Short Term Efficacy and Safety of Perispinal Administration of Etanercept in Mild to Moderate Alzheimer's Disease

Study Description

Go to 

Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Brief Summary:

While the cause of AD is still unknown, evidence suggests it develops because of a complex series of events in the brain that occur over time. Two pathways possibly involved in development of AD are inflammation and oxidative stress. Scientists have linked chronic inflammatory events in the brain with the onset and progression of Alzheimer's Disease. Oxidative stress has also been implicated in the pathogenesis of a number of neurological disorders including Alzheimer's Disease.

Etanercept (Enbrel®) is an approved drug for the treatment of several forms of arthritis when administered by injection. Some research suggests that etanercept, when administered by injection into the tissues close to the spinal column (perispinally), may modulate certain aspects of the immune system and provide some beneficial effect for people with Alzheimer's disease. Studies suggest that supplementation with specific nutrients may also have a positive effect in support of cognitive function.

This study will be conducted at one research office with volunteers who have been diagnosed with mild to moderate Alzheimer's disease. Each qualifying participant will be randomly assigned to receive an etanercept injection plus nutritional supplements for 6 weeks followed by a crossover and a washout period of 4 weeks to then receiving nutritional supplements alone or vice versa for another 6 weeks.

Participants will undergo blood and urine safety assessments at the beginning and end of each 6 week treatment period. During 4 of the 6 weekly visits in the treatment period with the injections, you will complete the cognitive tests twice; once before and once 2 hours after the injection. During 4 of the 6 weekly visits in the treatment period without the injections, you will also complete the cognitive tests twice; once before and once 2 hours after being asked to lie down onto a table for 5 minutes. You will be allowed to continue your standard of care for Alzheimer's disease throughout your participation in the study.

Condition or disease	Intervention/treatment	Phase
Alzheimer's Disease	Biological: Etanercept; Dietary Supplement: Curcum.Luteol.Theaflav.Lip.Acid,FishOil,Quercet.,Resveratr.	Phase 1

Study Design

Go to 

Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	12 participants
Allocation:	Randomized
Intervention Model:	Crossover Assignment
Masking:	None (Open Label)
Primary Purpose:	Health Services Research
Official Title:	Open Label,Crossover,Pilot Study to Assess the Efficacy & Safety of Perispinal Admin.of Etanercept(Enbrel®) in Comb.w/Nutritional Supplements vs. Nutritional Supplements Alone in Subj. w/Mild to Mod. Alzheimer's Disease Receiving Std. Care.
Study Start Date :	February 2010
Actual Primary Completion Date :	October 2015
Actual Study Completion Date :	May 2016

Arms and Interventions

Go to 

Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Arm	Intervention/treatment
Active Comparator: Etanercept; 25 mg administered weekly for 6 weeks	Biological: Etanercept; Other Name: Enbrel® Dietary Supplement: Curcum.Luteol.Theaflav.Lip.Acid,FishOil,Quercet.,Resveratr.; Other Names: Super Bio-Curcumin; Super Omega-3; Optimized Quercetin; Optimized Resveratrol
Active Comparator: Nutritional Supplements; Nutritional supplements administered daily for 6 weeks in each period as well as an additional 12 weeks following visit 15.	Dietary Supplement: Curcum.Luteol.Theaflav.Lip.Acid,FishOil,Quercet.,Resveratr.; Other Names: Super Bio-Curcumin; Super Omega-3; Optimized Quercetin; Optimized Resveratrol

Outcome Measures

Go to 

Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Primary Outcome Measures :

1. Difference in effects of treatment for 6 weeks with etanercept + nutritional supplements versus nutritional supplements alone on the Mini-Mental Status Examination (MMSE) score. [ Time Frame: 16 weeks ]

Secondary Outcome Measures :

