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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, Universiti Sains Malaysia

Tracking Information
First Submitted Date  ICMJE October 24, 2013
First Posted Date  ICMJE October 31, 2013
Last Update Posted Date May 4, 2017
Study Start Date  ICMJE June 2011
Actual Primary Completion Date September 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 24, 2013)
Total Symptoms Score (TSS) (pain, paresthesia, burning, and numbness)of patients with diabetes type 1 and 2 neuropathy. [ Time Frame: 1 year ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 24, 2013)
Neuropathy Impairment Score (NIS) of patients with diabetes type 1 and 2 neuropathy [ Time Frame: 1 year ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: October 24, 2013)
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
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Neuroprotection by Tocotrienols in Type 1 and Type 2 Diabetes Mellitus
Official Title  ICMJE A Clinical Study on the Neuroprotection by Tocotrienols in Type 1 and Type 2 Diabetes Mellitus
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).

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Supportive Care
Condition  ICMJE
  • Diabetic Neuropathy
  • Cognitive Impairment
Intervention  ICMJE
  • Dietary Supplement: Tocotrienol
    Palm-Oil derived Vitamin E, tocotrienol
  • Dietary Supplement: Placebo
    Placebo
Study Arms  ICMJE
  • Experimental: Tocotrienol
    200 mg, twice a day, 12 months
    Intervention: Dietary Supplement: Tocotrienol
  • Placebo Comparator: Placebo
    200 mg, twice a day, 12 months
    Intervention: Dietary Supplement: Placebo
Publications * 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: October 24, 2013)
300
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE December 2016
Actual Primary Completion Date September 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 20 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Malaysia
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01973400
Other Study ID Numbers  ICMJE VENUS-7327
NMRR-10-948-7327 ( Registry Identifier: National Medical Research Register (Malaysia) )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Yuen Kah Hay, Universiti Sains Malaysia
Study Sponsor  ICMJE Universiti Sains Malaysia
Collaborators  ICMJE
  • Clinical Research Centre, Malaysia
  • Malaysia Palm Oil Board
Investigators  ICMJE
Principal Investigator: Kah Hay Yuen, PhD Universiti Sains Malaysia
PRS Account Universiti Sains Malaysia
Verification Date May 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP