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Neuroprotection by Tocotrienols in Type 1 and Type 2 Diabetes Mellitus (VENUS)

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ClinicalTrials.gov Identifier: NCT01973400
Recruitment Status : Completed
First Posted : October 31, 2013
Last Update Posted : May 4, 2017
Sponsor:
Collaborators:
Clinical Research Centre, Malaysia
Malaysia Palm Oil Board
Information provided by (Responsible Party):
Yuen Kah Hay, University of Science Malaysia

Brief Summary:
Given that the tocotrienols have been shown to possess neuroprotective effects and that both type 1 and type 2 diabetes can lead to peripheral neuropathy and cognitive impairment, the present study aims to determine the beneficial effects of tocotrienols in ameliorating such neurological related events in both type 1 and type 2 diabetic patients.

Condition or disease Intervention/treatment Phase
Diabetic Neuropathy Cognitive Impairment Dietary Supplement: Tocotrienol Dietary Supplement: Placebo Phase 3

Detailed Description:

Neuropathy affects approximately 30-50% of all diabetic patients and is the commonest form of neuropathy in the developed world. Pain is the most distressing symptom of neuropathy and the main factor that prompts the patient to seek medical advice. About 16-26% of diabetes patients experience chronic neuropathic pain. An animal study revealed that treating rats with α-tocopherol and tocotrienol for 10 weeks significantly improved all the biochemical and behavioral outcomes of alcohol-induced neuropathy in a dose-dependent manner with more potent effects observed with tocotrienols. The study demonstrates the effectiveness of tocotrienols in attenuation of alcoholic neuropathy.

Cognitive dysfunction is a less addressed and not as well recognized complication of diabetes. Patients with type 1 and type 2 diabetes mellitus have been found to have cognitive deficits that can be attributed to their disease. Both old age and diabetes are independently associated with an increased risk of cognitive dysfunction; the risk is even greater for older adults with diabetes. Cognitive Function is the term used to describe a person's state of consciousness (alertness and orientation), memory, and attention span. It has been suggested that Vitamin E, including tocopherols and tocotrienols, can help to improve cognitive function and stall cognitive decline through its antioxidant effects. A reason for this nutrient's success at preventing oxidative damage in brain cells is its fat-soluble criteria. During the World Alzheimer's Congress held in July 2001, it was reported that high intakes of vitamin E effectively lessened memory loss and cognitive dysfunction among more than 6,000 elderly subjects who were generally taking Vitamin E between 200 to 400 IU per day.

Tocotrienols, in particular α-tocotrienol have been shown to possess neuroprotective effect independent of anti-oxidant activity. Using cell-based studies, α-tocotrienol but not α-tocopherol was shown to prevent glutamate-induced neuronal cell death at nanomolar concentrations. Later studies showed that α-tocotrienol conferred protection against glutamate and stroke-induced neurodegeneration in rats.

In view of the above neuroprotective property of tocotrienols, researchers have proceeded to demonstrate that tocotrienols supplementation helped to reverse neuropathic pain in diabetic rats. It has been postulated the beneficial properties of tocotrienols are due to their suppressive effects on the oxidative-nitrosative stress, inflammatory cytokine release and caspase-3 which are implicated in the pathogenesis of diabetic neuropathy.

In the same year, tocotrienols were shown to prevent cognitive deficits and attenuate alcoholic peripheral neuropathy associated with selective neuronal damage due to chronic alcohol consumption. Moreover, the beneficial effects were found to be more pronounced with tocotrienols compared to tocopherols. It has been postulated that the anti-oxidants property of tocotrienols, the suppression of nitrosative stress and elevated cytokines levels together with acetylcholinesterase activity in the brain regions contributes significantly in preventing the chronic alcohol-induced cognitive deficits in rats.

Yuen and his group are currently conducting a clinical study in human subjects on neuroprotective effects of tocotrienols (NCT00753532). In the study, subjects were followed up for 2 years to determine the volume of white matter lesions on repeated MRI after treatment with tocotrienol as compared to placebo. White matter lesions are related to vascular events in the brain and represent subclinical infarcts, resulting in death/ degeneration of neurons and are positively correlated to cognitive impairment. Preliminary results from an interim analysis are encouraging; patients on tocotrienols shown significant reduction in volume of white matter lesion (confidential communication).


