The Effectiveness of Fixed Dose Combination of Alpha Lipoic Acid and Vitamin B Preparations for Treatment of Diabetic Polyneuropathy in Type 2 Diabetes Mellitus Patients: A Randomized Placebo-controlled Trial
Phase: PHASE2
Conditions: Diabetic Polyneuropathy
Sponsor: Universiti Sains Malaysia

1 
 
  
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
The Effectiveness of Fixed Dose Combination of 
8 
Alpha Lipoic Acid and Vitamin B Preparation 
9 
for Treatment of Diabetic Polyneuropathy in 
10 
Type 2 diabetes mellitus patients : A 
11 
randomized placebo-controlled trial. 
12 
 
13 
 
14 
DATE: 31ST MARCH 2024 
15 
 
16 
 
17 
 
18 
 
19 
 
20 
 
21 
 
22 
 
23 
 
24 
 
25 
 
26 
 
27 
 
28 
 
29 
 
30 
 
31 
 
32 
 
33 
 
34 
 
35 
 
36 

2 
 
RESEARCH TITLE 
37 
 
38 
The Effectiveness of Fixed Dose Combination of Alpha Lipoic Acid and Vitamin B 
39 
Preparations for Treatment of Diabetic Polyneuropathy in Type 2 diabetes mellitus patients: A 
40 
randomized placebo-controlled trial 
41 
 
42 
INVESTIGATORS 
43 
 
44 
Dr. Che Nur Ain Che Abdullah (MPM 67428) 
45 
Dr. Noraini Mohamad MMC (MPM: 42668) 
46 
Associate Professor Dr. Nani Draman (MPM 35488) 
47 
Dr. Zainab Mat Yudin@Badrin (MPM 40301) 
48 
Associate Professor Dr. Wan Muhamad Amir Bin Wan Ahmad 
49 
Dr. Ritzzaleena Rosli Binti Mohd Rosli (MPM 58719) 
50 
 
51 
1. INTRODUCTION 
52 
 
53 
Diabetes poses a significant non-communicable health challenge in both developed and 
54 
developing nations, including Malaysia. Individuals with diabetes are experiencing longer 
55 
lifespans but they are susceptible to microvascular and macrovascular complications. 
56 
 
57 
Diabetic peripheral neuropathy (DPN) stands as one of the most prevalent and debilitating 
58 
complications of type 2 diabetes mellitus (T2DM), attributed to chronic hyperglycaemia and is 
59 
characterized by peripheral nerve dysfunction following the elimination of other potential 
60 
causes (Darivemula et al., 2019). Diabetes mellitus (DM) is an escalating global epidemic that 
61 
leads to an increase in prevalence of peripheral neuropathy affecting 50.7% of patients (Mimi 
62 
et al., 2003). The collective occurrence of DPN varied across various countries, amounting to 
63 
26.71% (Lu et al., 2020). In Malaysia, a study conducted in Selangor found that, the proportion 
64 
of patients with positive neuropathy symptoms score (NSS) was 49.4%. However, only 0.2% 
65 
were diagnosed with positive DPN in their clinical foot examination record (Lee et al., 2022). 
66 
 
67 
This neuropathic condition arises from chronic hyperglycaemia-induced damage to peripheral 
68 
nerves and is characterized by a symmetrical, distal, and length-dependent pattern of sensory 
69 
and motor deficits. This diverse range of conditions impacts various aspects of the nervous 
70 
system and manifests with various clinical symptoms.  
71 
 
72 
The most prevalent form of diabetic neuropathies is chronic distal symmetric polyneuropathy 
73 
(DSPN), constituting approximately 75% of all cases of diabetic neuropathies. Painful DSPN 
74 
is encountered in 13–26% of diabetes patients (Pop-Busui et al., 2017b). 
75 
 
76 
While the exact pathophysiological mechanisms underlying DPN remain multifaceted and not 
77 
entirely elucidated, the cumulative effect of metabolic abnormalities, neurovascular 
78 
dysfunction, oxidative stress, and inflammatory processes play pivotal roles in its development 
79 
and progression. The reason remains unidentified in as many as 40% of individuals 
80 
experiencing neuropathy (Jensen et al., 2021). 
81 
 
82 
Clinically, DPN manifests with a spectrum of symptoms, reduced or abolished sensation to 
83 
touch, pinprick, temperature, vibration, and, more rarely, proprioception. Most of the patient is 
84 

3 
 
asymptomatic and abnormalities may only be revealed during the clinical examination (Jensen 
85 
et al., 2021). 
86 
 
87 
To diagnose painful DPN, a neurological examination with socks and shoes off is a basic 
88 
prerequisite for symptom assessment (Tesfaye et al., 2011). One of the methods to access the 
89 
presence and severity of neuropathy symptoms and signs by using the modified Neuropathy 
90 
Symptom Score (NSS) and Neuropathy Disability Score (NDS) which has 82% sensitivity and 
91 
67% specificity (Lee et al., 2022). 
92 
 
93 
DPN exerting a profound impact on patients' quality of life and overall health outcomes. This 
94 
chronic neuropathic pain has been linked to poor sleep, anxiety and depressive symptoms, and 
95 
a lower quality of life (QoL) in diabetic patients (Gylfadottir et al., 2020). This will also 
96 
increase risk of falls, foot ulceration and amputation (Callaghan et al., 2020). So early detection 
97 
and comprehensive management strategies are paramount in mitigating the impact of DPN and 
98 
preventing its severe complications (Debele et al., 2023).  
99 
 
100 
2. PROBLEM STATEMENT AND RATIONALE 
101 
 
102 
As the incidence of T2DM continues to rise globally, the prevalence of DPN is also escalating, 
103 
representing a significant healthcare burden (Jadhao et al., 2024). Although initially the patient 
104 
may have no symptoms, it can cause significant morbidity later as DPN primarily changes 
105 
symmetrical sensory function, leading to abnormal sensations and numbness (Debele et al., 
106 
2023). This resulting in amputations, foot ulcers, incontinence, and sexual dysfunction (Juster-
107 
Switlyk and Smith, 2016). Furthermore, the distressing symptoms of DPN frequently result in 
108 
sleep disturbances, feelings of anxiety and depression, and a low quality of life (Kioskli et al., 
109 
2019).   
110 
 
111 
Diabetic peripheral neuropathy frequently under treated, and the impact of enhancing 
112 
glycaemic control, particularly in type-2 diabetes, is still uncertain. First-line pharmacotherapy 
113 
options for painful diabetic neuropathy are Tricyclic antidepressants (imipramine and 
114 
amitriptyline). But because of cholinergic side effects such dry mouth, orthostatic hypotension, 
115 
constipation and urinary retention their usage has been restricted (Khdour, 2020). While 
116 
research has also shown that opioids are effective in treating the neuropathic pain linked to 
117 
DPN, their limited effectiveness, tendency for misuse, and long-term safety issues make them 
118 
unsuitable for routine usage (Zhu et al., 2023). 
119 
 
120 
A combination of alpha lipoic acid and vitamin B preparations is increasingly favoured for the 
121 
treatment of diabetic polyneuropathy in patients with type 2 diabetes mellitus as its showed 
122 
decreased incidence of adverse effects. The main adverse effect associated with alpha-lipoic 
123 
acid is predominantly nausea (Reljanovic et al., 1999; Papanas and Ziegler, 2014). 
124 
 
125 
A systematic review on alpha-lipoic acid's effect in treating diabetic neuropathy found the 
126 
results were incongruent regarding the efficacy of ⍺-lipoic acid in treating diabetic neuropathy 
127 
(Abubaker et al., 2022). Four trials observed a significant improvement in symptoms, including 
128 
a reduction in the total symptom score (TSS), a reduction in the symptoms of autonomic 
129 
neuropathy, and improvements in measures of nerve conduction (Ziegler and Gries, 1997; 
130 
Tankova et al., 2004; Liu et al., 2007; El-Nahas et al., 2020). On the contrary, the remaining 
131 
four trials did not detect any significant outcomes (Reljanovic et al., 1999; Ziegler et al., 1999; 
132 
Won et al., 2020b; Gilron et al., 2021). 
133 
 
134 

4 
 
All studies revealed alpha-lipoic acid was deemed a safe and well-tolerated intervention, with 
135 
no adverse effects reported. Its administration may lead to symptom reduction, providing a safe 
136 
and tolerable treatment alternative (Abubaker et al., 2022).  
137 
 
138 
Therefore, more research is demanded to evaluate the efficacy of a fixed-dose combination of 
139 
vitamin B and alpha lipoic acid formulations for the treatment of diabetic polyneuropathy in 
140 
individuals with type 2 diabetes mellitus. 
141 
 
142 
Hence, this study aims to determine the effectiveness of a fixed dose combination of alpha 
143 
lipoic acid and vitamin B preparations in comparison with placebo for treatment of diabetic 
144 
polyneuropathy (DPN) in type 2 diabetes mellitus patients. 
145 
 
146 
3. OBJECTIVES AND HYPOTHESIS 
147 
 
148 
3.1 RESEARCH QUESTIONS 
149 
 
150 
1. Are there any significant differences in mean total symptom score (TSS) and neuropathic 
151 
symptoms score (NSS) over 12 weeks between diabetic polyneuropathy patients taking a 
152 
fixed dose combination of alpha lipoic acid and vitamin B Preparations and diabetic 
153 
polyneuropathy patients taking a placebo? 
154 
2. Are there any significant differences in total symptom score (TSS) and neuropathic 
155 
symptoms score (NSS) among diabetic polyneuropathy patients at baseline and 12 weeks 
156 
after taking a fixed dose combination of alpha lipoic acid and vitamin B Preparations? 
157 
3. Are there any significant differences in fasting plasma glucose, HbA1C level, fasting lipid 
158 
profile, body mass index (BMI), blood pressure and diabetes quality of life over 12 a week 
159 
between diabetic polyneuropathy patients taking a fixed dose combination of alpha lipoic 
160 
acid and vitamin B preparations and diabetic patients taking placebo? 
161 
4. Are there any significant differences in the safety parameters of renal function and liver 
162 
function tests among diabetic polyneuropathy patients at baseline and 12 weeks after taking 
163 
a fixed dose combination of alpha lipoic acid and vitamin B preparations?  
164 
5. Are there any significant differences in fasting plasma glucose, HbA1C level, fasting lipid 
165 
profile, body mass index (BMI), blood pressure and diabetes quality of life among diabetic 
166 
polyneuropathy patients at baseline and 12 weeks after taking a fixed dose combination of 
167 
alpha lipoic acid and vitamin B preparations? 
168 
 
169 
3.2 OBJECTIVES 
170 
 
171 
To determine the effectiveness of a fixed dose combination of alpha lipoic acid and vitamin B 
172 
preparations in comparison with placebo for treatment of diabetic polyneuropathy (DPN) in 
173 
type 2 diabetes mellitus patients 
174 
 
