Research

JAMA Neurology | Original Investigation

Efficacy of Oral Mixed Tocotrienols

in Diabetic Peripheral Neuropathy
A Randomized Clinical Trial
The Vitamin E in Neuroprotection Study (VENUS) Investigators

Supplemental content
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 ⱖ2.03 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.

Group Information: The Vitamin E in

TRIAL REGISTRATION National Medical Research Registry Identifier: NMRR-10-948-7327 and
Neuroprotection Study (VENUS)
clinicaltrials.gov Identifier: NCT01983400 Investigators are listed at the end of
this article.
Corresponding Author: Kah Hay
Yuen, PhD, School of Pharmaceutical
Sciences, Universiti Sains Malaysia,
JAMA Neurol. doi:10.1001/jamaneurol.2017.4609 Minden, 11800 Penang, Malaysia
Published online January 29, 2018. (khyuen@usm.my).

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 Research Original Investigation
D
iabetic peripheral neuropathy (DPN) remains under-
diagnosed and thus undertreated.1 It affects 26% to
53% of patients with diabetes, imposing a significant
public health burden worldwide.2,3 Neuropathic pain occurs
in 21% to 53% of patients with DPN4,5 and impairs quality of
life.2 Neuropathy has been associated with a quarter of the total
cost of diabetes care,6 whereas direct medical cost for those
with neuropathic pain was reported to be 4.2-fold higher than
for those without.5
Improved glycemic control and pain management are the
mainstay strategies to manage DPN.6 Various pharmacologic
therapies are available to treat DPN.7,8 Used alone or in com-
bination, these therapies achieve a varying degree of satisfac-
tory outcomes9 but are partly limited by their adverse ef-
fects. They mainly provide symptomatic relief and do not affect
the underlying neuropathic process.10
Oxidative stress exerts an important role for the patho-
genesis of DPN.11 Efficacy of alternative agents, such as α-lipoic
acid (ALA),10,12-15 benfotiamine,16,17 acetyle-L-carnitine,18
vitamin E,19 vitamin D2,20 and actovegin,21 have been stud-
ied with variable results.
Tocotrienols are naturally occurring subtypes of vitamin
E that modulate glutamate-induced neuronal apoptosis via in-
hibition of the 12-lipoxygenase pathway in in vitro studies.22,23
Tocotrienols reverse neuropathic pain via modulation of oxi-
dative-nitrosative stress, inflammatory cytokine release, and
caspase-3 in rats with diabetes. 24 Oral administration of
400 mg/d of tocotrienols for 2 years among 121 volunteers at-
tenuated the progression of brain white matter lesions with-
out notable adverse reactions, suggestive of neuroprotective
properties.25 These observations have led to the inception and
conduct of this study, which evaluated the efficacy of oral
mixed tocotrienols in patients with DPN during 12 months.
Methods
Study Design and Participants
The Vitamin E Neuroprotection Study (VENUS) was a multi-
center, randomized, double-blind, placebo-controlled trial con-
ducted from November 30, 2011, to August 7, 2015. The trial
protocol can be found in Supplement 1. Patients 20 years or
older with diabetes were prescreened by face-to-face inter-
view at outpatient units in 6 public primary care clinics and
medical outpatient clinics in 5 public hospitals located in the
Penang and Kedah states of Malaysia. Potential participants
with symptomatic DPN were invited to attend screening vis-
its at respective study clinics. This study was approved by the
Medical Research Ethics Committee, Ministry of Health. Writ-
ten informed consents were obtained from all participants.
During the screening visit, patients were assessed with
Total Symptom Score (TSS) and Neuropathy Impairment Score
(NIS), and venous blood samples were obtained for measure-
ment of fasting blood glucose level, hemoglobin A1c (HbA1c)
level, and renal and liver profiles. Patients were eligible for re-
cruitment with a TSS of 3 or higher and an NIS of 2 or higher.
These cutoffs were selected to allow detection of the least clini-
cally significant improvements in scores.10,15 We excluded in-
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Efficacy of Oral Mixed Tocotrienols in Diabetic Peripheral Neuropathy
Key Points
Question Are oral mixed tocotrienols efficacious in reducing
neuropathic symptoms in patients with diabetic peripheral
neuropathy?
Findings In this randomized clinical trial of 300 adults with
diabetic peripheral neuropathy, tocotrienols administered for 1
year did not reduce the overall neuropathic Total Symptom Score.
Post hoc subgroup analyses revealed that tocotrienols might
improve lancinating pain in those with uncontrolled diabetes and
normal homocysteine levels.
Meaning Supplementation of oral mixed tocotrienols, 400 mg/d
for 1 year, did not improve neuropathic symptoms for diabetic
peripheral neuropathy; the effects on lancinating pain require
further investigation.
dividuals with uncontrolled diabetes (HbA1c>12% [to convert
to proportion of total hemoglobin, multiply by 0.01]), drug
