentiality of personal 
health information.   
Specific Potential Risks.  Potential risks for this study are related to the following: (1) use of 
study product, (2) blood draw procedure, (3) blood pressure measurement procedure, (4) 
testing for depression and cognitive function; (5) the physical performance tests, and (6) 
potential loss of confidentiality related to study participation 
1.  Risks associated with curcumin.  Curcumin and chemically-related “curcuminoids” are 
bioactive polyphenolic compounds extracted from turmeric.  These compounds are used in large 
amounts in Eastern cooking (e.g., curry), as dietary supplements, and to treat inflammatory 
conditions in India for centuries. Findings over the past few decades indicate that curcumin has a 
broad range of biological properties, including anti-inflammatory and anti-oxidative properties, 

 
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directly relevant to human health. In recent clinical trials, doses ranging from 1000-2500 mg of 
curcumin per day have been found to be safe and well tolerated.41 
C3 Complex (Sabinsa Corporation, Piscataway NJ) was chosen for this study due to 
reproducibility of the curcuminoid content and the curcumin dose.  and is currently commercially 
available as a neutraceutical “bio-protectant.” 
Potential disease or drug interactions with curcumin have been suggested in animal studies and 
human case reports; however, the clinical implications of these findings are largely unknown73. 
• 
Curcumin may reduce levels of blood glucose and glycosylated hemoglobin (HbA1c), 
possibly through a PPAR-γ mechanism43.  Persons currently taking medication to lower 
blood glucose are excluded from participation. 
• 
Turmeric has been reported to have antiplatelet effects, so that concurrent use of 
curcumin with anticoagulants or antiplatelet drugs could theoretically increase the risk of 
bleeding.  Persons with bleeding disorders or persons taking anticoagulant medications or 
antiplatelet agents (other than aspirin 81 mg daily) are excluded from participation.  
Participants taking low dose aspirin are monitored for increased bruising or bleeding and 
study medication is discontinued should this occur. 
• 
Turmeric has been reported to cause gall bladder contractions.  Persons with cholelithiasis 
or other gall bladder or biliary tract disease are excluded from participation. 
• 
Curcumin may chelate iron and reduce its absorption. Serum ferritin will be checked at 
screening. Persons with chronic gastrointestinal blood loss or iron deficiency (serum 
ferritin < 12 ng/mL, with or without anemia) are excluded from participation 
• 
In vitro evidence suggests that curcumin can competitively inhibit binding of 3H-estradiol 
or β-galactosidase to estrogen receptors and thus, theoretically, may have mild estrogenic 
effects.  Persons with a history of estrogen-sensitive conditions including breast, uterine, 
and ovarian cancers; endometriosis, and uterine fibroids are excluded from participation. 
• 
In vitro and animal studies suggest that curcumin may suppress cytochrome P450 1A1 
(CYP1A1), cytochrome P450 1A2 (CYP1A2) cytochrome P450 3A4 (CYP3A4), so 
theoretically curcumin could increase levels of drugs metabolized by these enzymes.  
These interactions have not been reported in humans.  However, persons taking MAO 
inhibitors or cholinesterase inhibitors are excluded from participation. 
Specific information on side effects observed in clinical trials is limited due to the small size of 
most studies, the patient populations (ages and diseases studied), different doses and 
composition of curcumin, and the efficacy focus of the clinical research.  The most commonly 
reported side effects include upset stomach, nausea, dizziness, and diarrhea.  In a recently 
published multi-center clinical trial comparing ibuprofen to curcumin extract in the treatment of 
osteoarthriti74, curcumin extract was associated with fewer adverse events than ibuprofen in all 
complaints except loose stools, although differences were statistically significant only for 
abdominal pain/distension (see Table 3 below). 
Table 3. Adverse 
Events 
 
Ibuprofen 
1200 mg 
(n = 182) 
Curcumin extract 
1500 mg/day 
(n = 187) 
 
 
P-value 

 
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Mean age 60.9 yr  
Mean age 60.3 yr 
Number of patients 
with AE 
 
 
65 (35.7%) 
 
55 (29.7%) 
 
