Curcumin and Yoga Therapy for Those at Risk for Alzheimer's Disease

• ClinicalTrials.gov Identifier: NCT01811381
• Recruitment Status: Unknown
• First Posted: March 14, 2013
• Last Update Posted: September 17, 2020
• Sponsor: VA Office of Research and Development
• Information provided by (Responsible Party): VA Office of Research and Development

Tracking Information

• First Submitted Date: February 11, 2013
• First Posted Date: March 14, 2013
• Last Update Posted Date: September 17, 2020
• Actual Study Start Date: January 20, 2014
• Actual Primary Completion Date: March 16, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 17, 2016)

Curcumin effects (first six month period) or curcumin and aerobic yoga effects (second six month period) on the changes in the levels of blood biomarkers for Mild Cognitive Impairment relative to baseline or relative to placebo or non-aerobic yoga. [ Time Frame: 0, 6, and 12 months ]

Blood samples at baseline & follow-ups are collected & analyzed for changes in biomarkers associated with MCI and/or curcumin: Clusterin, C-reactive protein, N-terminal prohormone of brain natriuretic peptide, Apolipoprotein E, beta-amyloid, vascular cell adhesion molecule protein-1, Brain derived neurotrophic factor, Interleukin-6, Interleukin-1 beta, Interleukin 1 receptor accessory protein-like 2, Tumor necrosis factor alpha, Osteopontin. The investigators will test whether supplements and/or exercise type are associated with a decrease in the biomarkers thought to be associated with MCI

Original Primary Outcome Measures (submitted: March 12, 2013)

Curcumin effects (first six month period) or curcumin and aerobic yoga effects (second six month period) on the changes in the levels of blood biomarkers for Mild Cognitive Impairment relative to baseline or relative to placebo or non-aerobic yoga. [ Time Frame: 0 , 6 and 12 months ]

Blood samples at baseline and in follow-up will be collected and analyzed for changes in biomarkers either associated MCI and/or curcumin: Clusterin, C-reactive protein, N-terminal prohormone of brain natriuretic peptide, Apolipoprotein E, beta-amyloid, vascular cell adhesion molecule protein-1, Brain derived neurotrophic factor, Interleukin-6, Interleukin-1 beta, Interleukin 1 receptor accessory protein-like 2, Tumor necrosis factor alpha, Osteopontin. We will test whether supplements are associated with a decrease in the biomarkers thought to be associated with MCI (blood biomarker levels among those receiving supplements vs. placebo (first six month period).We will assess if the combination of curcumin and aerobic exercise significantly changes the levels of biomarkers thought to be associated with MCI (blood biomarker levels among those receiving supplements vs. placebo (with aerobic yoga or with non-aerobic yoga, second six month period).

Current Secondary Outcome Measures (submitted: February 17, 2016)

• Changes in 18F-fluorodeoxyglucose (FDG) Positron Emission Tomography (PET) glucose metabolism neuroimaging after supplementation compared to baseline and compared to placebo [ Time Frame: 0 and 6 months ]
  Functional connectivity multivariate discriminant analysis of neuroimaging changes using 18FDG-PET predicting rapid conversion to Alzheimer will be examined in subjects on supplements compared to those on placebo. Cerebral metabolism of glucose will be assessed for those receiving supplements vs. placebo and vs baseline (first six months).
• Curcumin effects on changes in Neuropsychological parameters compared to baseline and to placebo (first six month period) and in combination with aerobic yoga, compared to baseline and to non-aerobic yoga with curcumin or aerobic yoga with supplement [ Time Frame: 0, 6, 12 months ]
  Cognitive changes shown to precede Alzheimer's will be assessed using a neuropsychological battery. Behavioral symptoms will be assessed with the Neuropsychiatric Inventory Questionnaire (NPI-Q). Instrumental activities of daily living will be assessed with the Functional Activities Questionnaire. Overall assessment of disease severity will be assessed with the Clinical Dementia Rating Scale Sum of Boxes. subjects on supplements compared to those on placebo. Neuropsychiatric parameters will be assessed for those receiving supplements vs baseline or vs placebo or with those performing aerobic yoga with placebo or non aerobic yoga with curcumin (second six month period).
• Number of Participants with Adverse Events [ Time Frame: 0,3,6,9,12 months ]
  The investigators will perform routine comprehensive blood panel test to monitor safety and tolerability of Curcumin in subjects at risk for MCI by means of adverse events, vital signs and safety laboratory assessments. [ Time Frame: is at each timepoint in the study, 3, 6, 9 and 12 months].