175 
3.2.1 Primary endpoint  
176 
 
177 
1. To compare the mean change in total symptom score (TSS) and neuropathic symptoms 
178 
score (NSS) over 12 a week period between diabetic polyneuropathy patients taking a 
179 

5 
 
fixed dose combination of alpha lipoic acid and vitamin B preparations versus diabetic 
180 
polyneuropathy patients taking placebo (inter-group comparison) 
181 
2. To compare the mean change in total symptom score (TSS) and neuropathic symptoms 
182 
score (NSS) among diabetic polyneuropathy patients at baseline and 12 weeks after 
183 
taking a fixed dose combination of alpha lipoic acid and vitamin B preparations (intra-
184 
group comparison) 
185 
 
186 
3.2.2 Secondary endpoint  
187 
 
188 
1. To compare changes and differences in fasting plasma glucose, HbA1C level, fasting 
189 
lipid profile, body mass index (BMI), blood pressure and diabetes quality of life over 
190 
12 a week period between diabetic polyneuropathy patients taking a fixed dose 
191 
combination of alpha lipoic acid and vitamin B preparations and in diabetic 
192 
polyneuropathy patients taking placebo (inter-group comparison). 
193 
2. To compare the changes in the safety parameters of the renal function and liver function 
194 
tests among diabetic polyneuropathy patients at baseline and 12 weeks after taking a 
195 
fixed dose combination of alpha lipoic acid and vitamin B preparations (intra-group 
196 
comparison).  
197 
3. To compare changes and differences of fasting plasma glucose, HbA1C level, fasting 
198 
lipid profile, body mass index (BMI), blood pressure and diabetes quality of life among 
199 
diabetic polyneuropathy patients at baseline and 12 weeks after taking a fixed dose 
200 
combination of alpha lipoic acid and vitamin B preparations (intra-group comparison). 
201 
 
202 
3.3 HYPOTHESIS 
203 
 
204 
1. There are significant improvements in mean total symptom score (TSS) and neuropathic 
205 
symptoms score (NSS) in diabetic polyneuropathy patients taking a fixed dose combination 
206 
of alpha lipoic acid and vitamin B preparations as compared to diabetic polyneuropathy 
207 
patients taking a placebo. 
208 
2. There are significant improvements in total symptom score (TSS) and neuropathic 
209 
symptoms score (NSS) among diabetic polyneuropathy patients taking a fixed dose 
210 
combination of alpha lipoic acid and vitamin B preparations for 12 weeks. 
211 
3. There are significant improvements in fasting plasma glucose, HbA1C level, fasting lipid 
212 
profile, body mass index (BMI), and diabetes quality of life in diabetic patients taking a 
213 
fixed dose combination of alpha lipoic acid and vitamin B preparations as compared to 
214 
diabetic patients taking placebo. 
215 
4. There are no significant differences in the safety parameters of renal function and liver 
216 
function tests among diabetic polyneuropathy patients at baseline and 12 weeks after taking 
217 
a fixed dose combination of alpha lipoic acid and vitamin B preparations. 
218 
5. There are significant improvements in fasting plasma glucose, HbA1C level, fasting lipid 
219 
profile, body mass index (BMI), and diabetes quality of life among diabetic patients taking 
220 
a fixed dose combination of alpha lipoic acid and vitamin B preparations for 12 weeks.  
221 
 
222 
 
223 

6 
 
4. LITERATURE REVIEW 
224 
 
225 
4.1 Diabetic peripheral neuropathy (DPN) 
226 
 
227 
Diabetic polyneuropathy (DPN) is a serious diabetes complication and one of the most 
228 
prevalent complications of both type 1 and type 2 diabetes. Around half of patient with diabetes 
229 
experience neuropathy during the progression of their condition, with neuropathic pain 
230 
occurring in 30–40% of cases (Jensen et al., 2021). 
231 
 
232 
The peripheral nerve damage can present as progressive distal symmetric polyneuropathy, 
233 
autonomic neuropathy, radiculo-plexopathies, and mononeuropathies. The prevalent form, 
234 
distal symmetric polyneuropathy (DSPN), typically exhibits a glove-and-stocking-like pattern 
235 
of distal sensory or motor function loss (Jensen et al., 2021). Patients can present with 
236 
numbness, tingling, pain, or a combination of these that typically starts in their toes and slowly 
237 
spreads proximally (Callaghan et al., 2020). Typically, symptoms manifest in the knees before 
238 
extending to the fingertips. Weakness in DPN is a late sign and often initially detected as a lack 
239 
of strength in toe extension, followed by ankle dorsiflexion (Callaghan et al., 2020). 
240 
 
241 
4.2 Screening and diagnosis of distal symmetric polyneuropathy (DSPN) 
242 
 
243 
American Diabetes Association recommends regular examination of people with diabetes 
244 
mellitus for the diagnosis of DPN and loss of protective sensation using simple standard tests 
245 
to identify those at risk for diabetic foot ulcer(Association, 2020).  The screening should be 
246 
considered for people with prediabetes/T2DM who have symptoms of peripheral neuropathy. 
247 
The guidelines stated that, all type 2 diabetes should be assessed for DSPN starting at diagnosis 
248 
and for type 1 diabetes it needs to be started 5 years after the diagnosis. These bedside tests 
249 
should be performed at least annually (Pop-Busui et al., 2017a; Association, 2020).  
250 
 
251 
More commonly, screening for DSPN involves history taking for neuropathic symptoms and 
252 
examination of the feet, along with a screening test(Yang et al., 2018). In most cases, DSPN 
253 
can be diagnosed clinically, and electrophysiological tests are rarely required. 
254 
Electrophysiological tests can be considered if there are atypical features such as rapid onset 
255 
or progression of neuropathy, asymmetrical neuropathy, predominantly motor neuropathy or 
256 
in cases of diagnostic uncertainty (Pop-Busui et al., 2017a).  
257 
 
258 
DSPN should be assessed with a 10-g monofilament (starting from the dorsum of hallux, then 
259 
moving proximally); and one other modality including pin prick, vibration sense using a 128-
260 
Hz tuning fork, ankle reflexes or vibration perception threshold testing using a biothesiometer. 
261 
These increase the sensitivity of detecting DSPN by 87%(Perkins et al., 2001; Herman et al., 
262 
2012; Malaysia, 2020). The 10-g monofilament is a useful clinical tool mainly for detecting 
263 
more advanced neuropathy and identifying patients at increased risk of ulceration and 
264 
amputation (Tan, 2010). Monofilament test is a simply performed office test to diagnose 
265 
patients at risk for ulcer formation due to peripheral sensory neuropathy. The test is abnormal 
266 

7 
 
if the patient cannot sense the touch of the monofilament when it is pressed against the foot 
267 
with just enough pressure to bend the filament (Figure 1) (Armstrong and Lavery, 1998) 
268 
 
269 
 
270 
Figure 1: Nylon monofilament test. There is a risk of ulcer formation if the patient is unable to 
271 
feel the monofilament when it is pressed against the foot with just enough pressure to bend the 
272 
fi lament. The patient is asked to say “yes”each time he or she feels the filament. Failure to feel 
273 
the filament at four of 10 sites is 97 percent sensitive and 83 percent specific for identifying 
274 
loss of protective sensation(Armstrong and Lavery, 1998) 
275 
 
276 
4.2.1 Diagnostic Tests For DSPN  
277 
 
278 
The diagnosis of DSPN is principally based on clinical findings.  A combination of typical 
279 
symptomatology and symmetrical distal sensory loss or typical signs in the absence of 
280 
symptoms in a patient with diabetes is highly suggestive of DSPN and may not require 
281 
additional evaluation or referral. As up to half of the patients may be asymptomatic, a diagnosis 
282 
may only be made on examination or, in some cases, when the patient presents with a painless 
283 
foot ulcer(Pop-Busui et al., 2017a).  
284 
Based on this, the diagnostic tests are focused on assessing the symptoms and signs of nerve 
285 
dysfunctions. Numerous testing methods are available to assess the peripheral nervous 
286 
system’s structure and function, with each test having its advantages and disadvantages. 
287 
Bedside tests aid DSPN diagnosis—including the 10g monofilament, the Ipswich Touch Test, 
288 
and vibration perception threshold testing with the Vibratip and a 128-Hz tuning fork. 
289 
However, these tests tend to diagnose DSPN when it is already well established. Late diagnosis 
290 
hampers the potential benefits of intensified multifactorial intervention at an early stage of the 
291 
disease, which could prevent the sequelae of DSPN. Unfortunately, when DPN is detected with 
292 

8 
 
the current crude tests, it is often very well established and consequently impossible to reverse 
293 
or halt the inexorable neuropathic process. Early diagnosis and timely intervention are thus 
294 
essential in preventing the development of DSPN(Carmichael et al., 2021). 
295 
 
296 
4.2.2: Scoring systems for DSPN (Symptoms) 
297 
 
298 
Various clinical scoring systems available for DPN screening involve symptom scoring, sign 
299 
scoring or both. These systems may enhance diagnostic accuracy through a composite score of 
300 
different combined tests and are useful tools for aiding the diagnosis of DPN, along with 
301 
quantitative measures. Each questionnaire has a scoring system that can diagnose and, in some, 
302 
stratify disease severity (Carmichael et al., 2021). The commonly used screening tests to assess 
303 
important symptoms and signs of DSPN are described below. 
304 
 
305 
1. Neurological Symptom Score (NSS) and Neuropathy Disability Score (NDS) 
306 
 
307 
The NSS and NDS criteria were first used in a study on the prevalence of diabetic peripheral 
308 
neuropathy in hospital-based among UK population (Young et al., 1993). The NSS and NDS 
309 
questionnaire is a validated instrument used to aid in the diagnosis of DPN. The NSS and NDS 
310 
have 71.1% sensitivity (indicating positive predictive value) and 90% specificity (referring to 
311 
negative predictive value)(Chawla et al., 2013). Hence, applying NDS+NSS >10 as per ” 
312 
Young et al criterion “ could pick up early DPN in 96 out of 135 (sensitivity of 71.1% & 
313 
specificity of 90% ). This has a +ve predictive value of 57.14% & negative predictive value of 
314 
94.32% as validated & documented(Chawla et al., 2013).  
315 
 
316 
The sensitivity, specificity and diagnostic efficacy of NSS and NDS score was checked in a 
317 
study conducted by Asad et al., 2010, taking nerve conduction studies as the gold standard. It 
318 
was found that, NSS and NDS had 82.05%, 92.31% sensitivity and 66.67%, 47.62% specificity, 
319 
respectively. The diagnostic efficacy of NSS and NDS was 77%(Asad et al., 2010). Studies 
320 
that have been conducted in Brazil, Germany, United Kingdom, Uganda, Egypt and Malaysia 
321 
used NSS and NDS scores as a criterion to establish the diagnosis of distal symmetric 
322 
polyneuropathy (DSP)(Abbott et al., 2011; Kamel et al., 2015; Kisozi et al., 2017; Li-Ying et 
323 
al., 2017; André Pfannkuche et al., 2020; Reis de Matos et al., 2020) 
324 
 