0.222 
Number of events 
 
 
 
Abdominal pain 
and/or distension 
33 (18.1) 
20 (10.8) 
0.046* 
Dyspepsia 
29 (15.9%) 
21 (11.1%) 
0.201 
Nausea 
15 (8.2%) 
9 (4.9%) 
0.091 
Loose stools 
16 (8.8%) 
22 (11.9%) 
0.324 
Melena 
2 (1.1%) 
- 
0.245 
Pitting edema 
13 (7.1%) 
7 (3.8%) 
 
Kuptmiratsakul V et al.  Efficacy and safety of Curcuma domestica extracts compared with 
ibuprofen in patients with knee osteoarthritis:  a multicenter study.  Clinical Interventions in 
Aging 2014:9 451-458 (Reference 74) 
 
Monitoring for Adverse Events (AEs).  An Adverse Event (AE) is any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with a study intervention that may or may not be related to the intervention.   At 
monthly study visits, participants will be queried about specific AEs as above and instructed to 
report any additional adverse effects they experience related to the study coordinator or other 
member of the investigative team. Basic blood chemistry and CBC from each visit will be 
reviewed by the Safety Monitor (study physician).   
 
Grading scales found in the National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 (http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-
06-14_QuickReference_8.5x11.pdf ) will be utilized for AE reporting. All AEs will be reviewed by 
the Safety Monitor (study physician) upon ascertainment. 
  
• 
Grade 1 adverse events are mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated 
 
• 
Grade 2 adverse events are moderate; minimal, local, or noninvasive intervention 
indicated; limit age-appropriate instrumental ADLs (preparing meals, shopping for 
groceries or clothes, using the telephone, managing money, etc.) 
 
• 
Grade 3 adverse events are severe or medically significant but not immediately life 
threatening; hospitalization or prolongation of hospitalization indicated disabling or limit 
self-care ADLs (bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden) 
 
• 
Grade 4 adverse events have life-threatening consequences, urgent intervention 
indicated 
 
• 
Grade 5 adverse event are fatal, resulting in death. 
 

 
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Common Terminology Criteria for Adverse Events (CTCAE) (Version 4.0) are defined for 
gastrointestinal side effects reported with curcumin in Appendix A. 
 
Study medication will be stopped for the following reasons: 
 
• 
Moderate to severe adverse effect symptoms limiting participant continuation in the 
study (Grade 3 or 4 toxicity) 
• 
Elevation in liver function tests to 2x upper limits of normal or increase in serum 
creatinine to 1.5x baseline value 
• 
Decrease in hemoglobin of > 1 g/dL from previous visit  
• 
Development of medical problems listed as exclusion criteria 
• 
Need for medications listed as exclusion criteria 
 
As curcumin is well-tolerated, no Grade 3 or 4 toxicities are expected and no dose modifications 
are planned for this study. 
 
This study will have a Safety Monitor (study physician) for continuous monitoring of individual 
participant results, and aggregate data will be reviewed semiannually by the Claude D. Pepper 
OAIC DSMB (see above). 
2.  Risks associated with blood draw.  Risks include discomfort with the puncture and the 
possibility of a small bruise at the puncture site.  To avoid these risks, research staff are trained 
in proper phlebotomy techniques  
3.  Risks associated with blood pressure measurement.  The risks of placing a blood pressure 
cuff on a participant’s arms are that it may cause pinching or slight bruising. To avoid this risk, 
research staff are trained in procedures for measuring blood pressure 
4.  Risks associated with cognitive function tests. Participants may experience fatigue and 
feelings of frustration while completing the cognitive function tests. Participation also includes a 
risk of loss of confidentiality of personal health information. To minimize these risks, research 
staff are trained in the conduct of the cognitive function tests and certified by Dr. Anton or his 
designee before they work with study participants.  
6.  Risks associated with physical performance tests.  The 400-meter test may be associated 
with the risk of falling or development of chest discomfort due to coronary ischemia or dyspnea 
due to heart failure or lung disease.  Rarely, falling during the 400-meter walk test may result in 
a fracture.  Similar to the six-minute walk test, completion of the SPPB may be associated with 
the risk of falling or development of chest discomfort due to coronary ischemia or dyspnea due 
to heart failure or lung disease. Rarely, falling during the SPPB test may result in a fracture.  
To minimize these risks, research staff are trained in the conduct of all physical performance 
tests and certified by Dr. Anton or his designee before they work with study participants.  Study 
staff are instructed not to perform these tests if they feel that testing is unsafe for an individual 
participant or if the participant is concerned about safety.  If safety concerns are identified by 
either the study staff or the participant during the testing procedures, testing is halted and the 
participant is not allowed to complete the test. In either case, the participant is assessed to 
determine the need for medical intervention and the cause for concern is evaluated. All study 
staff are trained in activating the emergency response system at The University of Florida 
facility.   