and/or alcohol dependency, psychiatric disorders, and im-
paired renal (serum creatinine level ≥1.7 mg/dL [to convert to
micromoles per liter, multiply by 88.4]) and/or liver (level of
hepatic transaminases ≥5-fold upper limit of normal) func-
tions. We also excluded pregnant or lactating women, those
who were immunocompromised, and those with sympto-
matic peripheral vascular disease or other diseases that might
interfere with the administration of the investigational prod-
ucts or interpretation of the results.
Randomization and Masking
A total of 300 participants were recruited and randomly assigned
to 2 groups with a 1:1 allocation ratio using permuted block ran-
domization (block size of 10). The patients received 1 capsule of
200 mg of mixed tocotrienols or 1 capsule of identical-looking
placebo twice daily for 12 months. Both active (containing 200 mg
of tocotrienols in a 1-g capsule) and placebo (containing 1 g of
tocotrienols-free palm oil in a capsule) capsules were manufac-
tured by Hovid Bhd. The randomization allocation sequence
was generated by an independent pharmacist using an offsite
computer who also prepared the investigational products with
allocated coding and unique identification numbers. Random-
ization and allocation were fully concealed from the principal
investigators, all participating clinicians, research officers, and
participants until the study was completed.
Procedures
The participants were interviewed for their clinical histories
and underwent anthropometric examinations for body mass
index, TSS and NIS assessments, and blood sampling for fast-
ing blood glucose, HbA1c, serum homocysteine, folate, vita-
min B12, and total tocotrienol levels. The TSS and NIS were as-
sessed again at 6 months and at the end of the study at 12
months. Blood samples used to test for the aforementioned bio-
markers were obtained during the follow-up visits.
Serum homocysteine level was measured using a chemi-
luminescent microparticle immunoassay (Architect homocys-
teine assay, Abbott Laboratories) for the quantitative deter-
mination of total L-homocysteine in human serum on the
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 Efficacy of Oral Mixed Tocotrienols in Diabetic Peripheral Neuropathy
Architect i System. Serum folate and vitamin B12 levels were
measured using competitive immunoassays with direct che-
miluminescent technology (Advia Centaur Folate and Advia
Centaur VB12 assays, Bayer Diagnostics). Plasma total tocot-
rienol levels were determined using a simple, validated high-
performance liquid chromatographic method with fluores-
cence detection.26
Sensory nerve conduction tests (NCTs) were performed at
the baseline visit and the end of the study. The NCTs were con-
ducted by a single operator at Seberang Jaya Hospital and inter-
preted by a clinical neurologist (I.L.). Patients were selected if they
were able to travel to the center and consented to undergo NCTs.
All patients attended follow-up visits every 3 months to
obtain the investigational products. They were advised to con-
tact research officers immediately if they suspected a reac-
tion toward the investigational products. All the adverse events
(AEs) and serious adverse events (SAEs) were reported to the
Medical Research Ethics Committee according to the local pro-
tocol. All events in relation to the study intervention were ex-
amined by subinvestigators at respective clinical sites fol-
lowed by a detailed discussion at study update meetings.
Outcomes
Our primary outcome of the study was the mean difference in
TSS changes at 12 months of supplementation compared with
baseline between the tocotrienols and placebo groups. The sec-
ondary outcome was a change in NIS evaluated at 12 months
compared with baseline. A minimal reduction of 1.83 (a half-
range of a maximal single symptom) in the TSS and 2 in the
NIS are considered to be clinically meaningful responses to
treatment.10,15
For TSS assessment, participants were asked to grade the
severity and frequency of the neuropathic symptoms that they
experienced over peripheral limbs (eTable 1 in Supplement 2).27
The TSS ranges from 0 to 14.64. The NIS assessment was per-
formed by the study clinicians on participants to assess their
neuropathy impairment.28 All study clinicians underwent stan-
dardized training with a neurologist (I.L.). The NCT assessed
the latency, amplitude, and velocity conduction of sensory
components of median, radial, and sural nerves.
Adherence
Adherence to study treatment was monitored by returned cap-
sule count. Participants were required to return all remaining
capsules at each follow-up visit, which were counted and docu-
mented. Plasma total tocotrienol levels were measured to en-
sure that participants in both groups were adherent to inves-
tigational product use at baseline and 3-month intervals up to
12 months. The levels were analyzed at the end of study to
maintain masking.
