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

May 1, 2017 updated by: Yuen Kah Hay, Universiti Sains Malaysia

A Clinical Study on the Neuroprotection by Tocotrienols in Type 1 and Type 2 Diabetes Mellitus

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.

Study Overview

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

Enrollment (Actual)

300

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • Penang
      • Seberang Jaya, Penang, Malaysia, 13700
        • Seberang Jaya Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

20 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: SUPPORTIVE_CARE
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: QUADRUPLE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: Tocotrienol
200 mg, twice a day, 12 months
Palm-Oil derived Vitamin E, tocotrienol
PLACEBO_COMPARATOR: Placebo
200 mg, twice a day, 12 months
Placebo

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure
Time Frame
Neuropathy Impairment Score (NIS) of patients with diabetes type 1 and 2 neuropathy
Time Frame: 1 year
1 year

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
1 year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

June 1, 2011

Primary Completion (ACTUAL)

September 1, 2015

Study Completion (ACTUAL)

December 1, 2016

Study Registration Dates

First Submitted

October 24, 2013

First Submitted That Met QC Criteria

October 24, 2013

First Posted (ESTIMATE)

October 31, 2013

Study Record Updates

Last Update Posted (ACTUAL)

May 4, 2017

Last Update Submitted That Met QC Criteria

May 1, 2017

Last Verified

May 1, 2017

More Information

Terms related to this study

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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