Resveratrol for Alzheimer's Disease

• ClinicalTrials.gov Identifier: NCT01504854
• Recruitment Status: Completed
• First Posted: January 6, 2012
• Results First Posted: June 14, 2016
• Last Update Posted: June 14, 2016
• Sponsor: Alzheimer's Disease Cooperative Study (ADCS)
• Collaborator: National Institute on Aging (NIA)
• Information provided by (Responsible Party): Alzheimer's Disease Cooperative Study (ADCS)

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Alzheimer's Disease
• Interventions: Drug: Resveratrol; Drug: Placebo
• Enrollment: 119

Participant Flow

Recruitment Details	A multicenter, double-blind, placebo-controlled trial was conducted June 2012-March 2014 with participants recruited from 26 US academic clinics affiliated with the Alzheimer's Disease Cooperative Study (ADCS).
Pre-assignment Details	119 subjects were recruited rather than 120.

Arm/Group Title	Resveratrol	Placebo
Arm/Group Description	Subjects will take 500 mg by mouth once daily increasing at 13 week intervals to a maximum of 1 gram by mouth twice daily with or without food. Resveratrol: The dosage will begin at 500 mg taken once daily and increase at 13 week intervals to 1 gram taken by mouth twice daily, supplied as 500 mg capsules (two capsules twice daily).	Subjects will receive a matching placebo to be taken with or without food. Placebo: The matching placebo will begin at a capsule taken once daily and increase at 13 week intervals to two capsules twice daily.
Period Title: Overall Study
Started	64	55
Completed	56	48
Not Completed	8	7

Baseline Characteristics

Arm/Group Title		Resveratrol	Placebo	Total
Arm/Group Description		60 subjects will take 500 mg by mouth once daily increasing at 13 week intervals to a maximum of 1 gram by mouth twice daily with or without food. Resveratrol: The dosage will begin at 500 mg taken once daily and increase at 13 week intervals to 1 gram taken by mouth twice daily, supplied as 500 mg capsules (two capsules twice daily).	60 subjects will receive a matching placebo to be taken with or without food. Placebo: The matching placebo will begin at a capsule taken once daily and increase at 13 week intervals to two capsules twice daily.	Total of all reporting groups
Overall Number of Baseline Participants		64	55	119
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	64 participants	55 participants	119 participants
		69.8 (7.7)	73 (8.2)	71.4 (7.95)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	64 participants	55 participants	119 participants
	Female	40 62.5%	28 50.9%	68 57.1%
	Male	24 37.5%	27 49.1%	51 42.9%

Outcome Measures

1. Primary Outcome

Title	Number of Adverse Events
Description	The safety and tolerability of treatment with resveratrol will be assessed by analysis of adverse events, including symptoms, abnormal findings on physical examinations, standard laboratory tests and PK analysis of resveratrol and its major metabolites. The frequencies of adverse events or laboratory abnormalities between the participants who receive resveratrol and those receiving placebo will be compared.
Time Frame	Baseline, Weeks 6, 13, 19, 26, 32, 39, 45, and 52

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Resveratrol	Placebo
Arm/Group Description:	60 subjects will take 500 mg by mouth once daily increasing at 13 week intervals to a maximum of 1 gram by mouth twice daily with or without food. Resveratrol: The dosage will begin at 500 mg taken once daily and increase at 13 week intervals to 1 gram taken by mouth twice daily, supplied as 500 mg capsules (two capsules twice daily).	60 subjects will receive a matching placebo to be taken with or without food. Placebo: The matching placebo will begin at a capsule taken once daily and increase at 13 week intervals to two capsules twice daily.
Overall Number of Participants Analyzed	56	48
Measure Type: Number; Unit of Measure: number of AEs
	355	302

2. Primary Outcome

Title	Change From Baseline in Volumetric Magnetic Resonance Imaging (MRI)
Description	MRI will be used to assess the effect of treatment on rate of whole brain volume
Time Frame	Baseline and Week 52