Original Secondary Outcome Measures (submitted: March 12, 2013)

• Changes in 18F-fluorodeoxyglucose (FDG) Positron Emission Tomography (PET) glucose metabolism neuroimaging after supplementation compared to baseline and compared to placebo [ Time Frame: 0 and 6 months ]
  Functional connectivity multivariate discriminant analysis of neuroimaging changes using 18FDG-PET predicting rapid conversion to Alzheimer will be examined in subjects on supplements compared to those on placebo. Cerebral metabolism of glucose will be assessed for those receiving supplements vs. placebo and vs baseline (first six months).
• Curcumin effects on changes in Neuropsychological parameters compared to baseline and to placebo (first six month period) and in combination with aerobic yoga, compared to baseline and to non-aerobic yoga with curcumin or aerobic yoga with supplement [ Time Frame: 0, 6, 12 months ]
  Cognitive changes shown to precede Alzheimer's will be assessed using a neuropsychological battery. Behavioral symptoms will be assessed with the Neuropsychiatric Inventory Questionnaire (NPI-Q). Instrumental activities of daily living will be assessed with the Functional Activities Questionnaire. Overall assessment of disease severity will be assessed with the Clinical Dementia Rating Scale Sum of Boxes. subjects on supplements compared to those on placebo. Neuropsychiatric parameters will be assessed for those receiving supplements vs baseline or vs placebo or with those performing aerobic yoga with placebo or non aerobic yoga with curcumin (second six month period).

• Current Other Pre-specified Outcome Measures: Not Provided

Original Other Pre-specified Outcome Measures (submitted: March 12, 2013)

Number of Participants with Adverse Events [ Time Frame: 0,3,6,9,12 months ]

We will perform routine comprehensive blood panel test to monitor safety and tolerability of Curcumin in subjects st risk for MCI by means of adverse events, vital signs and safety laboratory assessments. [ Time Frame: is at each timepoint in the study, 3, 6, 9 and 12 months].

Descriptive Information

• Brief Title: Curcumin and Yoga Therapy for Those at Risk for Alzheimer's Disease
• Official Title: Curcumin and Yoga Exercise Effects in Veterans at Risk for Alzheimer's Disease
• Brief Summary: Physical exercise has proven to improve memory including in the elderly. Drugs developed to stop the underlying disease processes that cause Alzheimer's disease may succeed only with multimodal efforts to stimulate brain function. One purpose of the study is to test the clinical benefits of curcumin, a safe and effective compound isolated from the turmeric root (a component of Indian curry spices), which has been found to inhibit several potential disease pathways in Alzheimer's disease. Another purpose of this study is to determine how the addition of a physical exercise program in individuals with early memory problems may affect memory function or brain imaging and blood-based markers associated with Alzheimer's disease.
• Detailed Description: Subjects with Mild cognitive impairment (MCI) or Subjective Cognitive Impairment (SCD) are eligible for this study. MCI often represents the earliest stages of Alzheimer's disease (AD), as individuals meeting criteria for MCI are subsequently diagnosed with AD at much higher rates than their cognitively normal elderly peers. Subjects with MCI are at risk of developing AD, within 6 years. Subjects with SCD may be at risk to develop MCI. The study is stratified according to whether subjects have SCD or MCI. The goal of the current study is to determine whether dietary supplementation with a novel formulation of curcumin (a component of the curry spice turmeric), which is better absorbed and more efficiently transported into the brain, can alter biological and clinical markers associated with AD risk, and to determine whether the potential beneficial effects of curcumin supplementation are synergistic with aerobic exercise. The investigators will recruit 80 elderly participants meeting criteria for MCI. Over the second 6 months of the study, the curcumin and placebo groups will be further divided into groups receiving training in either aerobic or non-aerobic yoga to determine the synergism between curcumin supplementation and aerobic exercise. The effectiveness of these interventions will be measured using plasma samples (for expression of Alzheimer-related biomarkers), and neuropsychological, functional, and behavioral assessments (i.e. clinical measures) collected at baseline, 6 months, and 12 months after initiation of treatments, with a subset of participants receiving brain imaging at baseline and 6 months. Dosage is titered up two weeks prior to study start (1 capsule BID, first five days, then 2 capsules BID for five days, then 6 capsules BID for five days, then 8 capsules BID- study dosage). Over the first 6 months of the study, participants will be randomized into equal groups receiving dietary supplementation with either curcumin or placebo. Patients are stratified according to whether they have only subjective memory complaints without MCI versus those that have MCI. Over the second 6 months of the study, participants will be further randomized into equal groups receiving dietary supplementation with either curcumin or placebo.
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Factorial Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Prevention
• Condition: Mild Cognitive Impairment