325 
2. Michigan Neuropathy Screening Instrument (MNSI) 
326 
 
327 
The Michigan neuropathy screening instrument (MNSI) is another commonly used composite 
328 
scoring system that includes a questionnaire and a foot examination. The MNSI was designed 
329 
by Feldman et al., 1994 to diagnose diabetic polyneuropathy in outpatient clinics (Feldman et 
330 
al., 1994). The MNSI can be administered by any health care professional involved in the 
331 
treatment of diabetic patients. 
332 
 
333 
The MNSI is used widely to evaluate distal symmetrical peripheral neuropathy (DSPN) in 
334 
diabetes. The MNSI assesses both the key symptoms and signs of diabetic polyneuropathy in 
335 
two separate parts (Feldman et al., 1994). The first part is on the history/symptom portion of 
336 

9 
 
the MNSI that consists of a 15-items. It can be self-administered by the respondents by 
337 
answering “Yes” or “No” for each item (Feldman et al., 1994). The responses are added to 
338 
obtain a total score. ‘Yes’ responses to questions 1,2,3,4 5,6, 8,9,10,11,12,14,15 are each 
339 
counted as one point. Questions 7 and 13 were reversed and scored so that ‘no’ responses 
340 
indicated an abnormality and counted as one point in the scoring algorithms. All items on the 
341 
questionnaire were coded as 0 for a negative response and 1 for a positive response (negative 
342 
responses on items 7 and 13 counted as 1 point) (Feldman et al., 1994; Herman et al., 2012). 
343 
Original cut of point to detect neuropathy can be defined as seven or more positive responses 
344 
to this symptoms section alone (Feldman et al., 1994). However, in 2012, Herman et al., altered 
345 
the cut point to define an abnormal test from ≥ 7 abnormal to ≥ 4 abnormal items to improves 
346 
the performance of the MNSI questionnaire. When the threshold to define an abnormal test was 
347 
set at ≥ 4, the questionnaire was 40% sensitive and 92% specific and had a positive predictive 
348 
value of 69% and a negative predictive value of 78%. However, when the threshold to define 
349 
an abnormal test for the MNSI questionnaire was ≥ 7, the questionnaire was 13% sensitive and 
350 
99% specific in identifying confirmed clinical neuropathy. Positive and negative predictive 
351 
values were 84 and 73%, respectively(Herman et al., 2012).  
352 
 
353 
The second part of MNSI was lower extremity examination that includes inspection for 
354 
appearance and ulcer, assessment of vibratory sensation and ankle reflexes and is scored by 
355 
assigning points for abnormal findings. During the MNSI examination, a health professional 
356 
need to inspects each foot for deformities, dry skin, calluses, infections and fissures. Each foot 
357 
with any abnormality receives a score of 1. Each foot is also inspected for ulcers and each foot 
358 
with an ulcer receives a score of 1. The ankle reflexes are also elicited. If the reflex is absent, 
359 
the patient is asked to perform the Jendrassic manoeuver and, if present, the reflex is designated 
360 
as present with reinforcement and is scored as 0.5. If the reflex is absent with the Jendrassic 
361 
manoeuver, the reflex is designated as absent and is scored as 1. Vibration sensation is then 
362 
tested in the great toe using a 128-Hz tuning fork. In general, the examiner should be able to 
363 
feel vibration in his or her hand for 5 s longer than a normal subject can at the great toe. 
364 
Vibration is scored as present if the examiner senses the vibration on his or her finger for < 10 
365 
s longer than the subject feels it in the great toe, decreased if sensed for  10 second (scored as 
366 
0.5) or absent (scored as 1). The total possible score is 8 points and, in the published scoring 
367 
algorithm, a score ≥ 2.5 is considered abnormal (Feldman et al., 1994; Herman et al., 2012). 
368 
When the threshold to define an abnormal MNSI examination was set at ≥ 2.5, the MNSI 
369 
examination was 61% sensitive and 79% specific in defining confirmed clinical neuropathy 
370 
and had a positive predictive value of 55% and a negative predictive value of 83%(Herman et 
371 
al., 2012). 
372 
 
373 
3. Total symptoms score (TSS) 
374 
 
375 
The total symptoms score (TSS) was used by Ziegler et al. (1995) to evaluate the effects of the 
376 
antioxidant alpha-lipoic acid in a 3-week multicentre, randomized, double-blind placebo-
377 
controlled trial (Alpha-Lipoic Acid in Diabetic Neuropathy: ALADIN) study among 328 non-
378 
insulin-dependent diabetic patients with symptomatic peripheral neuropathy(Ziegler et al., 
379 
1995). The TSS is a summation of symptom scores for stabbing pain, burning pain, paresthesia, 
380 

10 
 
and numbness by symptoms frequency (occasionally, often, or continuous) and intensity (not 
381 
present, mild, moderate, or severe) on which scores range from 0 to 14.64 (table 1)(Ziegler et 
382 
al., 1995; Won et al., 2020a).The severity score needs to be conducted by the physician or a 
383 
trained nurse. 
384 
 
385 
4.3 Alpha-lipoic acid (ALA) in treating Diabetic peripheral neuropathy 
386 
 
387 
Alpha-lipoic acid (ALA) is a potent antioxidant that might be effective in the treatment of 
388 
diabetic peripheral neuropathy. ALA could potentially serve as both a pain-relieving therapy 
389 
and an enhancer of nerve function by mitigating the harmful effects of hyperglycemia 
390 
(Bartkoski and Day, 2016). 
391 
 
392 
Studies revealed that ALA enhanced endothelium-dependent vasodilation mediated by nitric 
393 
oxide in diabetic patients and enhanced microcirculation in patient suffering from diabetic 
394 
polyneuropathy (Vallianou et al., 2009). An animal model study done proposed that ALA 
395 
exhibits effectiveness against moderate ischemia-reperfusion injury, particularly in cases 
396 
where the distal sensory nerves suffer damage (Khan et al., 2022). Additionally, ALA has been 
397 
shown to lower plasma levels of plasminogen activator 1 and interleukin 6, which may indicate 
398 
that ALA improves endothelial dysfunction by acting as an anti-thrombotic and anti-
399 
inflammatory agent (Sola et al., 2005). 
400 
 
401 
Ziegler et al. conducted a meta-analysis of four trials—ALADIN I, ALADIN III, SYDNEY, 
402 
and NATHAN II—to assess the effectiveness and safety of intravenous administration of 600 
403 
mg of ALA over a three-week period. Their findings demonstrated that the treatment was well-
404 
tolerated and effectively reduced positive neuropathic symptom. Alpha-lipoic acid (ALA) 600 
405 
mg daily is recommended for individuals who are resistive to or intolerant of first-line 
406 
pharmacotherapies and interested in a nutritional supplement approach as it is safe and 
407 
significantly improves both positive neuropathic symptoms and neuropathic deficits to a 
408 
clinically meaningful degree in diabetic patients with symptomatic polyneuropathy (Ziegler et 
409 
al., 2004). 
410 
 
411 
Another study done in the Oral Pilot (ORPIL) trial revealed that administering oral 600 mg 
412 
ALA three times daily for three weeks could improve symptoms and deficits caused by 
413 
polyneuropathy in type 2 diabetes patients, despite the trial's smaller sample size (Ruhnau et 
414 
al., 1999). 
415 
 
416 
While a systematic review conducted by Abubaker et al. revealed that the use of ALA alone 
417 
did not significantly improve neuropathic pain in patients with diabetes but still played a role 
418 
in reducing neuropathic symptoms (Abubaker et al., 2022). 
419 
 
420 
 
421 
 
422 
 
423 
 
424 

11 
 
4.4 Alpha lipoic acid and different metabolic parameters 
425 
 
426 
ALA, also known as thioctic acid, is a naturally occurring compound found in various foods 
427 
and synthesized in small amounts by the human body. It serves as a cofactor for several 
428 
mitochondrial enzymes involved in energy metabolism, making it a vital component in cellular 
429 
energy production (Agathos et al., 2018). 
430 
 
431 
ALA is a potent antioxidant that can scavenge a variety of reactive oxygen species (ROS) and 
432 
reactive nitrogen species (RNS). By reducing oxidative stress, ALA may help to mitigate 
433 
inflammation and cellular damage associated with metabolic disorders such as diabetes and 
434 
obesity (Nagamatsu et al., 1995). In one study done by (Papanas and Ziegler, 2014) in addition 
435 
to reduces oxidative stress in diabetic neuropathy, ALA also improve nerve blood flow and 
436 
nerve conduction velocity. 
437 
 
438 
Study done by (Salehi et al., 2019) ALA has been shown to improve glucose uptake and 
439 
utilization in skeletal muscle cells by enhancing insulin sensitivity. This effect is attributed to 
440 
ALA's ability to activate AMP-activated protein kinase (AMPK), a key regulator of cellular 
441 
energy metabolism. 
442 
 
443 
ALA has also been reported to have beneficial effects on lipid metabolism by reducing levels 
444 
of triglycerides and LDL cholesterol (Mousavi et al., 2019). These effects may be mediated in 
445 
part by ALA's antioxidant properties, which help to prevent lipid peroxidation and 
446 
inflammation.  
447 
 
448 
4.5 Quality of life in patients with Diabetic peripheral neuropathy 
449 
 
450 
The impact of DPN on the quality of life (QoL) of affected individuals can be profound and 
451 
multifaceted as symptoms such as pain, numbness, tingling, and weakness in the extremities 
452 
may interfere with patient daily activities which lead to poor quality of life (Pop-Busui et al., 
453 
2017b). 
454 
 
455 
Despite advancements in therapy, diabetic neuropathy continues to be linked with significant 
456 
morbidity, elevated mortality rates, and diminished quality of life (QoL) when compared to 
457 
diabetic patients without neuropathy (Agathos et al., 2018). 
458 
 
459 
One of the most significant ways DPN affects QoL is through its impact on physical 
460 
functioning. Pain and discomfort associated with DPN can limit mobility, impair balance, and 
461 
decrease overall physical activity levels (Chiles et al., 2014). This can lead to a reduced ability 
462 
to perform daily tasks, such as walking, standing, and even simple activities like dressing or 
463 
cooking. 
464 
 
465 
Chronic pain and discomfort from DPN can also take a toll on psychological well-being. Many 
466 
patients experience anxiety, depression, or frustration due to the constant presence of 
467 
symptoms and the limitations they impose on daily life which usually lead to diabetes distress 
468 

12 
 
(Feldman et al., 2019). Diabetes distress refers to the emotional and psychological burden 
469 
experienced by individuals living with diabetes. It encompasses feelings of stress, anxiety, 
470 
frustration, and burnout related to the daily management of the condition (Fisher et al., 2012). 
471 
Sleep disturbances are also common, further exacerbating mental health issues and contributing 
472 
to a lower QoL (Gylfadottir et al., 2020). 
473 
 
474 
4.6 Vitamin B in treating diabetic peripheral neuropathy. 
475 
 
476 
Vitamin B, particularly certain B vitamins such as B1 (thiamine), B6 (pyridoxine), and B12 
477 
(cobalamin), has been studied for its potential role in treating diabetic peripheral neuropathy 
478 
(DPN). There is growing evidence in the literature indicating that these vitamins play a role in 
479 
promoting nerve repair by accelerate nerve tissue regeneration and aid in the recovery of nerve 
480 
function through various mechanisms (Altun and Kurutas, 2016). 
481 
 
482 
Thiamine plays a crucial role in nerve function and may be deficient in individuals with 
483 
diabetes, contributing to neuropathic symptoms. Some studies have suggested that thiamine 
484 
supplementation may help improve symptoms of DPN, particularly when the neuropathy is 
485 
associated with thiamine deficiency (Farah and Yammine, 2022). However, more research is 
486 
needed to confirm its effectiveness in broader populations of individuals with DPN. 
487 
 
488 
Vitamin B12 deficiency is also relatively common in individuals with diabetes and has been 
489 
linked with neurological complications such as neuropathy. Study done by (Altun and Kurutas, 
490 
2016) the use of vitamin B complex or specifically vitamin B12 has been demonstrated to 
491 
enhance the quantity of Schwann cells and myelinated nerve fibers as well as the diameter of 
492 
axons. This promotes the regeneration of myelinated nerve fibers and the proliferation of 
493 
Schwann cells which are essential for the structural integrity and maintenance of proper 
494 
nervous system functions. 
495 
 
496 
 
497 
 
498 
 
499 
 
500 
 
501 
 
502 
 
503 
 
504 
 
505 
 
506 
 
507 
 
508 
 
509 
 
510 
 
511 
 
512 
 
513 

13 
 
5. CONCEPTUAL FRAMEWORK 
514 
 
515 
 
516 
 
517 
 
518 
 
519 
 
520 
 
521 
 
522 
 
523 
 
524 
 
525 
 
526 
 
527 
 
528 
 
529 
 
530 
 
531 
 
532 
 
533 
 
534 
 
535 
 
536 
 
537 
 
538 
 
539 
 
540 
 
541 
 
542 
 
543 
 
544 
 
545 
 
546 
 
547 
 
548 
 
549 
 
550 
 
551 
 
552 
 
553 
 
554 
 
555 
 
556 
 
557 
 
558 
Intervention group: Bionerv 
Alpha lipoic acid 300mg, Vitamin B12 
(methylcobalamin) 500mcg, Vitamin B6 
(pyridoxine) 8mg, Vitamin B1 (thiamine) 
39mg 
 
Control group: Placebo 
Croscamellose Sodium, Microcrystalline 
Cellulose, Silicon Dioxide , Magnesium 
stearate, and 2 tablets once daily after 
meal. 
 
Primary outcome: 
•
Total symptom score (TSS) 
•
Neuropathic symptoms score (NSS) 
 
Secondary outcome 
•
Renal function  
•
Liver function tests 
•
Fasting plasma glucose 
•
HbA1C, 
•
Fasting lipid profile 
•
Body mass index (BMI)  
•
Blood pressure  
•
Diabetes quality of life 
 
Independent variable 
•
Sex 
•
Age 
•
Race 
•
Educational level 
•
Occupation 
•
Total income 
•
Marital status 
•
Diabetes duration 
•
Concomitant medical history 
•
Diabetes medication 

14 
 
6. METHODOLOGY 
559 
 
560 
6.1 Study design 
561 
 
562 
This is a single-center, randomized, double-blind, placebo-controlled trial study.  
563 
 
564 
6.2 Study area 
565 
 
566 
This study will be conducted at the Klinik Rawatan Keluarga and diabetes clinic Hospital 
567 
Universiti Sains Malaysia. 
568 
 
569 
6.3 Study duration 
570 
 
571 
This study will be conducted from February 2024 to January 2025 (1 year). 
572 
 
573 
6.4. Population and sample 
574 
 
575 
6.4.1 Reference population 
576 
 
577 
Patients with type 2 diabetes mellitus attending the Hospital Universiti Sains Malaysia. 
578 
 
579 
6.4.2 Source population 
580 
 
581 
Patients with type 2 diabetes mellitus attended Klinik Rawatan Keluarga and diabetes clinic 
582 
Hospital Universiti Sains Malaysia during the study period.  
583 
 
584 
6.4.3 Sampling frame  
585 
 
586 
Patients with type 2 diabetes mellitus attended and registered Klinik Rawatan Keluarga and 
587 
diabetes clinic Hospital Universiti Sains Malaysia, who fulfilled the criteria. 
588 
 
589 
Inclusion criteria  
590 
 
591 
• Aged 18 years and over  
592 
• Diagnosed with type 2 diabetes mellitus based on WHO diagnostic criteria for 
593 
diabetes (Organization, 2020). Diabetes patients refer to those who have fulfilled 
594 
the WHO diagnostic criteria for diabetes where:1) plasma glucose concentration 
595 
measured after an overnight fast above 7.0mmol/l and/or 2) plasma glucose 
596 
concentration measured two hours after a 75g oral glucose load above 11.1 
597 
mmol/l(Organization, 2020). 
598 
• Diagnose with diabetic polyneuropathy by Neurological Symptom Score (NSS) and 
599 
Neuropathy Disability Score (NDS). Presence of moderate signs (NDS >6) 
600 
regardless of symptoms or mild signs (NDS > 3) with moderate symptoms (NSS > 
601 
5) (Young et al., 1993). 
602 

15 
 
Exclusion Criteria  
603 
 
604 
• Those with a documented mental impairment which impacted on their ability to 
605 
answer questions independently. 
606 
• Patients with peripheral vascular disease (non-palpable foot pulses, intermittent 
607 
claudication) 
608 
• Patients with an amputated foot or leg 
609 
• Aspartate aminotransferase or alanine aminotransferase levels >3 times normal 
610 
levels 
611 
• Patients with renal impairment - CKD stage IV and V 
612 
• Patients using drugs with possible influence on the study results (antidepressants, 
613 
anticonvulsants, 
opiates, 
neuroleptics, 
antioxidants, 
and 
particularly 
614 
methylcobalamin, pyridoxine and other B complex preparations) 
615 
• Pregnancy, lactation, or childbearing age without safe contraception  
616 
• History of allergy with vitamin B complex preparations (i.e. Vitamin B12, B6 and 
617 
B1) and alpha lipoic acid  
618 
 
619 
6.5 Sample size estimation 
620 
 
621 
The sample size for this study was determined based on the primary study endpoint (change in 
622 
TSS and NSS from the beginning of treatment to week 12 after treatment) and the sample-sized 
623 
requirements were calculated using G*Power Software version 3.1.9.7. Since the intended 
624 
statistical analysis (Repeated measures ANOVA) investigates between-factor effect, within-
625 
factor effect, and within-between interaction effect, the sample sizes were calculated using 
626 
these three options. The sample size calculations were summarized in the table below. 
627 
 
628 
Table 1: Summary of sample size calculation. 
629 
 Calculation 
Option 
in 
G*Power Software 
Parameter used for calculation 
Total sample size 
Test family: F tests 
Statistical test: ANOVA, 
Repeated 
Measures, 
between factors 
Effect size f = 0.28 (Medium effect size) 
Type I error probability: 5% 
Power: 80% 
Number of groups: 2 
Number of measurements: 3 
Correlation among repeated measures: 0.5 
 
n=70  
(35 per group) 
Test family: F tests 
Statistical test: ANOVA, 
Repeated Measures, within 
factors 
Effect size f = 0.28 (Medium effect size) 
Type I error probability: 5% 
Power: 80% 
Number of groups: 2 
Number of measurements: 3 
Correlation among repeated measures: 0.5 
n=24 
(12 per group) 

16 
 
Test family: F tests 
Statistical test: ANOVA, 
Repeated Measures, within-
between interaction 
Effect size f = 0.28 (Medium effect size) 
Type I error probability: 5% 
Power: 80% 
Number of groups: 2 
Number of measurements: 3 
Correlation among repeated measures: 0.5 
n=24  
(12 per group) 
  
630 
In summary, the largest sample size was obtained with calculation for between subject effect 
631 
(35 participants per group). Anticipating a 10% dropout, the corrected sample size was 38 
632 
participants per group. The total number of participants required for this study was 76 
633 
participants. 
634 
 
635 
6.5.1: Interim Analysis 
636 
 
637 
No interim analysis is planned. 
638 
 
639 
6.5.2: Determination of end of clinical trial (all patients) 
640 
 
641 
The end of the study is defined as being the “last patient last visit” planned with the protocol, 
642 
including follow-up visit. 
643 
 
644 
6.6 Sampling method 
645 
 
646 
Purposive sampling method will be used in this study. The total number of participants required 
647 
for this study is 76 participants, which is 38 participants for intervention and 38 participants 
648 
for control group. The sample will be selected purposely based on inclusion and exclusion 
649 
criteria. 
650 
 
651 
6.7 Research tools 
652 
 
653 
6.7.1 Questionnaire 
654 
 
655 
A questionnaire guided the participants’ interviews will be used to collect the variables of 
656 
interest in this study. Participants will be interviewed in person by researchers who will be 
657 
trained before starting data collection. The case report form will consist of 2 parts: 
658 
 
659 
A. The first part is a neurological symptom score (NSS) and neuropathy disability score 
660 
(NDS). It will be used to screen the patients whether they have diabetes polyneuropathy or 
661 
not. If the patient fulfils the criteria for diagnosis of diabetes polyneuropathy with the 
662 
presence of moderate signs (NDS >6) regardless of symptoms or mild signs (NDS > 3) 
663 
with moderate symptoms (NSS > 5)(Young et al., 1993), and other inclusion and exclusion 
664 
criteria are fulfilled,  they will be recruited in the study. Neurological Symptom Score 
665 

17 
 
(NSS) will also be used to measure the severity of neuropathy symptoms and as a primary 
666 
outcome of the study.  
667 
 
668 
B. The second part will consist of 5 sections as follows: 
669 
(a) Sociodemographic characteristics 
670 
(b) Medical and diabetes profile 
671 
(c) Total symptoms score (TSS) 
672 
(d) The revised version of Diabetes Quality of Life (RV-DQoL) 
673 
(e) Physical examination (height, weight, BMI and blood pressure)  
674 
 
675 
Part A: Neurological Symptom Score (NSS) and neuropathy disability score (NDS) 
676 
 
677 
Neurological Symptom Score consists of 4 components. The first component is on reported 
678 
discomfort symptoms: burning/numbness/tingling (2 points), fatigue/cramping and aching 
679 
feelings (1point) and 0 point for none. Second component is on symptom location whether the 
680 
symptom occurs in the feet (2 points), calves (1 point) and 0 points for elsewhere. The third 
681 
component is on timing of symptoms, either nocturnal exacerbation (2 points), symptoms 
682 
present both day and night (1 point) and 0 for symptoms present during daytime only. A score 
683 
of 1 was added if the symptoms had ever woken the patient from sleep. The fourth component 
684 
is on a manoeuvre to reduce the symptoms by either walking (2 points) or standing (1pointand 
685 
and 0 for sitting or lying down. The maximum symptom score was 9 (Young et al., 1993; André 
686 
Pfannkuche et al., 2020).  
687 
 
688 
The NDS was derived from the neurological examination testing sensory modalities such as 
689 
vibration, temperature, pin prick and Achilles tendon reflex on both feet. Each test was assessed 
690 
with points to calculate the total disability score. Vibration sense was elicited using a 128 Hz 
691 
turning fork at the hallux of the big toe (Kisozi et al., 2017). The vibration was scored as either 
692 
present = 0 or reduced/absent = 1 for each side. The temperature perception on the dorsum of 
693 
the foot was determined by using the tip of cold tuning fork with scored as either present = 0 
694 
or reduced/absent = 1 for each side(Kamel et al., 2015). Pain perception was assessed by the 
695 
application of a pin prick at the proximal end of the big toe nail to distinguish sharp/blunt. The 
696 
results will scored as either present = 0 (when the patient could distinguish sharpness) or 
697 
reduced/absent = 1(when the patient was unable to distinguish it)  for each side (Kisozi et al., 
698 
2017). The ankle reflex was tested both-sided using a standard tendon hammer. By this, the 
699 
patient´s foot was in a relaxed position. The reflex was scored as normal = 0, present with 
700 
reinforcement = 1 or absent = 2 per side(Young et al., 1993; André Pfannkuche et al., 2020).  
701 
 
702 
Neuropathy symptoms were classified into mild (NSS 3-4), moderate (NSS 5-6) and severe 
703 
(NSS 7-9) while neuropathy signs were also classified mild (NDS 3-5), moderate (NDS 6-8) 
704 
and severe (NDS 9-10)(Young et al., 1993). 
705 
 
706 
 
707 
 
708 
 
709 

18 
 
Part B: Second Part of Proforma 
710 
 
711 
(a) Sociodemographic characteristics 
712 
 
713 
The first part will obtain the participants' demographic characteristics, including sex, age, race, 
714 
educational level, occupation, total income, and marital status.  
715 
 
716 
(b) Medical and diabetes profile  
717 
 
718 
The second part will obtain a diabetes profile including diabetes duration, concomitant medical 
719 
history (presence of hypertension, dyslipidaemia, retinopathy, IHD/MI), list of diabetes 
720 
medications are taken, and drug allergies. This part will be obtained from patients’ medical 
721 
records by the researcher. 
722 
 
723 
(c)Total symptoms score (TSS) 
724 
 
725 
Total Symptom Score is the sum of 4 neuropathic symptoms (stabbing pain, burning pain, 
726 
paraesthesia, and numbness) reported as symptoms frequency (occasionally, frequent, or 
727 
continuous) and symptom intensity (absent, slight, moderate, or severe) on which scores range 
728 
from 0 to 14.64(table 1)(Ziegler et al., 1995; Won et al., 2020a).  
729 
 
730 
Table 1: Scoring approach for the neuropathic symptoms included in the total symptom score 
731 
(stabbing pain, burning pain, paraesthesia, and numbness) 
732 
 
733 
 
734 
(d) The revised version of Diabetes Quality of Life (RV-DQoL) 
735 
 
736 
The revised version of Diabetes Quality of Life (Rv-DQoL) is adapted from the Diabetes 
737 
Quality of Life (DQoL) questionnaire (Jacobson et al., 1994). DQoL was intended to be used 
738 
for evaluating the quality of life specifically related to T2DM and was made up of three major 
739 
domains, namely, (i) Diabetes Life Satisfaction (QoL Satisfy), 18 items; (ii) Disease Impact 
740 
Scale (QoL Impact), 27 items; and (iii) Disease-Related Worries Scale (QoL Worry), 14 items 
741 
and one general question to reflect self-rating of overall general health. All items in the QoL 
742 
Satisfy domain are scored on a five-point scale, ranging from 1 (very satisfied) to 5 (very 
743 
dissatisfied), whereas the items in the QoL Impact and QoL Worry are scored on a five-point 
744 
scale, ranging from 1 (never) to 5 (all the time); the score was presented as the total of the items 
745 
of each scale divided by the number of items. A higher average score indicates poorer QoL 
746 
(79).  
747 

19 
 
A Malay version of the instrument was developed, keeping the three main domains of 
748 
‘satisfaction’, ‘impact’ and ‘worry’ with similar score scale. Each domain’s redundant 
749 
questions were removed, leaving the newly revised DQoL (Rv-DQoL) with a total of 13 
750 
questions. Cronbach’s α values for each domain ranged from 0.75 to 0.93, indicating good 
751 
internal consistency, and it was validated for use among adult T2DM patients in Malaysia.  
752 
 
753 
It has a 5-point Likert scale from “no impact/no worries” to “always satisfied/always affected”. 
754 
A higher score indicates a lower quality of life (Bujang et al., 2018). The questionnaires used 
755 
had permission from the authors. 
756 
 
757 
(e) Physical examination (height, weight, BMI and blood pressure) 
758 
 
759 
Respondents will be given instructions on how to measure weight and height correctly. BMI is 
760 
calculated by dividing a respondent’s body weight in kilograms by their height in meters 
761 
squared [weight (kg) / height (m2)]. Blood pressure will be measured using an OMRON 
762 
automated blood pressure machine.  
763 
 
764 
6.7.2:  Laboratory Evaluation (laboratory assessment)  
765 
 
766 
Baseline blood investigations will be measured at baseline (visit 1), and weeks 12 (last visit). 
767 
The blood investigations include: 
768 
 
769 
1. HbA1c  
770 
2. Fasting Blood Sugar 
771 
3. Fasting Lipid profile 
772 
4. Renal function test 
773 
5. Liver function test  
774 
 
775 
Fasting blood samples will be collected in heparinized tubes. Six ml will be drawn from each 
776 
subject and will be sent to a private lab: Pantai Premier Pathology (PPP) lab, for analysis. 
777 
 
778 
6.8 Study procedure  
779 
 
780 
Participants will be recruited from Klinik Rawatan Keluarga and diabetes clinic Hospital USM 
781 
via convenience sampling. Potential participants will be identified from the case notes of 
782 
patients. Then, the participants will be approached individually.  Those who are willing to 
783 
participate in this study will be given information regarding the study. The participants will be 
784 
screened to determine their eligibility criteria, including performing neurological symptom 
785 
score (NSS) and neuropathy disability score (NDS) to determine diabetes polyneuropathy 
786 
diagnosis. If all the inclusion and exclusion criteria are fulfilled, informed consent will be 
787 
obtained from all patients who agree to participate in this study. The consent will be obtained 
788 
by a study team that recruited the patient. Upon consented, the participant’s socio-demographic 
789 
data will be collected, and the medical record will be assessed to fill in their medical and 
790 
diabetes profiles. They will also answer the total symptoms score (TSS), and revised version 
791 

20 
 
of the Diabetes Quality of Life (Rv-DQoL) questionnaire. The physical examination includes 
792 
measurement of height, weight, calculated Body Mass Index (BMI), and blood pressure during 
793 
sitting will be done. Then 6ml of fasting venous blood will be taken for measurement of HbA1c, 
794 
fasting blood glucose, RFT, LFT and fasting lipid profile as baseline. All participants were 
795 
advised not to consume any special supplement or other replacement meal throughout the 
796 
study. 
797 
 
798 
The patients then will be randomized to either intervention or control group. The intervention 
799 
group will receive a fixed dose combination of alpha lipoic acid and vitamin B preparations, 
800 
and the control group will receive a placebo.  
801 
 
802 
The patients will be seen 6 weeks after taking the product. During this visit, they will be 
803 
assessed for any side effects or adverse events and compliance with the product supplied 
804 
(compliance form). The total symptoms score (TSS), neurological symptom score (NSS), a 
805 
revised version of Diabetes Quality of Life (Rv-DQoL), blood pressure, weight, height, 
806 
calculated Body Mass Index (BMI) will also be measured. Another 6-week supply of the 
807 
product will be given.  
808 
 
809 
Lastly, the patient will be assessed in week 12. During this visit, the same measurement will 
810 
be taken as visit 1, including answering the questionnaires. Adverse events, blood taking, and 
811 
compliance will also be assessed. 
812 
 
813 
The duration for visit 1 and visit 3 (at 12 weeks) is about 50-60 minutes for each visit since it 
814 
will involve blood taking procedure. Duration for visit 2 (at 6 weeks) is about 30 minutes since 
815 
it will not involve blood taking.  
816 
 
817 
6.8.1 Baseline screening and assessment  
818 
 
819 
Vital signs (supine blood pressure, pulse rate), weight, height, and calculated body mass index 
820 
(BMI) will be recorded on the baseline and every visit.  
821 
The weight of subjects will measure in light clothing without belts and shoes. All contents will 
822 
be removed from their pockets. Height will be measured to the nearest 0.1 cm from a scale 
823 
marked in cm. A standardized weighing machine and a height measuring scale will measure 
824 
both height and weight.  
825 
 
826 
Blood pressure will be measured using the OMRON automated blood pressure set. Systolic 
827 
and diastolic blood pressure will measure once while sitting on the chair.  
828 
 
829 
Then a qualified staff nurse will take 6 ml of venous blood to measure HbA1c, fasting blood 
830 
glucose, fasting lipid profile and safety parameters (RFT, LFT). All respondents need to fast 
831 
for 8 hours before blood taking. All the blood will be sent to the private lab Pantai Premier 
832 
Pathology (PPP) lab to process the blood sample.  
833 
 
834 
 
835 

21 
 
6.9 Study flow chart 
836 
 
837 
Eligible and consenting participants will be randomized into two groups: An intervention group 
838 
will receive a fixed dose combination of alpha lipoic acid and vitamin B and the control group 
839 
will receive a placebo. 
840 
 
841 
Outcome measurements will be assessed at the baseline and after the completion of the 12-
842 
week intervention.  
843 
 
844 
Sociodemographic data, diabetes and medical profile, total symptoms score (TSS), 
845 
neurological symptom score (NSS), a score of the revised version of Diabetes Quality of Life 
846 
(RV-DQoL), BMI, blood pressure, blood result HbA1c, FLP, FBS and safety parameters blood 
847 
(RFT, LFT) will be recorded in case report form. Hence, the total duration of the study is 12 
848 
weeks. A brief research flow chart is shown in Figure 1. 
849 
 
850 
 
851 
 
852 
 
853 
 
854 
 
855 
 
856 
 
857 
 
858 
 
859 
 
860 
 
861 
 
862 
 
863 
 
864 
 
865 
 
866 
 
867 
 
868 
 
869 
 
870 
 
871 
 
872 
 
873 
 
874 
 
875 
 
876 
 
877 
 
878 
 
879 

22 
 
 
880 
Flow chart of the study 
881 
 
882 
 
 
883 
 
884 
 
885 
 
886 
 
887 
 
888 
 
889 
 
890 
 
891 
  
892 
 
893 
 
894 
 
895 
 
896 
 
897 
 
898 
 
899 
 
900 
 
901 
 
902 
 
903 
 
904 
 
905 
 
906 
 
907 
 
908 
 
909 
 
910 
 
911 
 
912 
 
913 
 
914 
 
915 
Figure 1: Flow chart of the study 
916 
 
917 
 
918 
 
919 
 
920 
TSS,NSS, RV-DQoL questionnaire 
,BMI, BP, compliance, adverse effect 
TSS,NSS, RV-DQoL questionnaire, 
BMI, BP, compliance, adverse 
Completed(n=) 
TSS,NSS, RV-DQoL questionnaire, 
BP,BMI,HbA1c,FBS, FLP, RFT,LFT 
compliance, adverse effect 
Completed(n=) 
TSS,NSS, RV-DQoL questionnaire, 
BP,BMI,HbA1c,FBS, FLP, RFT,LFT 
compliance, adverse effect 
Withdrawn from 
study(n=) 
Lost follow-up 
(n=) 
Non compliance 
(n=) 
Request to 
discontinue(n=) 
Follow-up 12 weeks 
Randomized (n=76) 
Intervention(n=38) 
Received Fixed dose combination of 
alpha lipoic acid and vitamin B 
Control(n=38) 
Received placebo 
Follow-up 6 weeks 
Assess for eligibility (n=) 
Excluded (n=) 
Not meeting inclusion criteria(n=) 
Decline to participate(n=) 
Other reasons(n=) 
Recruitment (n=76) 
Initial examination (n=76) 
Baseline evaluation- Sociodemographic characteristics, medical and 
diabetes profiles TSS, RV-DQoL questionnaire, BP, BMI, HbA1c,FBS,FLP, 
RFT,LFT 
Fulfil inclusion and 
exclusion criteria. 
NSS and NDS score 
for DPN diagnosis. 

23 
 
6.10.1 Randomization methods 
921 
 
922 
Using mixed block randomization at a 1:1 ratio, independent statisticians randomly assign 
923 
patients to treatment and placebo groups using IBM SPSS software (group A and group B). An 
924 
independent statistician will code treatment and placebo into groups A and B. In a brown 
925 
opaque envelope, each participant received a written assignment with a code. After participant 
926 
recruitment, the researcher will open this envelope. The independent statistician will reveal the 
927 
allocation key after the study. An independent statistician tags the treatment and placebo groups 
928 
as ‘A' or ‘B'. 
929 
 
930 
6.10.2 Blinding and emergency unblinding procedures 
931 
 
932 
This study will be conducted as a double-blind, placebo-controlled trial study. Both the 
933 
participants and the assessor will not know the intervention received. The study's participants 
934 
and outcome assessor are blinded to allocation status. The medical monitor may break the 
935 
subject's sealed emergency code key and identify the test drug in the event of an adverse event 
936 
(AE). The medical monitor will have sealed emergency code keys (one per subject) in a secure 
937 
location and be always available by phone. Medical monitor is a hospital medical officer. 
938 
He/she knows hospital system and study protocol. If emergency unblinding is needed, the 
939 
investigator will call the medical monitor, who will break the subject's emergency code key, 
940 
identify the test coil, and notify the investigator. The medical monitor will attach a detailed 
941 
report to the case report form with the date and reason for identifying the study drug. The 
942 
medical monitor and investigator must sign this report. All unused sealed code keys will be 
943 
counted after the study. Except in emergencies, the treatment blind will remain until all subjects 
944 
have completed treatment and the database is cleaned and locked. A comment on the case 
945 
report form will justify and explain broken code, along with the date. 
946 
 
947 
6.10.3 Intervention group: Fixed dose combination of alpha lipoic acid and vitamin B 
948 
preparations 
949 
 
950 
At baseline, the intervention group will receive a fixed dose combination of alpha lipoic acid 
951 
and vitamin B preparations. This product is packaged and manufactured by BREGO Life 
952 
Sciences Sdn Bhd company with a brand name of Bionerv®. BIONERV® is the first 
953 
combination of alpha lipoic acid 300mg and vitamin B complex. Bionerv® is in oral film-
954 
coated, orange colour, oblong shape and no marking and embossing on the tablet. Each tablet 
955 
contains 4 active ingredients as follows: Alpha lipoic acid 300mg, Vitamin B12 
956 
(methylcobalamin) 500mcg, Vitamin B6 (pyridoxine) 8mg, Vitamin B1 (thiamine) 39mg. All 
957 
the above ingredients are synthetic. The shelf-life is 2 years. Storage condition is keeping in 
958 
dry place below 300oC and protecting from light and moisture. It has no bovine-gelatin capsule. 
959 
There are no precautions on drug-drug interaction, but it is not suitable for children (<18 years). 
960 
There is insufficient reliable data for pregnancy and breast feeding. It has JAKIM Halal 
961 
Certification with reference number JAKIM.700-2/3/5 017-07/2005. One bottle consists of 60 
962 
tablets. 
963 

24 
 
BIONERV® is approved and commercially marketed in Malaysia in 2018. BIONERV® is 
964 
prescribed as adjuvant therapy for the treatment of peripheral neuropathy i.e. carpal tunnel 
965 
syndrome, diabetic polyneuropathy and neuritis. 
966 
 
967 
BIONERV® is registered as Health Supplement by National Pharmaceutical Regulatory 
968 
Agency (NPRA), Ministry of Health Malaysia. Malaysia.  
969 
 
970 
BIONERV® is available in government teaching institution hospitals including University 
971 
Malaya Medical Centre (PPUM), Universiti Putra Malaysia Teaching Hospital (HPUPM), 
972 
Universiti Kebangsaan Malaysia Medical Centre (PPUKM), Hospital Universiti Sains 
973 
Malaysia (HUSM), Sultan Ahmad Shah Medical Centre (SASMEC @IIUM) and Universiti 
974 
Teknologi MARA Hospital (HUiTM). BIONERV® is also available in major private hospitals 
975 
such as KPJ Group Hospitals and IHH Malaysia (Pantai Hospitals, Prince Court Medical 
976 
Centre & Gleneagles Hospitals), Columbia Asia Hospitals, Subang Jaya Medical Centre, 
977 
Sunway Medical Group etc. 
978 
 
979 
This medication needs to take 2 tablets a day after a meal and need to drink more water. In this 
980 
study, the participants need to take 2 tablets once daily after breakfast. The duration of the 
981 
intervention will be 12 weeks. All participants are required to return to the clinic in the 6th and 
982 
12th week for a post-intervention assessment. 
983 
 
984 
6.10.4 Control group  
985 
 
986 
At baseline, the control group will receive a placebo drug consisting of Croscamellose Sodium, 
987 
Microcrystalline Cellulose, Silicon Dioxide and Magnesium stearate. The placebo was 
988 
manufactured by Yanling Natural Hygiene Sdn Bhd. The formulation of the placebo tablet is 
989 
derived from the excipients used in the Bionerv tablet, which are already approved with Halal 
990 
Certification, which means the excipients have already been evaluated by JAKIM earlier with 
991 
no issue in complying with the Halal requirements. 
992 
 
993 
The participants need to take 2 tablets once daily after breakfast. The placebo drugs will share 
994 
the same appearance and color as intervention drug.  
995 
 
996 
The duration of the intervention will be 12 weeks. All participants are required to return to the 
997 
clinic in the 6th and 12th week for a post-intervention assessment. 
998 
 
999 
6.10.5 Follow up group 
1000 
 
1001 
There are two follow-ups during this study. 1st follow-up will be on the 6th week and 2nd 
1002 
follow-up (final follow-up) will be during 12th week of the study. 
1003 
During the 6th week follow-up, participants will be checked for their weight, height, calculated 
1004 
Body Mass Index (BMI), TSS, NSS, RV-DQoL questionnaire, compliance, and adverse 
1005 
effects.  
1006 

25 
 
A final visit (12th week) to the clinic will be conducted on the 12th week. During these visits, 
1007 
the outcome measures will be assessed to determine the effect of the fixed-dose combination 
1008 
of alpha lipoic acid and vitamin B. During this visit, the same measurement will be taken as 
1009 
visit 1. 
1010 
 
1011 
6.10.6 Compliance and adverse effect monitoring. 
1012 
 
1013 
A daily checklist form will be handed out to the participants to monitor their compliance with 
1014 
the treatment product. After taking the fixed dose combination of alpha lipoic acid and vitamin 
1015 
B or placebo, they need to tick on the form. 
1016 
 
1017 
Monthly reminders will be sent through the WhatsApp application to remind the participants 
1018 
to ensure compliance with the medication given. Nonresponsive participants will be contacted 
1019 
through a phone call for an additional reminder.  
1020 
 
1021 
Participants will be considered non-compliant if they miss more than 30% of the medication 
1022 
given throughout the intervention period.  
1023 
 
1024 
Participants will also be asked to report any complications or adverse effects, and this 
1025 
information will be recorded on an adverse effect sheet. Any adverse events due to trial 
1026 
intervention will be reported to the clinic and attended to by a medical doctor from the research 
1027 
team if any treatment is needed. 
1028 
 
1029 
6.10.7 Patient’s withdrawal. 
1030 
 
1031 
The investigator may cease study treatment and withdraw the participants, or the participant 
1032 
may withdraw herself from participation in the study at any time. The reason for withdrawal 
1033 
of a patient will be recorded in the case report form (CRF).  
1034 
 
1035 
Reasons for patient withdrawal include: 
1036 
 
1037 
a. 
The need to take medication, which may interfere with study measurement. 
1038 
b. 
Patient experiences an intolerable/ unacceptable adverse event. 
1039 
c. 
Patient exhibits non-compliance with the protocol. 
1040 
d. 
Patient unwilling to proceed and/ or consent is withdrawn. 
1041 
e. 
Investigator withdrawn patient for reasons unrelated to the study drug (e.g undercurrent  
1042 
            illness). 
1043 
 
1044 
6.11 Statistical Analysis 
1045 
 
1046 
Data entry and analyses will be conducted using SPSS for windows version 27. Prior to 
1047 
analysis, the data will be explored to examine the pattern of missing data and appropriate 
1048 
method of missing data imputation will be executed. Both Intention-to-treat and per-protocol 
1049 
analysis will be conducted.  
1050 

26 
 
The numerical variables’ shape of distribution will be examined both quantitatively (by 
1051 
examining the coefficient of variation, skewness value, kurtosis value, Kolmogorov-Smirnov 
1052 
test, and Shapiro-Wilk test) and qualitatively (by examining the histogram with overlaid normal 
1053 
curve, Q-Q plot, and the Box and Whisker plot). Numerical variables with gaussian (normal) 
1054 
distribution will be described as mean and standard deviation (SD), whereas median and 
1055 
interquartile range (IQR) will be used to describe variables with non-gaussian distribution. 
1056 
 
1057 
Comparison of the participants’ baseline characteristics (between the intervention and control 
1058 
group) will be made using independent sample t-test or Mann-Whitney U test (for numerical 
1059 
variables depending on the shape of distribution) and Chi-squared test or Fisher exact test (for 
1060 
categorical variables depending on the presence of small cells).  
1061 
For all the study outcome (primary and secondary outcomes), independent T- test (inter-group 
1062 
comparison, Paired T-test (intra group-comparison) and repeated measures analysis of 
1063 
variances (ANOVA) will be conducted to determine whether there is any significant 1) within 
1064 
group changes over time (time effect), 2) overall between group differences (treatment effect), 
1065 
and 3) between group differences at each time level (time-treatment interaction effects). All 
1066 
the estimated will be reported as the estimated marginal means with its adjusted 95% 
1067 
Confidence Intervals. The 2-tailed p-values of less than 0.05 will be considered as significant. 
1068 
 
1069 
6.11.1 Approaches to Deal with Missing Data 
1070 
 
1071 
In this study, the Expectation and Maximization (EM) algorithm will be used to handle the 
1072 
missing data. EM is commonly used in various applications especially when dealing with data 
1073 
that has missing values. The SPSS software through the Expectation and Maximization (EM) 
1074 
algorithm will be utilized to impute good values for missing data. 
1075 
 
1076 
7.0 SAFETY MEASUREMENTS. 
1077 
 
1078 
The safety evaluation will be determined by the incidence of adverse events and the definition 
1079 
of adverse events (AE)s and serious adverse events (SAEs) are as follows: An adverse event 
1080 
(AE) is defined as any untoward medical occurrence (including clinically significant laboratory 
1081 
findings) in a patient or clinical investigation subject administered a pharmaceutical drug, and 
1082 
which did not necessarily have a causal relationship to the treatment. Adverse events may 
1083 
include: 
1084 
 
1085 
1. 
The significant worsening of the disease or symptoms of the disease under investigation 
1086 
following the administration of the drug. 
1087 
 
1088 
2. 
Any undercurrent illness with an onset after administration of the drug. 
1089 
 
1090 
3. 
Exacerbation (i.e increase in frequency or intensity) of a pre-existing condition or event. 
1091 
 
1092 
A serious adverse event (SAE) is defined as any untoward medical occurrence that at any dose 
1093 
of the investigational product, that fulfills one or more of the following criteria: 
1094 

27 
 
1. 
Results in death 
1095 
 
1096 
2. 
Is life threatening. A ‘life-threatening’ adverse event refers to an event, which puts the 
1097 
patient at risk of death. It does no refer to an event, which hypothetically might cause 
1098 
death if it is more severe. 
1099 
 
1100 
3. 
Requires in-patient hospitalization or prolongation of existing hospitalization. 
1101 
Hospitalization is defined as the patient being hospitalized overnight, or the patient’s 
1102 
hospital stay being prolonged for at least an additional overnight stay. Hospital 
1103 
admissions for elective surgery, for social reasons or for normal disease management 
1104 
procedures that are not the result of worsening an underlying condition will not be 
1105 
considered a serious adverse event. 
1106 
 
1107 
4. 
Results in persistent or significant disability/incapacity 
1108 
 
1109 
5. 
Is a congenital anomaly / birth defect. 
1110 
 
1111 
6. 
Is a malignancy. 
1112 
 
1113 
7. 
Is the result of an overdose? An important medical event jeopardizes the patient and 
1114 
may require medical or surgical intervention to prevent one of the above outcomes from 
1115 
occurring. 
1116 
 
1117 
6.11 Statistical Analysis 
1118 
 
1119 
Data entry and analyses will be conducted using SPSS for windows version 27. Prior to 
1120 
analysis, the data will be explored to examine the pattern of missing data and appropriate 
1121 
method of missing data imputation will be executed. Both Intention-to-treat and per-protocol 
1122 
analysis will be conducted.  
1123 
The numerical variables’ shape of distribution will be examined both quantitatively (by 
1124 
examining the coefficient of variation, skewness value, kurtosis value, Kolmogorov-Smirnov 
1125 
test, and Shapiro-Wilk test) and qualitatively (by examining the histogram with overlaid normal 
1126 
curve, Q-Q plot, and the Box and Whisker plot). Numerical variables with gaussian (normal) 
1127 
distribution will be described as mean and standard deviation (SD), whereas median and 
1128 
interquartile range (IQR) will be used to describe variables with non-gaussian distribution. 
1129 
 
1130 
Comparison of the participants’ baseline characteristics (between the intervention and control 
1131 
group) will be made using independent sample t-test or Mann-Whitney U test (for numerical 
1132 
variables depending on the shape of distribution) and Chi-squared test or Fisher exact test (for 
1133 
categorical variables depending on the presence of small cells).  
1134 
For all the study outcome (primary and secondary outcomes), independent T- test (inter-group 
1135 
comparison, Paired T-test (intra group-comparison) and repeated measures analysis of 
1136 
variances (ANOVA) will be conducted to determine whether there is any significant 1) within 
1137 
group changes over time (time effect), 2) overall between group differences (treatment effect), 
1138 

28 
 
and 3) between group differences at each time level (time-treatment interaction effects). All 
1139 
the estimated will be reported as the estimated marginal means with its adjusted 95% 
1140 
Confidence Intervals. The 2-tailed p-values of less than 0.05 will be considered as significant. 
1141 
 
1142 
6.11.1 Approaches to Deal with Missing Data 
1143 
 
1144 
In this study, the Expectation and Maximization (EM) algorithm will be used to handle the 
1145 
missing data. EM is commonly used in various applications especially when dealing with data 
1146 
that has missing values. The SPSS software through the Expectation and Maximization (EM) 
1147 
algorithm will be utilized to impute good values for missing data. 
1148 
 
1149 
7.0 SAFETY MEASUREMENTS. 
1150 
 
1151 
8.0 ETHICAL ISSUE 
1152 
 
1153 
The information regarding this study will be provided to all subjects involved. Informed 
1154 
consent will be taken from the respondents. The confidentiality of the subject will be 
1155 
maintained throughout this study. This study will obtain ethical approval from an ethic 
1156 
committee of Universiti Sains Malaysia. 
1157 
 
1158 
9.0 BUDGET  
1159 
 
1160 
This study will be sponsored by the BREGO life sciences Sdn. Bhd. Company 
1161 
 
1162 
10.0 ETHICAL STATEMENT 
1163 
 
1164 
10.1 Vulnerability 
1165 
 
1166 
This group of participants is considered a vulnerable group. However, participation in this 
1167 
study is entirely voluntary. Participants may refuse to take part in this study, or they may stop 
1168 
participation in this study at any time, without a penalty or loss of benefits to which the 
1169 
participant is otherwise entitled.  Their participation in this study also will be anonymous. They 
1170 
also will be brought to a separate room to answer the questionnaires.  
1171 
 
1172 
10.2 Declaration of absence of conflict of interest  
1173 
 
1174 
Researcher declared that one has no conflict of interest in this study in any form. The treating 
1175 
physician is not a part of the research team. If the patient refused to participate in this study, it 
1176 
will not affect the standard of care of the patient. 
1177 
 
1178 
10.3 Privacy and confidentiality 
1179 
 
1180 
Respondents will be told that the information provided is confidential and their identities are 
1181 
not revealed in association with the information they provided. All forms are anonymous and 
1182 

29 
 
will be entered into SPSS software. Only research team members can enter the data. Data will 
1183 
be presented as grouped data and will not identify the respondents individually.  
1184 
 
1185 
10.4 Possible Benefit (Community Sensitives & Benefits)    
1186 
 
1187 
Findings of the study are very important to determine the effectiveness of fixed dose 
1188 
combination of alpha lipoic acid and vitamin B in comparison placebo for treatment of diabetic 
1189 
polyneuropathy in type 2 diabetes mellitus patients. It will help in managing diabetes 
1190 
polyneuropathy by giving more effective options to the physicians and patients to choose the 
1191 
best treatment in treating diabetic polyneuropathy. 
1192 
 
1193 
10.5 Honorarium and incentives: 
1194 
 
1195 
 Honorarium will be given to both group with a value of RM50 for each visit.  
1196 
 
1197 
10.6 Other Ethical review board approval    
1198 
 
1199 
Not applicable 
1200 
 
1201 
10.7 Data destruction will be done at the end of the study. 
1202 
 
1203 
10.8 Conflict of interest 
1204 
 
1205 
There is no conflict of interest related to sponsorship, data analysis and publication 
1206 
 
1207 
10.9 Collaborative study terms of reference 
1208 
 
1209 
This study is an industry sponsored research by BREGO Life Sciences Sdn Bhd company. 
1210 
 
1211 
10.10 Ethical approval will be obtained from approval by the Jawatankuasa Etika 
1212 
Penyelidikan Manusia (JEPeM) Universiti Sains Malaysia 
1213 
 
1214 
10.11 The study already get approval from National Medical Research Register (NMRR) 
1215 
on 18.12.2023 
1216 
 
1217 
 
1218 
11.0 EXPECTED RESULTS 
1219 
 
1220 
Table 1: Sociodemographic data of the respondents (n=76) 
1221 
Variables 
 
Frequency (%) 
Mean 
Age (year) 
 
 
Gender 
 
 
  Male 
 
 
  Female 
 
 

30 
 
Race 
 
 
  Malay 
 
 
  Chinese  
 
 
  Indian  
 
 
  Others 
 
 
 
Education 
 
 
  No formal education/primary school 
 
 
  Secondary school 
 
 
  Tertiary educational level 
 
 
Occupation    
 
 
  Employed 
 
 
  Unemployed 
 
 
Monthly Income (RM) 
 
 
Marital status 
 
 
  Single/divorce/widow 
 
 
  Married 
 
 
Diagnosis of DM (year) 
 
 
Medication  
 
 
  Metformin 
 
 
  Glicazide 
 
 
  SGLT2i 
 
 
  DPP4I 
 
 
  Insulin 
 
 
  others 
 
 
Comorbidities 
 
 
  Retinopathy 
 
 
  IHD/MI 
 
 
  Hyperlipidemia  
 
 
  Hypertension 
 
 
  Others  
 
 
 
1222 
 
1223 
Table 2: Baseline biochemical and clinical characteristics of participants(n=76) 
1224 
Variable  
Mean (SD) 
 
 
 
Control 
Intervention Mean 
diff(95%CI) 
t-stat (df) 
p-value* 
Height  
 
 
 
 
 
Weight (kg) 
 
 
 
 
 
BMI 
 
 
 
 
 
SBP (mmHg) 
 
 
 
 
 
DBP (mmHg) 
 
 
 
 
 
FBS (mmol/L)  
 
 
 
 

31 
 
HbA1c (%) 
 
 
 
 
 
TC (mmol/L) 
 
 
 
 
 