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Resveratrol	Placebo
Arm/Group Description:	60 subjects will take 500 mg by mouth once daily increasing at 13 week intervals to a maximum of 1 gram by mouth twice daily with or without food. Resveratrol: The dosage will begin at 500 mg taken once daily and increase at 13 week intervals to 1 gram taken by mouth twice daily, supplied as 500 mg capsules (two capsules twice daily).	60 subjects will receive a matching placebo to be taken with or without food. Placebo: The matching placebo will begin at a capsule taken once daily and increase at 13 week intervals to two capsules twice daily.
Overall Number of Participants Analyzed	56	48
Mean (Standard Deviation); Unit of Measure: cm^3
	27 (12)	10 (7)

3. Secondary Outcome

Title	Change in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL)
Description	The ADCS-ADL is an activities of daily living inventory developed by the ADCS to assess functional performance in participants with AD. The ADCS-ADL includes some items from traditional basic ADL tests (e.g., grooming, dressing, walking, bathing, feeding, toileting) as well as instrumental (complex) activities of daily living (e.g., shopping, preparing meals, using household appliances, keeping appointments, reading). This structured questionnaire is administered to the subject's caregiver/study partner. The range of this instrument is 0 to 78 with lower numbers indicating greater impairment.
Time Frame	Week 52

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Resveratrol	Placebo
Arm/Group Description:	60 subjects will take 500 mg by mouth once daily increasing at 13 week intervals to a maximum of 1 gram by mouth twice daily with or without food. Resveratrol: The dosage will begin at 500 mg taken once daily and increase at 13 week intervals to 1 gram taken by mouth twice daily, supplied as 500 mg capsules (two capsules twice daily).	60 subjects will receive a matching placebo to be taken with or without food. Placebo: The matching placebo will begin at a capsule taken once daily and increase at 13 week intervals to two capsules twice daily.
Overall Number of Participants Analyzed	56	48
Mean (Standard Deviation); Unit of Measure: units on a scale
	6.3 (11.6)	9.2 (12.6)

4. Secondary Outcome

Title	Comparison of the Response to Treatment of Resveratrol Based on ApoE Genotype
Description	CSF Abeta40
Time Frame	Week 52

Outcome Measure Data

Analysis Population Description

ITT analyses. Total population and subpopulation of ApoE4 non-carriers.

Arm/Group Title	Resveratrol	Placebo
Arm/Group Description:	60 subjects will take 500 mg by mouth once daily increasing at 13 week intervals to a maximum of 1 gram by mouth twice daily with or without food. Resveratrol: The dosage will begin at 500 mg taken once daily and increase at 13 week intervals to 1 gram taken by mouth twice daily, supplied as 500 mg capsules (two capsules twice daily).	60 subjects will receive a matching placebo to be taken with or without food. Placebo: The matching placebo will begin at a capsule taken once daily and increase at 13 week intervals to two capsules twice daily.
Overall Number of Participants Analyzed	56	48
Mean (Standard Deviation); Unit of Measure: ng/ml
Total Population	6574 (2346)	6560 (2190)
ApoE4 non-carriers	5859 (2085)	6339 (1709)

5. Post-Hoc Outcome

Title	Change From Baseline in Cerebrospinal Fluid Amyloid β40 Concentration at 52 Weeks
Description	Mean change from baseline in cerebrospinal fluid amyloid β40 concentration at 52 weeks
Time Frame	Baseline and Week 52

Outcome Measure Data

Analysis Population Description

Post-hoc modified intention-to-treat (ITT) re-analysis of primary outcomes at Week 52 adjusting for age and AD duration in the mixed-model repeated measures model

Arm/Group Title	Resveratrol	Placebo
Arm/Group Description:	60 subjects will take 500 mg by mouth once daily increasing at 13 week intervals to a maximum of 1 gram by mouth twice daily with or without food. Resveratrol: The dosage will begin at 500 mg taken once daily and increase at 13 week intervals to 1 gram taken by mouth twice daily, supplied as 500 mg capsules (two capsules twice daily).	60 subjects will receive a matching placebo to be taken with or without food. Placebo: The matching placebo will begin at a capsule taken once daily and increase at 13 week intervals to two capsules twice daily.
Overall Number of Participants Analyzed	56	48
Mean (Standard Deviation); Unit of Measure: ng/ml
	6456 (2282)	5622 (1736)