Intervention

• Drug: Curcumin
  Subjects will take 800 mg of curcumin in 4 capsules BID per day prior to meals
  Other Name: Longvida Curcumin (Verdure Sciences, Indianapolis)
• Behavioral: aerobic yoga
  Each week, subjects will attend two one hour aerobic yoga classes under the supervision of certified yoga instructors and complete two 30 minute aerobic yoga practice sessions at home. If proficient, subjects will take a live-video conference remote class, HIPAA approved SecureVideo classes. Modification of consent has been approved.
• Behavioral: non aerobic yoga

  Subjects will take two non-aerobic (stretching) classes weekly as well as practice two 30 minutes yoga routines at home weekly.

  Each week, subjects will attend two one hour non-aerobic yoga classes under the supervision of certified yoga instructors and complete two 30 minute non-aerobic yoga practice sessions at home.

• Dietary Supplement: Placebo
  Subjects will take 4 capsules x BID of placebo

Study Arms

• Experimental: Curcumin and aerobic exercise
  For the first 6 months of the study, subjects will take 800 mg of curcumin (4 capsules x BID, p.o.) before meals. From six to 12 months after the beginning of the study, subjects will take curcumin (4 capsules BID before meals, total 800 mg/day) and also participate in an aerobic yoga exercise program (Attendance at 2 classes of 1 hour duration [or 1 hr SecureVideo Live videoconference remote classes for subject who become proficient] and 2 home practices of 30 minute duration per week).
  Interventions:

  • Drug: Curcumin
  • Behavioral: aerobic yoga
• Placebo Comparator: Placebo vs non-aerobic yoga
  For the first 6 months of the study, subjects will take Placebo (4 capsules x BID, p.o.) before meals. From six months to 12 months from the beginning of the study, subjects will take Placebo (4 capsules x BID) and participate in a weekly non-aerobic yoga program (Attendance at 2 classes of 1 hour duration or 1 hr SecureVideo Live videoconference remote classes for subject who become proficient] and 2 home practices of 30 minute duration per week).
  Interventions:

  • Behavioral: non aerobic yoga
  • Dietary Supplement: Placebo
• Active Comparator: Placebo vs Aerobic Yoga
  For the first 6 months of the study, subjects will take Placebo (4 capsules x BID, p.o.) before meals. From six months to 12 months from the beginning of the study, subjects will take Placebo (4 capsules x BID) and participate in a weekly aerobic yoga program (Attendance at 2 classes of 1 hour duration [or 1 hr SecureVideo Live videoconference remote classes for subject who become proficient] and 2 home practices of 30 minute duration per week).
  Interventions:

  • Behavioral: aerobic yoga
  • Dietary Supplement: Placebo
• Active Comparator: Curcumin vs non aerobic yoga
  For the first 6 months of the study, subjects will take 800 mg of curcumin (4 capsules x BID, p.o.) before meals. From six months to 12 months from the beginning of the study, subjects will take Curcumin (4 capsules x BID, total 800 mg/day) and participate in a weekly non-aerobic yoga program (Attendance at 2 classes of 1 hour duration [or 1 hr SecureVideo Live videoconference remote classes for subject who become proficient] and 2 home practices of 30 minute duration per week).
  Interventions:

  • Drug: Curcumin
  • Behavioral: aerobic yoga

Publications *

• Begum AN, Jones MR, Lim GP, Morihara T, Kim P, Heath DD, Rock CL, Pruitt MA, Yang F, Hudspeth B, Hu S, Faull KF, Teter B, Cole GM, Frautschy SA. Curcumin structure-function, bioavailability, and efficacy in models of neuroinflammation and Alzheimer's disease. J Pharmacol Exp Ther. 2008 Jul;326(1):196-208. doi: 10.1124/jpet.108.137455. Epub 2008 Apr 16.
• Frautschy SA, Cole GM. Why pleiotropic interventions are needed for Alzheimer's disease. Mol Neurobiol. 2010 Jun;41(2-3):392-409. doi: 10.1007/s12035-010-8137-1. Epub 2010 May 2.
• Frautschy SA, Hu W, Kim P, Miller SA, Chu T, Harris-White ME, Cole GM. Phenolic anti-inflammatory antioxidant reversal of Abeta-induced cognitive deficits and neuropathology. Neurobiol Aging. 2001 Nov-Dec;22(6):993-1005. doi: 10.1016/s0197-4580(01)00300-1.
• Garcia-Alloza M, Borrelli LA, Rozkalne A, Hyman BT, Bacskai BJ. Curcumin labels amyloid pathology in vivo, disrupts existing plaques, and partially restores distorted neurites in an Alzheimer mouse model. J Neurochem. 2007 Aug;102(4):1095-104. doi: 10.1111/j.1471-4159.2007.04613.x. Epub 2007 Apr 30.
• Geda YE, Roberts RO, Knopman DS, Christianson TJ, Pankratz VS, Ivnik RJ, Boeve BF, Tangalos EG, Petersen RC, Rocca WA. Physical exercise, aging, and mild cognitive impairment: a population-based study. Arch Neurol. 2010 Jan;67(1):80-6. doi: 10.1001/archneurol.2009.297.
• Gota VS, Maru GB, Soni TG, Gandhi TR, Kochar N, Agarwal MG. Safety and pharmacokinetics of a solid lipid curcumin particle formulation in osteosarcoma patients and healthy volunteers. J Agric Food Chem. 2010 Feb 24;58(4):2095-9. doi: 10.1021/jf9024807.
• Jankowsky JL, Melnikova T, Fadale DJ, Xu GM, Slunt HH, Gonzales V, Younkin LH, Younkin SG, Borchelt DR, Savonenko AV. Environmental enrichment mitigates cognitive deficits in a mouse model of Alzheimer's disease. J Neurosci. 2005 May 25;25(21):5217-24. doi: 10.1523/JNEUROSCI.5080-04.2005.
• Lazarov O, Robinson J, Tang YP, Hairston IS, Korade-Mirnics Z, Lee VM, Hersh LB, Sapolsky RM, Mirnics K, Sisodia SS. Environmental enrichment reduces Abeta levels and amyloid deposition in transgenic mice. Cell. 2005 Mar 11;120(5):701-13. doi: 10.1016/j.cell.2005.01.015.
• Liang KY, Mintun MA, Fagan AM, Goate AM, Bugg JM, Holtzman DM, Morris JC, Head D. Exercise and Alzheimer's disease biomarkers in cognitively normal older adults. Ann Neurol. 2010 Sep;68(3):311-8. doi: 10.1002/ana.22096.
• Lim GP, Chu T, Yang F, Beech W, Frautschy SA, Cole GM. The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse. J Neurosci. 2001 Nov 1;21(21):8370-7. doi: 10.1523/JNEUROSCI.21-21-08370.2001.
• Ma QL, Yang F, Rosario ER, Ubeda OJ, Beech W, Gant DJ, Chen PP, Hudspeth B, Chen C, Zhao Y, Vinters HV, Frautschy SA, Cole GM. Beta-amyloid oligomers induce phosphorylation of tau and inactivation of insulin receptor substrate via c-Jun N-terminal kinase signaling: suppression by omega-3 fatty acids and curcumin. J Neurosci. 2009 Jul 15;29(28):9078-89. doi: 10.1523/JNEUROSCI.1071-09.2009.
• Scarmeas N, Luchsinger JA, Brickman AM, Cosentino S, Schupf N, Xin-Tang M, Gu Y, Stern Y. Physical activity and Alzheimer disease course. Am J Geriatr Psychiatry. 2011 May;19(5):471-81. doi: 10.1097/JGP.0b013e3181eb00a9.
• Yang F, Lim GP, Begum AN, Ubeda OJ, Simmons MR, Ambegaokar SS, Chen PP, Kayed R, Glabe CG, Frautschy SA, Cole GM. Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J Biol Chem. 2005 Feb 18;280(7):5892-901. doi: 10.1074/jbc.M404751200. Epub 2004 Dec 7.
• Gifford KA, Liu D, Romano R 3rd, Jones RN, Jefferson AL. Development of a subjective cognitive decline questionnaire using item response theory: a pilot study. Alzheimers Dement (Amst). 2015 Dec 1;1(4):429-439. doi: 10.1016/j.dadm.2015.09.004.

Recruitment Information

• Recruitment Status: Unknown status
• Estimated Enrollment (submitted: March 12, 2013): 80
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 31, 2020
• Actual Primary Completion Date: March 16, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• age between 50 and 90 years;
• Mini-Mental Status Exam (MMSE) scores greater than 24;
• subjective cognitive complaints based on subjective cognitive impairment questionaire (Gifford et al. 2015) including non-amnestic or amnestic cognitive deficits MCI (performance 1.5 standard deviation (SD) below normative means on The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) word list learning test);
• essentially intact activities of daily living (FAQ scores < 6);
• Sedentary (exercise < 30 minutes a day, 3 times a week);
• ambulatory, able exercise safely without cardiovascular symptoms, and able to pass a graded treadmill test modified for the elderly;
• able to arrange transportation to the study;
• Willing and intellectually able to understand and to sign an informed consent and to adhere to protocol requirements;
• community dwelling; and
• fluent in written and spoken English
• must screen positive for a Modified abbreviated MCI or SCD screen on phone, before coming in to clinic for extensive testing

Exclusion Criteria:

• diagnosis of dementia,
• concurrent substance abuse disorder,
• psychosis or mood disorder,
• neurological disease affecting motor or cognitive abilities (e.g. Parkinson's disease),or other significant uncontrolled medical problems,
• cannot get up and down from floor
• initiation of any new medications/treatment for cognitive impairment (i.e. cholinesterase inhibitor, memantine) < 6 months prior to study enrollment

Sex/Gender

• Sexes Eligible for Study: All
• Gender Based Eligibility: Yes
• Gender Eligibility Description: Female subjects have the same inclusion and exclusion criteria as men. Although males have increased representation in the veteran population, which is prioritized, we make efforts to recruit females through the LA times.

• Ages: 50 Years to 90 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01811381
• Other Study ID Numbers: E0669-I; VA_RX00069 ( Other Grant/Funding Number: Veterans Affairs )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Supporting Materials: Study Protocol
• Supporting Materials: Informed Consent Form (ICF)
• Supporting Materials: Clinical Study Report (CSR)
• Time Frame: January 1, 2020 is our deadline to published the data.
• Access Criteria: we will share data in a publication (biomarker data, curcumin pharmacokinetics, cognitive and neuroimaging changes). we may also provide RNAseq data on exosomes.

• Current Responsible Party: VA Office of Research and Development
• Original Responsible Party: Sally A. Frautschy, PhD, University of California, Los Angeles, Professor, Dept. Neurology, UCLA and VA Research Health Scientist
• Current Study Sponsor: VA Office of Research and Development
• Original Study Sponsor: University of California, Los Angeles
• Collaborators: Not Provided

Investigators

• Principal Investigator: Sally A Frautschy, PhD; VA Greater Los Angeles Healthcare System, West Los Angeles, CA

• PRS Account: VA Office of Research and Development
• Verification Date: September 2020