Neuroprotection by Tocotrienols in Type 1 and Type 2 Diabetes Mellitus

NCT ID: NCT01973400

Last Updated: 2017-05-04

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 300 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-06-30
• Study Completion Date: 2016-12-31

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.

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).

Conditions

Diabetic Neuropathy; Cognitive Impairment

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: SUPPORTIVE_CARE
• Blinding Strategy: QUADRUPLE

Study Groups

Tocotrienol

200 mg, twice a day, 12 months

Group Type: EXPERIMENTAL

Tocotrienol

Intervention Type: DIETARY_SUPPLEMENT

Palm-Oil derived Vitamin E, tocotrienol

Placebo

200 mg, twice a day, 12 months

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DIETARY_SUPPLEMENT

Placebo

Interventions

Tocotrienol

Palm-Oil derived Vitamin E, tocotrienol

Intervention Type: DIETARY_SUPPLEMENT

Placebo

Placebo

Intervention Type: DIETARY_SUPPLEMENT

Eligibility 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.

• Minimum Eligible Age: 20 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Clinical Research Centre, Malaysia

OTHER

Sponsor Role: collaborator

Malaysia Palm Oil Board

OTHER_GOV

Sponsor Role: collaborator

Universiti Sains Malaysia

OTHER

Sponsor Role: lead

Responsible Party

Yuen Kah Hay

Professor Dr.

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Kah Hay Yuen, PhD

Role: PRINCIPAL_INVESTIGATOR

Universiti Sains Malaysia

Locations

Seberang Jaya Hospital

Seberang Jaya, Pulau Pinang, Malaysia

Countries

Malaysia

References

Vitamin E in Neuroprotection Study (VENUS) Investigators; Hor CP, Fung WY, Ang HA, Lim SC, Kam LY, Sim SW, Lim LH, Choon WY, Wong JW, Ch'ng ASH, Beh KKM, Wee HC, Ong LM, Khan NAK, Sulaiman SAS, Shuaib IL, Bakar A, Yusof Y, Yusof YM, Abu Bakar F, Tang WS, Teh HL, Wahid NA, Saaidin S, Idris N, Yoon CK, Ong HN, Ganapathy JT, Loo CE, Samy MM, Zainal H, Dharan SCS, Ooi BY, Teoh PY, Tye YL, Yeoh CA, Low DW, Looi I, Yuen KH. Efficacy of Oral Mixed Tocotrienols in Diabetic Peripheral Neuropathy: A Randomized Clinical Trial. JAMA Neurol. 2018 Apr 1;75(4):444-452. doi: 10.1001/jamaneurol.2017.4609.

Reference Type: DERIVED

PMID: 29379943 (View on PubMed)

Other Identifiers

NMRR-10-948-7327

Identifier Type: REGISTRY

Identifier Source: secondary_id

VENUS-7327

Identifier Type: -

Identifier Source: org_study_id