Adverse Events

Time Frame	Adverse event data were collected over a 52 week period (the duration of the subject's participation in the study).
Adverse Event Reporting Description	Participants received physical and neurologic examinations and vital signs at each visit. Site investigators classified AEs by severity and causality. If a participant withdrew, an early termination visit similar to a baseline visit was scheduled. An independent Data and Safety Monitoring Board reviewed data quarterly.
Arm/Group Title	Resveratrol		Placebo
Arm/Group Description	60 subjects will take 500 mg by mouth once daily increasing at 13 week intervals to a maximum of 1 gram by mouth twice daily with or without food. Resveratrol: The dosage will begin at 500 mg taken once daily and increase at 13 week intervals to 1 gram taken by mouth twice daily, supplied as 500 mg capsules (two capsules twice daily).		60 subjects will receive a matching placebo to be taken with or without food. Placebo: The matching placebo will begin at a capsule taken once daily and increase at 13 week intervals to two capsules twice daily.
All-Cause Mortality
	Resveratrol		Placebo
	Affected / at Risk (%)		Affected / at Risk (%)
Total	--/--		--/--
Serious Adverse Events
	Resveratrol		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/64 (20.31%)		10/55 (18.18%)
Cardiac disorders
Congestive heart failure † 1	0/64 (0.00%)	0	1/55 (1.82%)	1
Syncope/atrial fibrillation † 1	1/64 (1.56%)	1	0/55 (0.00%)	0
Gastrointestinal disorders
Perforated viscus with perforated sigmoid diverticulitis with peritonitis † 1	1/64 (1.56%)	1	0/55 (0.00%)	0
Hiatal hernia † 1	0/64 (0.00%)	0	1/55 (1.82%)	1
Infections and infestations
Pneumonia † 1	0/64 (0.00%)	0	1/55 (1.82%)	1
Urinary tract infection † 1	1/64 (1.56%)	1	1/55 (1.82%)	1
Infections † 1	0/64 (0.00%)	0	1/55 (1.82%)	1
Injury, poisoning and procedural complications
Fall † 1	2/64 (3.13%)	2	1/55 (1.82%)	1
Drowning † 1	1/64 (1.56%)	1	0/55 (0.00%)	0
Left femoral neck fracture † 1	1/64 (1.56%)	1	0/55 (0.00%)	0
Complications from colostomy reversal † 1	1/64 (1.56%)	1	0/55 (0.00%)	0
Investigations
Low hemoglobin † 1	0/64 (0.00%)	0	2/55 (3.64%)	2
Metabolism and nutrition disorders
Water intoxication † 1	0/64 (0.00%)	0	1/55 (1.82%)	1
Hypokalemia † 1	2/64 (3.13%)	2	0/55 (0.00%)	0
Musculoskeletal and connective tissue disorders
Rhabdomyolosis † 1	1/64 (1.56%)	1	0/55 (0.00%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Melanoma of the lung, Stage 4 † 1	0/64 (0.00%)	0	1/55 (1.82%)	1
Large pleural effusion secondary to stage 4 melanoma of the lung † 1	0/64 (0.00%)	0	1/55 (1.82%)	1
Bladder tumor † 1	1/64 (1.56%)	1	0/55 (0.00%)	0
Malignant glioma † 1	0/64 (0.00%)	0	1/55 (1.82%)	1
Nervous system disorders
Seizure † 1	2/64 (3.13%)	2	0/55 (0.00%)	0
Syncope † 1	0/64 (0.00%)	0	1/55 (1.82%)	1
Subdural hematoma † 1	0/64 (0.00%)	0	1/55 (1.82%)	1
Unresponsiveness † 1	0/64 (0.00%)	0	1/55 (1.82%)	1
Altered mental state † 1	1/64 (1.56%)	1	0/55 (0.00%)	0
Pregnancy, puerperium and perinatal conditions
Altered mental state † 1	1/64 (1.56%)	2	1/55 (1.82%)	1
Respiratory, thoracic and mediastinal disorders
Difficulty breathing † 1	0/64 (0.00%)	0	1/55 (1.82%)	1
"Blood clots" in the lung/pulmonary embolism † 1	1/64 (1.56%)	1	0/55 (0.00%)	0
Vascular disorders
Right peripheral vascular disease (status post Carotid Endarterectomy) † 1	1/64 (1.56%)	1	0/55 (0.00%)	0
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA (Unspecified)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Resveratrol		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	64/64 (100.00%)		52/55 (94.55%)
Gastrointestinal disorders
Diarrhoea † 1	26/64 (40.63%)	26	7/55 (12.73%)	7
Infections and infestations
Urinary Tract Infection † 1	19/64 (29.69%)	19	7/55 (12.73%)	7
Injury, poisoning and procedural complications
Fall † 1	22/64 (34.38%)	22	14/55 (25.45%)	14
Nervous system disorders
Dizzyness † 1	6/64 (9.38%)	6	5/55 (9.09%)	5
Headache † 1	11/64 (17.19%)	11	6/55 (10.91%)	6
Psychiatric disorders
Anxiety † 1	3/64 (4.69%)	3	5/55 (9.09%)	5
Skin and subcutaneous tissue disorders
Rash † 1	1/64 (1.56%)	1	7/55 (12.73%)	7
Vascular disorders
Hypertension † 1	4/64 (6.25%)	4	3/55 (5.45%)	3
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA (Unspecified)