1. Difference in the effects of treatment for 6 weeks with etanercept + nutritional supplements versus nutritional supplements alone on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) score. [ Time Frame: 16 weeks ]
2. Difference in the effects of treatment for 6 weeks with etanercept + nutritional supplements versus nutritional supplements alone on the Montreal Cognitive Assessment (MoCA) score. [ Time Frame: 16 weeks ]

Other Outcome Measures:

1. Difference in the effects of treatment for 6 weeks as well as an additional 12 weeks following visit 15 with nutritional supplementation alone on the MMSE score. [ Time Frame: 28 weeks ]
2. Difference in short term effects of etanercept on the MMSE score before and two hours after perispinal administration of etanercept. [ Time Frame: 16 weeks ]
3. To determine the safety and tolerability of nutritional supplements with perispinal adminstration of etanercept, as measured by various laboratory markers, vital signs (blood pressure and heart rate), and adverse events. [ Time Frame: 16 weeks ]
4. Difference in the effects of treatment for 6 weeks as well as an additional 12 weeks following visit 15 with nutritional supplementation alone on the ADAS-cog score. [ Time Frame: 28 weeks ]
5. Difference in the effects of treatment for 6 weeks as well as an additional 12 weeks following visit 15 with nutritional supplementation alone on the MoCA score. [ Time Frame: 28 weeks ]
6. Difference in short term effects of etanercept on the ADAS-cog score before and two hours after perispinal administration of etanercept. [ Time Frame: 16 weeks ]
7. Difference in short term effects of etanercept on the MoCA score before and two hours after perispinal administration of etanercept. [ Time Frame: 16 weeks ]
8. To determine the safety and tolerability of nutritional supplements without perispinal adminstration of etanercept, as measured by various laboratory markers, vital signs (blood pressure and heart rate), and adverse events. [ Time Frame: 16 weeks ]

Eligibility Criteria

Go to 

Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Ages Eligible for Study:	60 Years to 85 Years (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• Subject is aged 60-85 years
• Subject has a diagnosis of Alzheimer's disease according to the NINCDS- ADRDA criteria (National Institute of Neurological and Communicative Disorders and Stroke NINCDS] and Alzheimer's Disease and Related Disorders Association [ADRDA]).
• Subject is not institutionalized (for example, lives independently, lives independently in a residential home for the elderly, or is a day patient at a care center)
• Subject has a Hachinski Ischemia Score of ≤ 4.
• Subject has a total MoCA score of < 26 at screening.
• Subject has an MMSE score of 11 to 24 at screening.
• Subject has an ADAS-cog score of 12 to 25 at screening.
• Subject has experienced a gradual and progressive cognitive decline in the 6 months before the screening visit.
• Subject provides informed consent to participate in the study or has a legally acceptable representative who provides consent.
• Subject has a responsible caregiver who consents to supporting the subject in his/her study participation (for example, by accompanying the subject on each study visit).
• Subject is surgically sterile, agrees to use an acceptable method of birth control as defined in section 5.4 or, for females, is post- menopausal.
• Subject agrees to stop taking any vitamin, mineral, or dietary supplements he/she is currently taking that have any components of the nutritional supplements utilized in the study at least 7 days before randomization (Visit 2) and agrees to not use any new vitamin, mineral, or dietary supplement product other than those provided by the investigator until after the subject is discharged from the study.

Exclusion Criteria:

• A neurologic disorder, such as seizures, multiple sclerosis, neurodegenerative disorders (eg, Parkinson's disease), or dementia other than Alzheimer's type (including that caused by small strokes or cerebrovascular disease)
• Cognitive impairment from any condition other than Alzheimer's disease, such as that resulting from acute cerebral trauma, cerebral damage due to a lack of oxygen, infections such as meningitis or AIDS, significant endocrine or metabolic disease, mental retardation, or a brain tumor
• Cardiovascular or cerebrovascular disease, such as congestive heart failure, uncontrolled hypertension (BP ≥ 140/90 mmHg at screening), and a history of stroke
• Renal impairment/disease, defined as serum creatinine > 1.5 mg/dL
• Hepatic impairment, defined as Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST) > 3 times the upper limit of normal OR has a history of a positive blood screen for hepatitis B surface antigen or hepatitis C antibody.
• Type I or II diabetes mellitus
• Significant or uncontrolled psychiatric disease
• Gastrointestinal disease, such as active peptic ulcer, gallstones, gallbladder disease, or biliary tract obstruction, or a history of cholecystectomy
• Hematologic disorders
• Pulmonary or lung disorders
• Immune system disorder, such as HIV/AIDS
• History of cancer within 10 years before screening (except localized skin cancer without metastases or in situ cervical cancer)
• History of chronic or recurrent infection (including tuberculosis) OR, in the 7 days before Visit 2 (randomization), any known infection or body temperature > 38.6º C (101.5º F)
• Subject is pregnant or breastfeeding at screening.
• Subject has intolerance or allergy to Enbrel®, latex, or any of Enbrel's components.
• Subject is currently consuming more than 6 standard alcoholic beverages a week. A standard alcoholic beverage is defined as 12 ounces of beer, 5 ounces of wine, or 1.5 ounces of liquor.
• Subject is currently taking and unable or unwilling to stop taking anticoagulant or antiplatelet herbs and supplements such as angelica, clove, danshen, garlic, ginger, ginkgo, Panax ginseng, red clover, or willow for at least 7 days before the randomization visit (Visit 2) and throughout the study.
• Subject is currently taking and unable or unwilling to stop taking any of the prohibited medications in protocol section 5.3.2 for at least 7 days before the randomization visit (Visit 2) and throughout the study.
• Subject had major surgery within the 4 weeks before screening.
• Subject has any condition or abnormality that, in the opinion of the investigator, would compromise the safety of the subject or the quality of the study data.
• Subject is participating or has participated in another research study within 30 days before the screening visit
• Subject or subject's caregiver is unable or unwilling to comply with the study procedures.

Contacts and Locations

Go to 

Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Locations

United States, Florida
Paul H. Wand M.D., P.A.
Coral Springs, Florida, United States, 33065
Brain Matters Research
Delray Beach, Florida, United States, 33445

Sponsors and Collaborators

Life Extension Foundation Inc.

Investigators

Principal Investigator:	Paul H. Wand, M.D.	Paul H. Wand M.D., P.A.
Principal Investigator:	Mark L. Brody, M.D.	Brain Matters Research Inc.

More Information

Go to 

Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Publications:

Centers for Disease Control and Prevention website. CDC Features: Alzheimer's Disease. http://www.cdc.gov/Features/Alzheimers/. 12-15-2008. 6-23-2009.

Mrak RE, Griffin WS. Interleukin-1, neuroinflammation, and Alzheimer's disease. Neurobiol Aging. 2001 Nov-Dec;22(6):903-8. Review.

Alzheimer's Disease Education & Referral (ADEAR) Center, National Institutes of Health. Alzheimer's Disease Fact Sheet. 2008.

Mrak RE, Griffin WS. Glia and their cytokines in progression of neurodegeneration. Neurobiol Aging. 2005 Mar;26(3):349-54. Review.

Tarkowski E, Andreasen N, Tarkowski A, Blennow K. Intrathecal inflammation precedes development of Alzheimer's disease. J Neurol Neurosurg Psychiatry. 2003 Sep;74(9):1200-5.

McGeer PL, McGeer EG. Local neuroinflammation and the progression of Alzheimer's disease. J Neurovirol. 2002 Dec;8(6):529-38. Review.

Kaur C, Ling EA. Antioxidants and neuroprotection in the adult and developing central nervous system. Curr Med Chem. 2008;15(29):3068-80. Review.

Tobinick E, Gross H, Weinberger A, Cohen H. TNF-alpha modulation for treatment of Alzheimer's disease: a 6-month pilot study. MedGenMed. 2006 Apr 26;8(2):25.