Baseline Serum Homocysteine Level Stratification
Hyperhomocysteinemia exerts neurotoxic effects and corre-
lates with development of neuropathy.29 Although the cutoff
for hyperhomocysteinemia is arbitrary,30 the upper refer-
ence limit for total homocysteine level in adults younger than
65 years was set at 2.03 mg/L (to convert to micromoles per
liter, multiply by 7.397).31 We adopted the conservative cut-
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Original Investigation Research
off of 2.03 mg/L to initiate treatment for reduction of hyper-
homocysteinemia. All participants with hyperhomocystein-
emia in both groups received concurrent supplementation of
oral folic acid, 5 mg/d, and methylcobalamin, 500 μg thrice
daily, as part of the treatment proposed to reduce hyperho-
mocysteinemia, with evidence from the Heart Outcomes Pre-
vention Evaluation (HOPE) 2 study.32 In the stratified analy-
sis, participants were further categorized to an A subgroup
(homocysteine level <2.03 mg/L) and an H subgroup (homo-
cysteine level ≥2.03 mg/L) at baseline.
Statistical Analysis
Sample size for this study was calculated using PS: Power and
Sample Size Calculation software, version 3.1.2,33 based on the
SYDNEY 2 trial (Assessment of Efficacy and Safety of Oral Al-
pha-Lipoic Acid for Symptomatic Diabetic Neuropathy), which
investigated the effects of ALA on DPN.15 Reductions in TSS
were computed after treatment, with a corresponding SD of
3.37. Our study was designed for a minimum of 272 partici-
pants (136 in each arm) to achieve 90% power to detect a dif-
ference between groups of 1.33 of the primary end point after
12 months of supplementation, which reflects a minimum
1-level reduction in frequency and pain severity. To accom-
modate a dropout rate of 10%, we increased the sample size
to 150 per arm for a total of 300 participants.
All the data were hosted at Universiti Sains Malaysia. The
data were deidentified before their use in analyses. All data
were analyzed according to a modified intention-to-treat pro-
tocol. All normally distributed continuous variables were re-
ported as mean (SD) except for serum total tocotrienol level,
which was reported as mean (SEM). Comparison for categori-
cal variables between the tocotrienol and placebo groups was
performed using χ2 tests or Fisher exact tests if the assump-
tions for the χ2 test were unmet. Paired t tests were used to de-
tect differences in clinical and biochemical markers before and
after supplementation in both groups at 6 and 12 months,
whereas independent t tests were performed to compare these
markers and AE rates across both groups. P < .05 was consid-
ered to be statistically significant for all analyses. Statistical
analyses were performed using SPSS, version 23.0. Adverse
events were reported in the full trial population, with refer-
ence to the Medical Dictionary for Regulatory Activities, ver-
sion 12.0.
Results
From November 30, 2011, to July 4, 2014, a total of 14 289 pa-
tients with diabetes were prescreened, and 391 who reported
neuropathic symptoms were assessed with TSS and NIS. The
last follow-up for the last patient was August 7, 2015. A total
of 300 patients who fulfilled the study criteria were recruited
for this study, and 229 (76.3%) completed the trial during 12
months (130 [43.3%] male; mean [SD] age, 57.6 [8.9] years;
mean [SD] duration of diabetes, 11.4 [7.8] years). Among those
who completed the study, 111 participants (74.0%) received to-
cotrienols and 118 (78.7%) received placebo (Figure 1). Seventy-
one participants discontinued the study, among whom 37 were
(Reprinted) JAMA Neurology Published online January 29, 2018 E3
 Research Original Investigation
Figure 1. Trial Profile
14 289 With diabetes prescreened using TSS
391 With DPN symptoms assessed
for eligibility
91 Excluded
75 Did not meet inclusion
criteria
300 Randomized
150 Randomized to receive placebo 150 Randomized to receive tocotrienols
118 Completed trial 111 Completed trial
32 Did not complete trial 39 Did not complete trial
20 Unavailable for follow-up 17 Unavailable for follow-up
7 Adverse events 12 Adverse events
4 Withdrew consent 5 Withdrew consent
1 Poor adherence 5 Poor adherence
150 Included in primary analysis 150 Included in primary analysis
DPN indicates diabetic peripheral neuropathy; TSS, Total Symptom Score.
lost to follow-up, 19 because of AEs, 9 because of personal rea-
sons, and 6 because of poor adherence. The baseline charac-
teristics were similar between the groups (eTable 2 in
Supplement 2).
Baseline characteristics were similar between the groups ex-
cept for distribution of antidiabetic therapies (Table 1). More pa-
tients in the placebo arm were treated solely with oral antidia-
betics, whereas more in the tocotrienols arm received insulin
therapy, although the HbA1c levels were comparable between the
groups. Two patients in each group had type 1 diabetes, with the
remaining having type 2 diabetes. The patients had diabetes with
