1. JAMA Neurol. 2018 Apr 1;75(4):444-452. doi: 10.1001/jamaneurol.2017.4609.

Efficacy of Oral Mixed Tocotrienols in Diabetic Peripheral Neuropathy: A
Randomized Clinical Trial.

Vitamin E in Neuroprotection Study (VENUS) Investigators, Hor CP(1), Fung WY(2), 
Ang HA(3), Lim SC(2), Kam LY(2), Sim SW(2), Lim LH(2), Choon WY(2), Wong JW(4),
Ch'ng ASH(3), Beh KKM(3), Wee HC(5), Ong LM(5), Khan NAK(2), Sulaiman SAS(2),
Shuaib IL(6), Bakar A(7), Yusof Y(8), Yusof YM(9), Abu Bakar F(10), Tang WS(11), 
Teh HL(12), Wahid NA(13), Saaidin S(14), Idris N(12), Yoon CK(15), Ong HN(11),
Ganapathy JT(11), Loo CE(3), Samy MM(3), Zainal H(5), Dharan SCS(12), Ooi BY(3), 
Teoh PY(3), Tye YL(16), Yeoh CA(16), Low DW(16), Looi I(3), Yuen KH(2).

Author information: 
(1)Department of Medicine, Kepala Batas Hospital, Penang, Malaysia.
(2)School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang,
Malaysia.
(3)Clinical Research Centre, Seberang Jaya Hospital, Penang, Malaysia.
(4)Attest Research Sdn Bhd, Penang, Malaysia.
(5)Clinical Research Centre, Penang General Hospital, Penang, Malaysia.
(6)Oncological and Radiological Sciences Cluster, Advanced Medical and Dental
Institute, Universiti Sains Malaysia, Penang, Malaysia.
(7)Butterworth Health Clinic, Penang, Malaysia.
(8)Bandar Tasek Mutiara Health Clinic, Penang, Malaysia.
(9)Seberang Jaya Health Clinic, Penang, Malaysia.
(10)Penaga Health Clinic, Penang, Malaysia.
(11)Bayan Baru Health Clinic, Penang, Malaysia.
(12)Department of Medicine, Kulim Hospital, Kedah, Malaysia.
(13)Sejahtera Centre, Universiti Sains Malaysia, Penang, Malaysia.
(14)Department of Outpatient Care, Sungai Bakap Hospital, Penang, Malaysia.
(15)Department of Medicine, Penang General Hospital, Penang, Malaysia.
(16)Department of Medicine, Seberang Jaya Hospital, Penang, Malaysia.

Importance: Management of painful diabetic peripheral neuropathy remains
challenging. Most therapies provide symptomatic relief with varying degrees of
efficacy. Tocotrienols have modulatory effects on the neuropathy pathway and may 
reduce neuropathic symptoms with their antioxidative and anti-inflammatory
activities.
Objective: To evaluate the efficacy of oral mixed tocotrienols for patients with 
diabetic peripheral neuropathy.
Design, Setting, and Participants: The Vitamin E in Neuroprotection Study (VENUS)
was a parallel, double-blind, placebo-controlled trial that recruited
participants from January 30, 2011, to December 7, 2014, with 12 months of
follow-up. This trial screened 14 289 patients with diabetes from 6 health
clinics and ambulatory care units from 5 public hospitals in Malaysia. A total of
391 patients who reported neuropathic symptoms were further assessed with Total
Symptom Score (TSS) and Neuropathy Impairment Score (NIS). Patients 20 years or
older with a TSS of 3 or higher and an NIS of 2 or higher were recruited.
Interventions: Patients were randomized to receive 200 mg of mixed tocotrienols
twice daily or matching placebo for 12 months. Patients with hyperhomocysteinemia
(homocysteine level ≥2.03 mg/L) received oral folic acid, 5 mg once daily, and
methylcobalamin, 500 μg thrice daily, in both groups.
Main Outcomes and Measures: The primary outcome was patient-reported neuropathy
TSS (lancinating pain, burning pain, paresthesia, and asleep numbness) changes at
12 months. The secondary outcomes were NIS and sensory nerve conduction test
result.
Results: Of 391 eligible patients, 300 were recruited (130 [43.3%] male; mean
[SD] age, 57.6 [8.9] years; mean [SD] duration of diabetes, 11.4 [7.8] years) and
229 (76.3%) completed the trial. The TSS changes between the tocotrienols and
placebo groups at 12 months (-0.30; 95% CI, -1.16 to 0.56; P = .49) were similar.
No significant differences in NIS (0.60; 95% CI, -1.37 to 2.65; P = .53) and
sensory nerve conduction test assessments were found between both groups. In post
hoc subgroup analyses, tocotrienols reduced lancinating pain among patients with 
hemoglobin A1C levels greater than 8% (P = .03) and normohomocysteinemia
(homocysteine level <2.03 mg/L; P = .008) at 1 year. Serious adverse events in
both groups were similar, except more infections were observed in the
tocotrienols group (6.7% vs 0.7%, P = .04). Results reported were of modified
intention-to-treat analyses.
Conclusions and Relevance: Supplementation of oral mixed tocotrienols, 400 mg/d
for 1 year, did not improve overall neuropathic symptoms. The preliminary
observations on lancinating pain among subsets of patients require further
exploration.
Trial Registration: National Medical Research Registry Identifier:
NMRR-10-948-7327 and clinicaltrials.gov Identifier: NCT01973400.

DOI: 10.1001/jamaneurol.2017.4609 
PMCID: PMC5885181
PMID: 29379943