Limitations and Caveats

This phase 2 study has limitations. A larger study is required to determine whether resveratrol may be beneficial. More potent and bioavailable SIRT1 activators are also in development.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: Michael Rafii, MD, PhD
• Organization: Alzheimer's Disease Cooperative Study
• Phone: 858-846-1300
• EMail: mrafii@ucsd.edu

Publications:

Vang O, Ahmad N, Baile CA, Baur JA, Brown K, Csiszar A, Das DK, Delmas D, Gottfried C, Lin HY, Ma QY, Mukhopadhyay P, Nalini N, Pezzuto JM, Richard T, Shukla Y, Surh YJ, Szekeres T, Szkudelski T, Walle T, Wu JM. What is new for an old molecule? Systematic review and recommendations on the use of resveratrol. PLoS One. 2011;6(6):e19881. doi: 10.1371/journal.pone.0019881. Epub 2011 Jun 16. Review.

Smoliga JM, Baur JA, Hausenblas HA. Resveratrol and health--a comprehensive review of human clinical trials. Mol Nutr Food Res. 2011 Aug;55(8):1129-41. doi: 10.1002/mnfr.201100143. Epub 2011 Jun 20. Review.

Patel KR, Scott E, Brown VA, Gescher AJ, Steward WP, Brown K. Clinical trials of resveratrol. Ann N Y Acad Sci. 2011 Jan;1215:161-9. doi: 10.1111/j.1749-6632.2010.05853.x. Review.

Timmers S, Konings E, Bilet L, Houtkooper RH, van de Weijer T, Goossens GH, Hoeks J, van der Krieken S, Ryu D, Kersten S, Moonen-Kornips E, Hesselink MKC, Kunz I, Schrauwen-Hinderling VB, Blaak E, Auwerx J, Schrauwen P. Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metab. 2011 Nov 2;14(5):612-22. doi: 10.1016/j.cmet.2011.10.002.

Albani D, Polito L, Forloni G. Sirtuins as novel targets for Alzheimer's disease and other neurodegenerative disorders: experimental and genetic evidence. J Alzheimers Dis. 2010;19(1):11-26. doi: 10.3233/JAD-2010-1215. Review.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Moussa C, Hebron M, Huang X, Ahn J, Rissman RA, Aisen PS, Turner RS. Resveratrol regulates neuro-inflammation and induces adaptive immunity in Alzheimer's disease. J Neuroinflammation. 2017 Jan 3;14(1):1. doi: 10.1186/s12974-016-0779-0.

• Responsible Party: Alzheimer's Disease Cooperative Study (ADCS)
• ClinicalTrials.gov Identifier: NCT01504854
• Other Study ID Numbers: ADC-037-RES
• First Submitted: December 23, 2011
• First Posted: January 6, 2012
• Results First Submitted: January 28, 2016
• Results First Posted: June 14, 2016
• Last Update Posted: June 14, 2016