a mean duration of more than 10 years, with a mean HbA1c level
exceeding 8%. Most were overweight and had multiple comor-
bidities. The TSSs and NISs were similar between the groups ex-
cept for the TSS subscore for paresthesia.
The mean investigational product adherence during 12
months, reported by pill counting, was 81.7% in the tocotri-
enols group and 86.1% in the placebo group (P = .16). The mean
level of tocotrienol at baseline was 0.03 (0.003) μg/mL in the
tocotrienol group and 0.03 (0.002) μg/mL in the placebo group.
The mean level of plasma total tocotrienols increased signifi-
cantly by 5.3-fold to 0.19 (0.018) μg/mL in the intervention
group after 3-month supplementation and plateaued after-
ward (Figure 2).
The treatment and placebo groups achieved clinically
meaningful responses of reductions greater than 1.83 in TSS
at 12 months (Table 2). No significant differences were found
in TSS change between the tocotrienol and placebo groups at
12 months (−0.30; 95% CI, −1.16 to 0.56; P = .49).
Slight improvements in total NIS were observed in both
groups, without significant between-group differences by 12
months (0.6; 95% CI, −1.37 to 2.65; P = .53) (eTable 3 in
Supplement 2). Sensory scores for the upper and lower limbs
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Efficacy of Oral Mixed Tocotrienols in Diabetic Peripheral Neuropathy
and tendon reflex score improved in the placebo group but not
in the tocotrienol group. Muscle strength over the peripheral
upper and lower limbs was unaffected by either intervention.
Latency, amplitude, and velocity conduction for sensory me-
dian, radial, and sural nerves was similar between the groups
(eTable 4 in Supplement 2).
Glycemic control between the groups was similar (eTable 5
in Supplement 2). However, the placebo group had a progressive
significant increase of 0.4% in HbA1c level (P = .01) and of
23 mg/dL (to convert to millimoles per liter, multiply by 0.0555)
in fasting blood glucose level (P = .002) during 1 year. In contrast,
glycemic control in the tocotrienol group remained stable.
Most patients had adequate folate (293 patients [97.7%];
>2.8 ng/mL [to convert to nanomoles per liter, multiply by 2.266])
and vitamin B12 (296 [98.7%]; >211 pg/mL [to convert to picomoles
per liter, multiply by 0.7378]). A total of 108 (72.0%) in the pla-
cebo group and 101 (67.3%) in the tocotrienols group had normal
homocysteine levels (<2.03 mg/L). Four patients had vitamin B12
levels that ranged from 184 to 205 pg/mL with hyperhomocys-
teinemia (homocysteine level ≥2.03 mg/L). Patients with normo-
homocysteinemia in both groups had progressive increment in
their serum homocysteine levels, although their folate and vi-
tamin B12 levels remained within the normal range (eTable 6 in
Supplement 2). In contrast, patients with hyperhomocysteinemia
had lower folate and vitamin B12 levels at baseline. After oral fo-
lic acid and methylcobalamine supplementation, their homocys-
teine levels had decreased significantly, whereas their serum fo-
late and vitamin B12 levels were increased.
In post hoc subgroup analyses, the tocotrienols group ex-
perienced a significant reduction in lancinating pain score at
6 months compared with the placebo group (−0.6; 95% CI,
−0.71 to −0.01; P = .04). A further reduction occurred at 12
months, but it did not achieve statistical significance (−0.64;
95% CI, −0.70 to 0.02; P = .07). Reduction in other compo-
nents of TSS were similar between the groups during the study
period. Compared with patients with baseline HbA1c levels of
8.0% or less, those with HbA1c levels greater than 8% in the
tocotrienols group had their lancinating pain score reduced by
0.7 at 12 months (95% CI, −0.92 to −0.05; P = .03) (Table 3).
Patients with normohomocysteinemia in the tocotrienols group
experienced reduction in their lancinating pain at the end of
the study (−0.9; 95% CI, −1.06 to −0.16; P = .008) but not
among those with hyperhomocysteinemia despite treatment
with homocysteine-lowering agents.
Nineteen patients withdrew from the study because of AEs
(7 from the placebo group and 12 from the tocotrienol group)
(eTable 2 in Supplement 2). All events occurred after 1 month
of supplementation of the investigational products.
Sixty patients reported at least 1 AE (eTable 7 in Supplement
2). In a total of 69 AEs reported, 34 events (49.3%) occurred
among 30 patients in the placebo group and 35 events (50.7%)
among 30 patients in the tocotrienols group (χ 21 < 0.001,
P > .99). Skin and soft-tissues disorders, minor traumatic in-
juries, and infections were among the most common AEs re-
ported. More infectious events occurred in the placebo group,
whereas more unintended traumatic injuries were observed
in the tocotrienol groups. Most AEs occurred after 3 months
of study enrollment.
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 Efficacy of Oral Mixed Tocotrienols in Diabetic Peripheral Neuropathy Original Investigation Research