 
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7.  Risks associated with questionnaire administration.  Sensitive information collected for this 
study includes lifestyle factors (e.g., alcohol use) and personal health information (PHI) and are 
used predominantly in screening for eligibility and safety. Participation includes a risk of loss of 
confidentiality of this information. 
To minimize risk, questionnaire data are collected in secure spaces where the interview cannot 
be overheard. Participants are reminded that they can decline to answer questions that are 
uncomfortable or concerning.  All research staff members complete annual HIPPA for 
Researchers training as required by UF.  
Collected data are maintained in locked computer files and file cabinets to which only study 
investigators have access.  Only study investigators and key research staff (i.e. data manager 
and study programmers) have access to the study forms or database.  Participants are 
assigned a unique study identifier; individual names will be removed from the study database 
and only the unique study identifier used to distinguish participants in the database.  Collected 
data will be used only for research purposes, and publications will not contain any individual 
identifiers. 
8. Possible Benefits: 
Benefit to study participants.  This study offers possible benefit to some participants (those 
receiving curcumin). Curcumin is categorized as “possibly effective” in improving symptoms of 
osteoarthritis by the Natural Medicines Comprehensive Database (NMCD)73.  While preliminary 
clinical research suggests efficacy for other medical conditions (including Alzheimer’s disease, 
type 2 diabetes mellitus, inflammatory bowel disease, and rheumatoid arthritis), NMCD 
considers “insufficient reliable evidence to rate” efficacy in these conditions. 
Public health implications.  Older participants with functional impairment are less likely to remain 
independent in the community, have higher rates of hospitalization, and have poorer quality of 
life than those without functional impairment.  Thus simple effective interventions to improve 
functional capabilities or mitigate functional decline have important potential impact in public 
health and medical economics.  
9. Conflict of Interest:  None 
 
 
 

 
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http://naturaldatabase.therapeuticresearch.com/nd/Search.aspx?cs=CEPDA&s=ND&pt=
100&id=662&ds=&name=Curcumin+(TURMERIC)&searchid=52904596 
 
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Appendix A:  Common Terminology Criteria for Adverse Events (CTCAE) (Version 4.0) for 
gastrointestinal side effects reported with curcumin 
 
Common Terminology Criteria for Adverse Events (CTCAE) (Version 4.0) 
Gastrointestinal Disorders relevant to Curcumin 
 
Grade 
AE 
1 
2 
3 
4 
5 
Abdominal 
distension: A 
disorder 
characterized by 
swelling of the 
abdomen 
Asymptomatic; 
clinical or 
diagnostic 
observations 
only; 
intervention not 
indicated 
Symptomatic; 
limiting 
instrumental 
ADLs 
Severe 
discomfort; 
limiting self-
care ADLs 
 
 
Abdominal pain:  A 
disorder 
characterized by  a 
sensation of marked 
discomfort in the 
abdominal region 
Mild pain 
Moderate 
pain; limiting 
instrumental 
ADLs 
Severe pain; 
limiting self-
care ADLs 
 
 
Bloating:  A disorder 
characterized by 
subject-reported 
feeling of 
uncomfortable 
fullness of the 
abdomen 
 
No change in 
bowel function 
or oral intake 
Symptomatic; 
decreased 
oral intake; 
change in 
bowel function 
 
 
 