Tarkowski E, Liljeroth AM, Minthon L, Tarkowski A, Wallin A, Blennow K. Cerebral pattern of pro- and anti-inflammatory cytokines in dementias. Brain Res Bull. 2003 Aug 15;61(3):255-60. Review.

Laws SM, Perneczky R, Wagenpfeil S, Müller U, Förstl H, Martins RN, Kurz A, Riemenschneider M. TNF polymorphisms in Alzheimer disease and functional implications on CSF beta-amyloid levels. Hum Mutat. 2005 Jul;26(1):29-35.

Tobinick EL, Gross H. Rapid improvement in verbal fluency and aphasia following perispinal etanercept in Alzheimer's disease. BMC Neurol. 2008 Jul 21;8:27. doi: 10.1186/1471-2377-8-27.

Becker RE. Modifying clinical trial designs to test treatments for clinical significance in individual patients. Clin Drug Invest 2001:21:727-733.

Griffin WS. Perispinal etanercept: potential as an Alzheimer therapeutic. J Neuroinflammation. 2008 Jan 10;5:3. doi: 10.1186/1742-2094-5-3.

Tobinick E. Perispinal etanercept for neuroinflammatory disorders. Drug Discov Today. 2009 Feb;14(3-4):168-77. doi: 10.1016/j.drudis.2008.10.005. Epub 2008 Dec 6. Review.

Tobinick E. Perispinal etanercept for treatment of Alzheimer's disease. Curr Alzheimer Res. 2007 Dec;4(5):550-2. Review.

Tobinick EL. A critique of intradiscal administration for treatment of radiculopathy. Anesthesiology. 2008 Feb;108(2):334; author reply 335. doi: 10.1097/01.anes.0000300072.56020.10.

Tobinick E. Perispinal etanercept produces rapid improvement in primary progressive aphasia: identification of a novel, rapidly reversible TNF-mediated pathophysiologic mechanism. Medscape J Med. 2008 Jun 10;10(6):135.

Chainani-Wu N. Safety and anti-inflammatory activity of curcumin: a component of tumeric (Curcuma longa). J Altern Complement Med. 2003 Feb;9(1):161-8. Review.

Pendurthi UR, Williams JT, Rao LV. Inhibition of tissue factor gene activation in cultured endothelial cells by curcumin. Suppression of activation of transcription factors Egr-1, AP-1, and NF-kappa B. Arterioscler Thromb Vasc Biol. 1997 Dec;17(12):3406-13.

Antony S, Kuttan R, Kuttan G. Immunomodulatory activity of curcumin. Immunol Invest. 1999 Sep-Dec;28(5-6):291-303.

Jobin C, Bradham CA, Russo MP, Juma B, Narula AS, Brenner DA, Sartor RB. Curcumin blocks cytokine-mediated NF-kappa B activation and proinflammatory gene expression by inhibiting inhibitory factor I-kappa B kinase activity. J Immunol. 1999 Sep 15;163(6):3474-83.

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.

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. Epub 2004 Dec 7.

Ueda H, Yamazaki C, Yamazaki M. Luteolin as an anti-inflammatory and anti-allergic constituent of Perilla frutescens. Biol Pharm Bull. 2002 Sep;25(9):1197-202.

Xagorari A, Papapetropoulos A, Mauromatis A, Economou M, Fotsis T, Roussos C. Luteolin inhibits an endotoxin-stimulated phosphorylation cascade and proinflammatory cytokine production in macrophages. J Pharmacol Exp Ther. 2001 Jan;296(1):181-7.

Rezai-Zadeh K, Douglas Shytle R, Bai Y, Tian J, Hou H, Mori T, Zeng J, Obregon D, Town T, Tan J. Flavonoid-mediated presenilin-1 phosphorylation reduces Alzheimer's disease beta-amyloid production. J Cell Mol Med. 2009 Mar;13(3):574-88. doi: 10.1111/j.1582-4934.2008.00344.x. Epub 2008 Apr 9. Erratum in: J Cell Mol Med. 2009 May;13(5):1001.