Table 1. Baseline Characteristics by Study Groupa

Placebo Tocotrienols
Characteristic (n = 150) (n = 150) P Value
Male 63 (42.0) 67 (44.7) .64
Age, mean (SD), y 57.2 (8.9) 58.0 (8.9) .45
Ethnicity
Malay 81 (54.0) 86 (57.3) .53
Chinese 16 (10.7) 9 (6.0)
Indian 52 (34.7) 54 (36.0)
Others 1 (0.7) 1 (0.7)
Duration of diabetes, mean (SD), y 11.1 (8.0) 11.8 (7.6) .46
Treatment
Oral OADs only 87 (58.0) 64 (42.7) .008
Insulin only 4 (2.7) 12 (8.1) .04
Combined insulin and OADs 58 (38.7) 73 (48.7) .08
Comorbidities
Hypertension 106 (70.7) 103 (68.7) .71
Dyslipidemia 119 (79.3) 130 (86.7) .09
Ischemic heart disease 33 (22.0) 23 (15.3) .14
BMI, mean (SD) 28.2 (5.06) 27.6 (5.36) .29 Abbreviations: BMI, body mass index
HbA1c level, mean (SD), % 8.7 (1.82) 9.2 (1.97) .06 (calculated as weight in kilograms
divided by height in meters squared);
Fasting blood glucose level, mean (SD), mg/dL 151 (60) 164 (76) .15 HbA1c, hemoglobin A1c; OADs, oral
Serum homocysteine level, mean (SD), mg/L 1.80 (0.70) 1.84 (0.91) .66 antidiabetics; TSS, Total Symptom
Serum folate level, mean (SD), ng/mL 9.4 (5.3) 9.2 (5.4) .79 Score.
SI conversion factors: To convert
Serum vitamin B12 level, mean (SD), pg/mL 594.5 (307.6) 606.2 (317.1) .74
fasting blood glucose to millimoles
TSS, mean (SD) 7.6 (2.5) 8.2 (2.9) .07 per liter, multiply by 0.0555;
Component TSS, mean (SD) homocysteine to micromoles per
liter, multiply by 7.397; folate to
Lancinating pain 0.8 (1.3) 1.1 (1.4) .10
nanomoles per liter, multiply by
Burning pain 1.7 (1.3) 1.7 (1.4) .75 2.266; and B12 to picomoles per liter,
Paresthesia 2.4 (0.9) 2.6 (0.8) .009 multiply by 0.7378.
a
Asleep numbness 2.8 (0.6) 2.8 (0.8) .89 Data are presented as number
(percentage) of patients unless
Neuropathy Impairment Score, mean (SD) 15.8 (8.4) 16.2 (9.0) .73
otherwise indicated.

A total of 48 SAEs that involved hospitalization for preex-

Figure 2. Mean Plasma Total Tocotrienol Levels During 12 Months
isting conditions or other causes (eTable 8 in Supplement 2) by Study Group
were reported. Of these, 21 events occurred among 15 pa-
tients in the placebo group and 27 events among 24 patients 0.25
Placebo group Tocotrienols group
Plasma Total Tocotrienols Levels, μg/mL

in the tocotrienols group (χ 21 = 1.926, P = .16). Most patients had

concomitant comorbidities and macrovascular and microvas- 0.20
cular complications of diabetes. Three patients with diabetic
foot ulcers underwent lower limb amputations. The inci- 0.15
dence of SAEs was similar between the groups, with the ex-
ception that more infections were observed in the tocotri- 0.10
enols group (6.7% vs 0.7%, P = .04). One patient in the
tocotrienols group died of nosocomial sepsis complicated with
0.05
renal failure and severe metabolic acidosis after 11 months of
supplementation. Most of the events occurred after 3 months
0
of enrollment in the study. All reported SAEs were unlikely to Baseline 3 6 9 12
be related to the study treatments. Treatment Duration, mo

Error bars indicate SEM.

Discussion tion of tocotrienols for 1 year did not influence the TSS, NIS,
This is a novel study on the efficacy and safety of oral admin- and sensory NCT outcomes for patients with DPN.
istration of mixed tocotrienols for the treatment of DPN in a To date, evidence on the clinical efficacies of nutraceuti-
multiethnic Asian population. In this study, supplementa- cals on DPN is limited. Although previous studies12,13 have re-

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 Research Original Investigation Efficacy of Oral Mixed Tocotrienols in Diabetic Peripheral Neuropathy

Table 2. Total and Component TSS Changes During 12 Months by Study Group

Placebo (n = 150) Tocotrienols (n = 150)

P Value P Value P Value
(Within (Within (Between
Assessment Mean (SD) Group) Mean (SD) Group) Groups)
TSS
Baseline 7.6 (2.5) NA 8.1 (2.9) NA NA
6 mo 5.6 (3.2) <.001 5.7 (3.2) <.001 NA
12 mo 4.9 (3.3) <.001 5.0 (3.3) <.001 NA
Change (6 mo minus baseline) −2.2 (3.1) NA −2.6 (3.3) NA .24
Change (12 mo minus baseline) −3.0 (3.3) NA −3.3 (3.3) NA .49
Lancinating pain
Baseline 0.8 (1.3) NA 1.0 (1.4) NA NA
6 mo 0.6 (1.2) .08 0.5 (1.0) <.001 NA
12 mo 0.6 (1.2) .02 0.4 (1.0) <.001 NA
Change (6 mo minus baseline) −0.2 (1.4) NA −0.6 (1.4) NA .04
Change (12 mo minus baseline) −0.3 (1.4) NA −0.6 (1.3) NA .07
Burning pain
Baseline 1.7 (1.3) NA 1.7 (1.4) NA NA
6 mo 1.1 (1.3) <.001 1.2 (1.3) <.001 NA
12 mo 0.9 (1.2) <.001 0.9 (1.2) <.001 NA
Change (6 mo minus baseline) −0.6 (1.5) NA −0.6 (1.4) NA .93
Change (12 mo minus baseline) −0.8 (1.4) NA −0.9 (1.5) NA .83
Paresthesia
Baseline 2.4 (0.9) NA 2.6 (0.8) NA NA
6 mo 1.6 (1.2) <.001 1.7 (1.3) <.001 NA
12 mo 1.3 (1.3) <.001 1.5 (1.3) <.001 NA
Change (6 mo minus baseline) −0.9 (1.4) NA −0.9 (1.2) NA .66
Change (12 mo minus baseline) −1.1 (1.4) NA −1.1 (1.3) NA .82
Asleep numbness
Baseline 2.8 (0.6) NA 2.8 (0.8) NA NA
6 mo 2.3 (1.1) <.001 2.3 (1.0) <.001 NA
12 mo 2.1 (1.0) <.001 2.2 (1.1) <.001 NA
Change (6 mo minus baseline) −0.5 (1.1) NA −0.5 (1.0) NA .87
Abbreviations: NA, not applicable;
Change (12 mo minus baseline) −0.7 (1.1) NA −0.6 (1.2) NA .43
TSS, Total Symptom Score.