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 300 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Supportive Care
Official Title: A Clinical Study on the Neuroprotection by Tocotrienols in Type 1 and Type 2 Diabetes Mellitus
Study Start Date : June 2011
Actual Primary Completion Date : September 2015
Actual Study Completion Date : December 2016

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Vitamin E

Arm Intervention/treatment
Experimental: Tocotrienol
200 mg, twice a day, 12 months
Dietary Supplement: Tocotrienol
Palm-Oil derived Vitamin E, tocotrienol

Placebo Comparator: Placebo
200 mg, twice a day, 12 months
Dietary Supplement: Placebo
Placebo




Primary Outcome Measures :
  1. Total Symptoms Score (TSS) (pain, paresthesia, burning, and numbness)of patients with diabetes type 1 and 2 neuropathy. [ Time Frame: 1 year ]

Secondary Outcome Measures :
  1. Neuropathy Impairment Score (NIS) of patients with diabetes type 1 and 2 neuropathy [ Time Frame: 1 year ]

Other Outcome Measures:
  1. Mini Mental State Examination (MMSE) score, Montreal Cognitive Assessment (MoCA) test. [ Time Frame: 1 year ]
    Measures the effects of tocotrienols on cognitive impairment in type 1 and type 2 diabetes mellitus



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Ages Eligible for Study:   20 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diabetic adults ( both type 1 or 2) ≥20 years old with diabetic peripheral neuropathy with Total Symptom Score(TSS) ≥ 3 points.
  • Patients with type 1 diabetes (duration of ≥5 years).
  • Patients with type 2 diabetes (at diagnosis).
  • Patients with Neuropathy Impairment Score(NIS) > 2

Exclusion Criteria:

  • Patients HbA1c >12%.
  • Patients with hypoglycemia or conscious impairment at the time of test conduction.
  • Patients exhibiting symptoms of peripheral vascular disease with absence of 2 foot pulses on the same foot (Posterior tibialis, Dorsalis pedis)
  • Immuno-compromised patients.
  • Patients with severe visual impairment, history of psychosis; schizophrenia; bipolar disorder; current depression or brain trauma and patients with alcohol dependence or drug abuse such as cocaine, heroin, etc.
  • Those having lesions with a propensity to bleed (e.g., bleeding peptic ulcers), those having a history of hemorrhagic stroke and those with inherited bleeding disorders (e.g., hemophilia) or patients on warfarin.
  • Pregnancy and lactation.
  • Patients with renal function test of more than 150 umol/L (serum creatinine).
  • Patients with liver function test of more than 5 times of the upper normal range
  • Active infection or infectious diseases.
  • Other significant uncontrolled medical illnesses that may interfere with drug administration or interpretation of results.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01973400


Locations
Malaysia
Seberang Jaya Hospital
Seberang Jaya, Penang, Malaysia, 13700
Sponsors and Collaborators
University of Science Malaysia
Clinical Research Centre, Malaysia
Malaysia Palm Oil Board
Investigators
Principal Investigator: Kah Hay Yuen, PhD University of Science Malaysia

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Yuen Kah Hay, Professor Dr., University of Science Malaysia
ClinicalTrials.gov Identifier: NCT01973400     History of Changes
Other Study ID Numbers: VENUS-7327
NMRR-10-948-7327 ( Registry Identifier: National Medical Research Register (Malaysia) )
First Posted: October 31, 2013    Key Record Dates
Last Update Posted: May 4, 2017
Last Verified: May 2017

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Cognitive Dysfunction
Diabetic Neuropathies
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Cognition Disorders
Neurocognitive Disorders
Mental Disorders
Peripheral Nervous System Diseases
Neuromuscular Diseases
Nervous System Diseases
Diabetes Complications
Tocotrienols
Vitamin E
Tocopherols
Antioxidants
Molecular Mechanisms of Pharmacological Action
Protective Agents
Physiological Effects of Drugs
Vitamins
Micronutrients
Growth Substances