Diarrhea:  A disorder 
characterized by 
frequent and watery 
bowel movements 
Increase of < 4 
stools per day 
over baseline; 
mild increase 
in ostomy 
output 
compared to 
baseline 
Increase of 4 - 
6 stools per 
day over 
baseline; 
moderate 
increase in 
ostomy output 
compared to 
baseline 
Increase of > 
7 stools per 
day over 
baseline; 
incontinence; 
hospitalization 
indicated; 
severe 
increase in 
ostomy output 
compared to 
baseline; 
limiting self-
care ADLs 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
 
Dyspepsia:  A 
disorder 
characterized by an 
uncomfortable, often 
painful feeling in the 
stomach, resulting 
from impaired 
digestion.  
Symptoms include 
burning stomach, 
bloating, heartburn, 
nausea and vomiting 
Mild 
symptoms, 
intervention not 
indicated 
Moderate 
symptoms; 
medical 
intervention 
indicated 
Severe 
symptoms; 
surgical 
intervention 
indicated 
 
 

 
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Common Terminology Criteria for Adverse Events (CTCAE) (Version 4.0) 
Gastrointestinal Disorders relevant to Curcumin (Cont.) 
 
 
AE 
Grade 
1 
2 
3 
4 
5 
Flatulence:  A 
disorder 
characterized by 
excessive gas in the 
alimentary canal. 
Mild 
symptoms, 
intervention not 
indicated 
Moderate 
symptoms; 
psychosocial 
sequelae 
 
 
 
Gastroesophageal 
reflux disease:  A 
disorder 
characterized by 
reflux of the gastric 
and/or duodenal 
contents into the 
distal esophagus.  It 
is chronic in nature 
and usually caused 
by incompetence of 
the lower 
esophageal 
sphincter and may 
result in injury to the 
esophageal mucosa.  
Symptoms include 
heartburn and acid 
indigestion. 
Mild 
symptoms, 
intervention not 
indicated 
Moderate 
symptoms; 
medical 
intervention 
indicated 
Severe 
symptoms; 
surgical 
intervention 
indicated 
 
 
Gastrointestinal 
pain:  A disorder 
characterized by a 
sensation of marked 
discomfort in the 
gastrointestinal 
region. 
Mild pain 
Moderate 
pain; limiting 
instrumental 
ADLs 
Severe pain; 
limiting self-
care ADLs 
 
 
Nausea: A disorder 
characterized by a 
queasy sensation 
and/or the urge to 
vomit. 
Loss of 
appetite 
without 
alteration in 
eating habits 
Oral intake 
decreased 
without 
significant 
weight loss, 
dehydration, 
or malnutrition 
Inadequate 
oral caloric or 
fluid  intake; 
tube feeding, 
TPN, or  
hospitalization 
indicated  
 
 
Stomach pain:  A 
disorder 
characterized by a 
sensation of marked 
discomfort in the 
stomach 
Mild pain 
Moderate 
pain; limiting 
instrumental 
ADLs 
Severe pain; 
limiting self-
care ADLs 
 
 
Vomiting:  A 
disorder 
characterized by the 
1 – 2 episodes 
(separated by 
3 – 5 
episodes 
(separated by 
> 6 episodes 
(separated by 
5 minutes) in 
Life-threatening 
consequences; 
urgent 
Death 

 
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reflexive act of 
ejecting the contents 
of the stomach 
through the mouth 
5 minutes) in 
24 hours 
5 minutes) in 
24 hours 
24 hours; tube 
feeding, TPN, 
or  
hospitalization 
indicated 
intervention 
indicated 
Gastrointestinal 
disorders – Other, 
specify 
Asymptomatic 
or mild 
symptoms; 
clinical or 
diagnostic 
observations 
only; 
intervention not 
indicated 
Moderate; 
minimal, local 
or noninvasive 
intervention 
indicated; 
limiting age-
appropriate 
instrumental 
ADLs  
Severe or 
medically 
significant but 
not 
immediately 
life 
threatening; 
hospitalization 
or 
prolongation of 
existing 
hospitalization 
indicated; 
disabling; 
limiting self-
care ADLs 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death