ported on the efficacy of DPN after ALA injection, oral ALA had
conflicting results, depending on the measured outcomes and
treatment duration.10,14,15 Our study findings were similar to
those of the NATHAN 1 (Assessment of Efficacy and Safety of
Oral Alpha-Lipoic Acid for Diabetic Neuropathy [Stage 1 or 2])
study, 10 which also did not meet its primary end point using
a composite score after daily supplementation of 600 mg of
ALA for 4 years. The pilot BEDIP (Benfotiamine in Diabetic Poly-
neuropathy) trial found that 200 mg/d of benfotiamine for 3
weeks improved neuropathic symptoms,16 but higher dos-
ages up to 600 mg/d did not improve the Neuropathy Symp-
tom Score or TSS as demonstrated in the BENDIP (Benfo-
tiamine in Diabetic Polyneuropathy) study.17
The prominent placebo effects observed in this trial are
relatively common. This phenomenon has increased in re-
cent trials on the treatment of various types of neuropathic pain
and might lead to an underestimation of drug effects.34 The
close monitoring might have partially contributed to the pla-
cebo responses, especially in patient-reported outcome such
as TSS. In addition, pain threshold can vary among individu-
als. A Cochrane review reported that a moderate placebo ef-
fect was detected in self-reported continuous outcomes across
interventional trials on any clinical condition, and such an ef-
fect was greater for trials that involved self-reported pain
outcomes.35
The NIS is a more objective assessment that provides di-
rect measures of nerve dysfunction. It assesses predomi-
nantly evoked pain using pinprick, sensory, and vibration loss
but does not detect changes in spontaneous pain experi-
enced by patients with painful DPN, which may partially ex-
plain the absence of treatment effects on NIS in this study.
There was no apparent impairment in sensory nerve conduc-
tion for patients from both groups. Patients with painful DPN
had predominantly small fiber neuropathy, and abnormal elec-
trophysiologic findings may be absent in the presence of
symptoms,8,36 as observed in this study.
Post hoc subgroup analyses found that tocotrienols might
alleviate lancinating pain in patients with DPN who had poorly
controlled diabetes (HbA1c level >8%) and normohomocys-
teinemia (homocysteine level <2.03 mg/L) compared with pla-

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 Efficacy of Oral Mixed Tocotrienols in Diabetic Peripheral Neuropathy Original Investigation Research

Table 3. Lancinating Pain Score Changes According to Baseline Antidiabetic Regimen, HbA1c Level, and Serum Homocysteine Level by Study Group

By Month 6 By Month 12
Placebo Tocotrienols Placebo Tocotrienols
Score Change From Baseline (n = 150) (n = 150) P Value (n = 150) (n = 150) P Value
Baseline HbA1c
HBA1c ≤8.0% −0.4 (1.6) −0.4 (1.2) .97 −0.4 (1.7) −0.6 (1.1) .71
HBA1c >8.0% −0.1 (1.3) −0.7 (1.4) .008 −0.2 (1.2) −0.7 (1.4) .03
Baseline homocysteinea
A subgroup (<2.03 mg/L) −0.2 (1.5) −0.7 (1.5) .01 −0.3 (1.5) −0.9 (1.3) .008
H subgroup (≥2.03 mg/L) −0.4 (1.4) −0.3 (1.0) .71 −0.4 (1.1) −0.2 (1.2) .39
Abbreviation: HbA1c, hemoglobin A1c.
SI conversion factors: To convert homocysteine to micromoles per liter, multiply by 7.397; folate to nanomoles per liter, multiply by 2.266.
a
In the stratified analysis, participants were further categorized to an A subgroup (<2.03 mg/L) and an H subgroup (ⱖ2.03 mg/L) at baseline.