Borchers AT, Sakai S, Henderson GL, Harkey MR, Keen CL, Stern JS, Terasawa K, Gershwin ME. Shosaiko-to and other Kampo (Japanese herbal) medicines: a review of their immunomodulatory activities. J Ethnopharmacol. 2000 Nov;73(1-2):1-13. Review.

Lo CJ, Chiu KC, Fu M, Lo R, Helton S. Fish oil decreases macrophage tumor necrosis factor gene transcription by altering the NF kappa B activity. J Surg Res. 1999 Apr;82(2):216-21.

Lukiw WJ, Cui JG, Marcheselli VL, Bodker M, Botkjaer A, Gotlinger K, Serhan CN, Bazan NG. A role for docosahexaenoic acid-derived neuroprotectin D1 in neural cell survival and Alzheimer disease. J Clin Invest. 2005 Oct;115(10):2774-83.

Yano M, Kishida E, Iwasaki M, Kojo S, Masuzawa Y. Docosahexaenoic acid and vitamin E can reduce human monocytic U937 cell apoptosis induced by tumor necrosis factor. J Nutr. 2000 May;130(5):1095-101.

Calder PC. Immunomodulation by omega-3 fatty acids. Prostaglandins Leukot Essent Fatty Acids. 2007 Nov-Dec;77(5-6):327-35. Epub 2007 Nov 26. Review.

Venkatraman JT, Chu WC. Effects of dietary omega-3 and omega-6 lipids and vitamin E on serum cytokines, lipid mediators and anti-DNA antibodies in a mouse model for rheumatoid arthritis. J Am Coll Nutr. 1999 Dec;18(6):602-13.

Caughey GE, Mantzioris E, Gibson RA, Cleland LG, James MJ. The effect on human tumor necrosis factor alpha and interleukin 1 beta production of diets enriched in n-3 fatty acids from vegetable oil or fish oil. Am J Clin Nutr. 1996 Jan;63(1):116-22.

James MJ, Gibson RA, Cleland LG. Dietary polyunsaturated fatty acids and inflammatory mediator production. Am J Clin Nutr. 2000 Jan;71(1 Suppl):343S-8S. Review.

Kotani S, Sakaguchi E, Warashina S, Matsukawa N, Ishikura Y, Kiso Y, Sakakibara M, Yoshimoto T, Guo J, Yamashima T. Dietary supplementation of arachidonic and docosahexaenoic acids improves cognitive dysfunction. Neurosci Res. 2006 Oct;56(2):159-64. Epub 2006 Aug 14.

Freund-Levi Y, Eriksdotter-Jönhagen M, Cederholm T, Basun H, Faxén-Irving G, Garlind A, Vedin I, Vessby B, Wahlund LO, Palmblad J. Omega-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease: OmegAD study: a randomized double-blind trial. Arch Neurol. 2006 Oct;63(10):1402-8.

Rosen WG, Terry RD, Fuld PA, Katzman R, Peck A. Pathological verification of ischemic score in differentiation of dementias. Ann Neurol. 1980 May;7(5):486-8.

Responsible Party:	Life Extension Foundation Inc.
ClinicalTrials.gov Identifier:	NCT01716637 History of Changes
Other Study ID Numbers:	CL025
First Posted:	October 30, 2012
Last Update Posted:	May 12, 2016
Last Verified:	May 2016

Keywords provided by Life Extension Foundation Inc.:

Alzheimer's Disease; Dementia; Cognitive decline; Cognitive disorder	Degenerative brain disease; Cognitive impairment; Memory loss; TNF-alpha

Additional relevant MeSH terms:

Alzheimer Disease; Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders; Etanercept; Anti-Inflammatory Agents, Non-Steroidal	Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antirheumatic Agents; Gastrointestinal Agents; Immunosuppressive Agents; Immunologic Factors