cebo. Neuropathic pain is a complex group of positive sen-
sory phenomena attributable to neuronal dysfunction at
different levels, with each attributable to discrete pathophysi-
ologic mechanisms that operate at a defined level.37 Nonethe-
less, whether tocotrienols might modulate the mechanisms
that lead to lancinating pain but not the other neuropathic
symptoms with different underlying pathophysiologic mecha-
nisms remains unclear. Therefore, we interpret these prelimi-
nary observations with caution because the cutoff to define a
clinically meaningful change in a TSS subscale is lacking.
Homocysteine level is independently associated with the
development and severity of DPN.29 A total of 30.3% of our
study population had hyperhomocysteinemia. Patients with
normohomocysteinemia at baseline responded better to to-
cotrienols in reducing their lancinating pain. For those with
hyperhomocysteinemia, additional supplementation of oral fo-
lic acid and methylcobalamin significantly decreased homo-
cysteine levels by 26.3% in the placebo group and 24.7% in the
tocotrienols group. Despite normalization of hyperhomocys-
teine levels, we did not observe any effect of tocotrienols on
lancinating pain similar to that in patients with normohomo-
cysteinemia at the baseline visit. Because of the complex DPN
development and progression, a possible interaction be-
tween variable serum homocysteine and effect of pharmaco-
logic interventions on DPN require further investigation. Such
an investigation might provide insights into explaining why
previous alternative therapies produced variable results.
Oral mixed tocotrienols are well tolerated and relatively
safe. The high number of AEs and SAEs in both groups re-
flected the increased risk of complications associated with long-
standing diabetes.
Limitations
The main limitation in our study was the lack of an objective test,
such as a quantitative sensory test and/or nerve biopsy, in assess-
ing the peripheral nerve dysfunction. Nonetheless, patient-
reported outcome based on TSS was acceptable for patients.
Moreover, the diagnosis and assessment of painful DPN rely on
patients’ perception and description of pain, whereas external
observers’ impressions are noted to have limited value in the as-
sessment of patients’ responses toward new therapies for neu-
ropathic pain.38 In addition, the study population, which was
composed of patients with multiple comorbidities, duration of
diabetes of more than 10 years, and a mean suboptimal HbA1c
level greater than 8.5%, was reflective of real-life practice.
A lower cutoff TSS of 3 or higher was selected to include
patients with mild DPN compared with 4 or higher in the
ALADIN 3 (α-Lipoic Acid in Diabetic Neuropathy) trial14 and 5
or higher in the SYDNEY 2 trial.15 We acknowledged a drop-
out rate of 23.7% from this trial. However, our study had 83.4%
power to detect a mean difference of 1.33 for the TSS after a
12-month period in both groups. In addition, the placebo group
might have less severe disease, with a higher proportion tak-
ing only oral antidiabetics, whereas more in the tocotrienols
group received insulin. We recognized inclusion of patients
with vitamin B12 deficiency as a drawback. Two patients in each
group were found to have vitamin B12 levels of 211 pg/mL or
lower with concomitant hyperhomocysteinemia. After supple-
mentation of mecobalamin and folic acid, their serum vita-
min B12 and homocysteine levels were restored to normal lev-
els by 6 months.
Conclusions
Oral supplementation of 400 mg/d of mixed tocotrienols for
1 year did not reduce overall neuropathic symptoms of DPN.
Tocotrienols were relatively well tolerated and had a safety pro-
file comparable to that of placebo. The preliminary observa-
tions of the effect of tocotrienols on lancinating pain among
subsets of patients generate new hypotheses and need fur-
ther evaluation. We propose future trials on the effects of lon-
ger-term mixed tocotrienols on DPN progression and patient
quality of life.

ARTICLE INFORMATION
Accepted for Publication: October 30, 2017.
Published Online: January 29, 2018.
doi:10.1001/jamaneurol.2017.4609
Vitamin E in Neuroprotection Study (VENUS)
Investigators: The following investigators take
authorship responsibility for the study results: Chee
Peng Hor, MB BCh BAO; Wai Yee Fung, PhD; Hock
Aun Ang, FRCP; Sheau Chin Lim, PhD; Li Ying Kam,
PhD; Su-Way Sim, PhD; Luen Hui Lim, MSc; Wai Yee
Choon, PhD; Jia Woei Wong, PhD; Alan Swee Hock
Ch’ng, MMed (Int Med); Kelvin Khai Meng Beh, BM;
Hong Chin Wee, MD; Loke Meng Ong, FRCP;
Nurzalina Abdul Karim Khan, PhD; Syed Azhar Syed

jamaneurology.com (Reprinted) JAMA Neurology Published online January 29, 2018 E7

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 Research Original Investigation
Sulaiman, PhD; Ibrahim Lutfi Shuaib, FRCR; Adlina
Bakar, MMed (Fam Med); Yusnita Yusof, MMed
(Fam Med); Yusmawati Mohd Yusof, MMed (Fam
Med); Fatimah Abu Bakar, MMed (Fam Med); Wei
Shuong Tang, MMed (Fam Med); Hoon Lang Teh,
MRCP; Normala Abdul Wahid, MSc Com Med;
Suriani Saaidin, MBBS; Najihah Idris, MMed (Int
Med); Chee Kin Yoon, MRCP; Hoon Ngoh Ong, MD;
Jayasumithra T. Ganapathy, Dip (Fam Med); Ching
Ee Loo, MB BCh BAO; Michelle M. Samy, MD;
Hadzlinda Zainal, DrPH; Shalini C. Sree Dharan, MD;
Bee Yen Ooi, MBBS; Pei Yeing Teoh, MD; Yi Loon
Tye, MRCP; Chin Aun Yeoh, MRCP; Dy Win Low,
MRCP; Irene Looi, MRCP; Kah Hay Yuen, PhD.
Affiliations of Vitamin E in Neuroprotection
Study (VENUS) Investigators: Department of
Medicine, Kepala Batas Hospital, Penang, Malaysia
(Hor); School of Pharmaceutical Sciences, Universiti
Sains Malaysia, Penang, Malaysia (Fung, S. C. Lim,
Kam, Sim, L. H. Lim, Choon, Khan, Sulaiman, Yuen);
Clinical Research Centre, Seberang Jaya Hospital,
Penang, Malaysia (Ang, Ch’ng, Beh, Loo, Samy, Ooi,
Teoh, Looi); Attest Research Sdn Bhd, Penang,
Malaysia (Wong); Clinical Research Centre, Penang
General Hospital, Penang, Malaysia (Wee, L. M.
Ong, Zainal); Oncological and Radiological Sciences
Cluster, Advanced Medical and Dental Institute,
Universiti Sains Malaysia, Penang, Malaysia
(Shuaib); Butterworth Health Clinic, Penang,
Malaysia (Bakar); Bandar Tasek Mutiara Health
Clinic, Penang, Malaysia (Y. Yusof); Seberang Jaya
Health Clinic, Penang, Malaysia (Y. M. Yusof);
Penaga Health Clinic, Penang, Malaysia (Abu Bakar);
Bayan Baru Health Clinic, Penang, Malaysia (Tang,
H. N. Ong, Ganapathy); Department of Medicine,
Kulim Hospital, Kedah, Malaysia (Teh, Idris,
Dharan); Sejahtera Centre, Universiti Sains
Malaysia, Penang, Malaysia (Wahid); Department of
Outpatient Care, Sungai Bakap Hospital, Penang,
Malaysia (Saaidin); Department of Medicine,
Penang General Hospital, Penang, Malaysia (Yoon);
Department of Medicine, Seberang Jaya Hospital,
Penang, Malaysia (Tye, Yeoh, Low).
Author Contributions: Dr Yuen had full access to
all the data in the study and takes responsibility for
the integrity of the data and the accuracy of the
data analysis.
Study concept and design: Ang, S. Lim, Sim, L. Lim,
Choon, Wong, Wee, L. Ong, Abdul Karim Khan,
Syed Sulaiman, Bakar, Yusof, Mohd Yusof, Abdul
Wahid, Idris, Yoon, Ganapathy, Zainal, Ooi, Tye,
Yeoh, Low, Looi, Yuen.
Acquisition, analysis, or interpretation of data: Hor,
Fung, Ang, Kam, Sim, L. Lim, Choon, Ch'ng, Beh,
Wee, Abdul Karim Khan, Syed Sulaiman, Shuaib,
Bakar, Yusof, Mohd Yusof, Abu Bakar, Tang, Teh,
Abdul Wahid, Saaidin, Idris, Yoon, H. Ong,
Ganapathy, Loo, Zainal, C. Sree Dharan, Ooi, Teoh,
Tye, Low, Looi.
Drafting of the manuscript: Hor, Fung, Abdul Karim
Khan, Shuaib, Bakar, Saaidin, Idris, C. Sree Dharan,
Teoh, Looi.
Critical revision of the manuscript for important
intellectual content: Hor, Fung, Ang, S. Lim, Kam,
Sim, L. Lim, Choon, Wong, Ch'ng, Beh, Wee, L. Ong,
Syed Sulaiman, Yusof, Mohd Yusof, Abu Bakar, Tang,
Teh, Abdul Wahid, Yoon, H. Ong, Ganapathy, Loo,
Zainal, Ooi, Tye, Yeoh, Low, Looi, Yuen.
Statistical analysis: Hor.
Obtained funding: Yuen.
Administrative, technical, or material support: Hor,
Fung, Ang, S. Lim, Kam, Sim, L. Lim, Choon, Wong,
Beh, Wee, L. Ong, Abdul Karim Khan, Syed
E8 JAMA Neurology Published online January 29, 2018 (Reprinted)
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Efficacy of Oral Mixed Tocotrienols in Diabetic Peripheral Neuropathy
Sulaiman, Shuaib, Bakar, Yusof, Mohd Yusof, Abu
Bakar, Teh, Abdul Wahid, Yoon, Ganapathy, Loo,
Zainal, Ooi, Teoh, Tye, Yeoh, Low, Looi.
Study Supervision: Ang, Ch'ng, Yeoh.
Conflict of Interest Disclosures: Dr Yuen is an
executive director and shareholder of Hovid
Berhad. Dr Yuen reported receiving research grants
from the Performance Management and Delivery
Unit under the Prime Minister Department of
Malaysia and the Malaysian Palm Oil Board.
Dr Wong is the R&D manager of Attest Research
Sdn Bhd, a wholly owned subsidiary of Hovid
Berhad. No other disclosures were reported.
Funding/Support: This study was funded by the
Government of Malaysia through the Malaysian
Palm Oil Board (Dr Yuen).
Role of the Funder/Sponsor: The funding source
had no role in the design and conduct of the study;
collection, management, analysis, and
interpretation of the data; and the preparation of
the manuscript.
Additional Contributions: We thank the Malaysian
director general of health for his approval for this
publication.
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