LDL (mmol/L)  
 
 
 
 
HDL 
(mmol/L) 
 
 
 
 
 
TG (mmol/L) 
 
 
 
 
 
Creatinine 
 
 
 
 
 
Urea  
 
 
 
 
 
AST 
 
 
 
 
 
ALT 
 
 
 
 
 
ALP 
 
 
 
 
 
Score DQoL 
 
 
 
 
 
*Independent T-test 
1225 
 
1226 
 
1227 
 
1228 
Expected result for objective 1: To compare the mean change in total symptom score (TSS) 
1229 
and neuropathic symptoms score (NSS) over 12 a week period between diabetic 
1230 
polyneuropathy patients taking a fixed dose combination of alpha lipoic acid and vitamin B 
1231 
preparations versus diabetic polyneuropathy patients taking placebo (inter-group comparison) 
1232 
 
1233 
Table 3: Comparison of total symptom score (TSS) score between control and 
1234 
intervention group(n=76) 
1235 
Comparison between TSS versus Group: F-Stat (df); p-value a 
 
Mean (SD) Mean diff 
(95%CI) 
T-Statistic (df) p-valueb 
Total symptom score at baseline 
 
 
 
 
Control 
 
 
 
 
Intervention 
 
Total symptom score at 6 weeks 
 
 
 
 
Control 
 
 
 
 
Intervention 
 
Total symptom score at 12 weeks 
 
 
 
 
Control 
 
 
 
 
Intervention 
 
 
 
 
 
 
*Significant at 0.05 
1236 
 a: Repeated measures ANOVA was applied  
1237 
 b: Independent Sample T-test 
1238 
 
1239 
 
1240 
 
1241 
 
1242 
 
1243 

32 
 
Table 4: Comparison of neuropathic symptoms score (NSS) score between control and 
1244 
intervention group(n=76) 
1245 
Comparison between NSS versus Group: F-Stat (df); p-value a 
 
Mean (SD) Mean diff 
(95%CI) 
T-Statistic (df) p-valueb 
Neuropathic symptoms score at baseline  
 
 
 
Control 
 
 
 
 
Intervention 
 
Neuropathic symptoms score at 6 weeks  
 
 
 
Control 
 
 
 
 
Intervention 
 
Neuropathic symptoms score at 12 
weeks 
 
 
 
 
Control 
 
 
 
 
Intervention 
 
*Significant at 0.05 
1246 
 a: Repeated measures ANOVA was applied  
1247 
 b: Independent Sample T-test 
1248 
 
1249 
Expected result for objective 2: To compare the mean change in total symptom score (TSS) 
1250 
and neuropathic symptoms score (NSS) among diabetic polyneuropathy patients at baseline 
1251 
and 12 weeks after taking a fixed dose combination of alpha lipoic acid and vitamin B 
1252 
preparations (intra-group comparison) 
1253 
 
1254 
Table 5: Comparison of TSS and NSS score within the intervention group (n=38) 
1255 
 
Mean (SD) 
F -statistic 
(df) 
p- valuea,* 
Baseline  
(TSS_b) 
6 weeks 
(TSS_6) 
12 weeks 
(TSS_12) 
TSS  
 
 
 
 
 
Total score 
 
 
 
 
 
Pain  
 
 
 
 
 
Burning 
 
 
 
 
 
Paraesthesia 
 
 
 
 
 
Numbness 
 
 
 
 
 
Multiple Comparison [TSS_b(mean(SD)]vs. [TSS_6(mean(SD)]  :p-value b 
                                   [TSS_b(mean(SD)]vs. [TSS_12(mean(SD)] : p-valueb  
           [TSS_6(mean(SD)]vs. [TSS_12(mean(SD)]: p-valueb 
 
Mean (SD) 
F -statistic 
(df) 
p- valuea,* 
Baseline 
(NSS_b) 
6 weeks 
(NSS_6) 
12 weeks 
(NSS_12) 
NSS score 
 
 
 
 
 
Multiple Comparison [NSS_b(mean(SD)]vs. [NSS_6(mean(SD)]  :p-valueb 
                                   [NSS_b(mean(SD)]vs. [NSS_12(mean(SD)] : p-valueb  
                                    [NSS_6(mean(SD)]vs. [NSS_12(mean(SD)]: p-valueb 
*Significant at 0.05 
1256 
a: Repeated measures ANOVA was applied.  
1257 

33 
 
b: Paired samples T Test 
1258 
MulivariateNormality Assumption is fulfilled. 
1259 
 
1260 
Expected result for objective 3: To compare changes and differences in fasting plasma 
1261 
glucose, HbA1C level, fasting lipid profile, body mass index (BMI), blood pressure and 
1262 
diabetes quality of life over 12 a week period between diabetic polyneuropathy patients taking 
1263 
a fixed dose combination of alpha lipoic acid and vitamin B preparations and in diabetic 
1264 
polyneuropathy patients taking placebo (inter-group comparison). 
1265 
 
1266 
Table 6: Comparison of fasting plasma glucose (FBS) and HbA1C level and fasting lipid 
1267 
profile between control and intervention group (n=76) 
1268 
 
Mean (SD) Mean diff 
(95%CI) 
T-Statistic (df) p-valuea 
FBS level at baseline 
 
 
 
 
Control 
 
 
 
 
Intervention 
 
FBS level at 12 weeks 
 
 
 
 
Control 
 
 
 
 
Intervention 
 
 
 
 
 
 
HbA1C level at baseline 
 
 
 
 
Control 
 
 
 
 
Intervention 
 
HbA1C level at 12 weeks 
 
 
 
 
Control 
 
 
 
 
Intervention 
 
 
 
 
 
 
TC (mmol/L) level at baseline 
 
 
 
 
Control 
 
 
 
 
Intervention 
 
 
 
 
TC (mmol/L) level at 12 weeks 
 
 
 
 
Control 
 
 
 
 
Intervention 
 
 
 
 
 
 
 
 
 
LDL (mmol/L) level at baseline 
 
 
 
 
Control 
 
 
 
 
Intervention 
 
 
 
 
LDL (mmol/L) level at 12 weeks 
 
 
 
 
Control 
 
 
 
 
Intervention 
 
 
 
 
 
 
 
 
 
HDL (mmol/L)level at baseline 
 
 
 
 
Control 
 
 
 
 
Intervention 
 
 
 
 
HDL (mmol/L) level at 12 weeks 
 
 
 
 
Control 
 
 
 
 
Intervention 
 
 
 
 
 
 
 
 
 

34 
 
TG (mmol/L)level at baseline 
 
 
 
 
Control 
 
 
 
 
Intervention 
 
 
 
 
TG (mmol/L)level at 12 weeks 
 
 
 
 
Control 
 
 
 
 
Intervention 
 
 
 
 
 
 
 
 
 
BMI level at baseline 
 
 
 
 
Control 
 
 
 
 
Intervention 
 
 
 
 
BMI level at 12 weeks 
 
 
 
 
Control 
 
 
 
 
Intervention 
 
 
 
 
*Significant at 0.05 
1269 
a: Independent Sample T-test 
1270 
 
1271 
Table 7: Comparison of diabetes quality of life between control and intervention group 
1272 
(n=76) 
1273 
Comparison between diabetes quality of life versus Group: F-Stat (df); p-value a 
 
Mean (SD) Mean diff 
(95%CI) 
t-Statistic (df) p-valueb 
Diabetes quality of life at baseline 
 
 
 
 
Control 
 
 
 
 
Intervention 
 
Diabetes quality of life at 6 weeks 
 
 
 
 
Control 
 
 
 
 
Intervention 
 
Diabetes quality of life at 12 weeks 
 
 
 
 
Control 
 
 
 
 
Intervention 
 
*Significant at 0.05 
1274 
 a: Repeated measures ANOVA was applied.  
1275 
 b: Independent Sample T-test 
1276 
 
1277 
Table 8: Comparison of body mass index between control and intervention group (n=76) 
1278 
Comparison between diabetes quality of life versus Group: F-Stat (df); p-value a 
 
Mean (SD) Mean diff 
(95%CI) 
t-Statistic (df) p-valueb 
BMI level at baseline 
 
 
 
 
Control 
 
 
 
 
Intervention 
 
BMI level at 6 weeks 
 
 
 
 
Control 
 
 
 
 
Intervention 
 
BMI level at 12 weeks 
 
 
 
 
Control 
 
 
 
 
Intervention 
 
*Significant at 0.05 
1279 
 a: Repeated measures ANOVA was applied.  
1280 
 b: Independent Sample T-test 
1281 

35 
 
Table 9: Comparison of blood pressure between control and intervention group (n=76) 
1282 
Comparison between diabetes quality of life versus Group: F-Stat (df); p-value a 
 
Mean (SD) Mean diff 
(95%CI) 
t-Statistic (df) p-valueb 
BP level at baseline 
 
 
 
 
Control 
 
 
 
 
Intervention 
 
BP level at 6 weeks 
 
 
 
 
Control 
 
 
 
 
Intervention 
 
BP level at 12 weeks 
 
 
 
 
Control 
 
 
 
 
Intervention 
 
*Significant at 0.05 
1283 
 a: Repeated measures ANOVA was applied.  
1284 
 b: Independent Sample T-test 
1285 
 
1286 
Expected result for Objective 4: To compare the changes in the safety parameters of the renal 
1287 
function and liver function tests among diabetic polyneuropathy patients at baseline and 12 
1288 
weeks after taking a fixed dose combination of alpha lipoic acid and vitamin B preparations 
1289 
(intra-group comparison). 
1290 
 
1291 
Table 10: Comparison of renal function and liver function tests within intervention group 
1292 
(n=38) 
1293 
 
Mean (SD) 
t-statistic 
(df) 
p- valuea,* 
Baseline 
12 weeks 
Creatinine 
 
 
 
  
Urea  
 
 
 
 
AST 
 
 
 
 
ALT 
 
 
 
 
ALP 
 
 
 
 
*Significant at 0.05  
1294 
a: Paired samples T Test 
1295 
 
1296 
Expected result for Objective 5: To compare changes and differences of fasting plasma 
1297 
glucose, HbA1C level, fasting lipid profile, body mass index (BMI), blood pressure and 
1298 
diabetes quality of life among diabetic polyneuropathy patients at baseline and 12 weeks after 
1299 
taking a fixed dose combination of alpha lipoic acid and vitamin B preparations (intra-group 
1300 
comparison). 
1301 
 
1302 
 
1303 
 
1304 
 
1305 
 
1306 

36 
 
Table 11: Comparison of fasting plasma glucose, HbA1C level, and fasting lipid profile 
1307 
within intervention group (n=38) 
1308 
 
Mean (SD) 
t-statistic 
(df) 
p- valuea,* 
Baseline 
12 weeks 
Fasting plasma glucose 
 
 
 
  
HbA1C level 
 
 
 
 
Fasting lipid profile 
 
 
 
 
   TC (mmol/L) 
 
 
 
 
   LDL (mmol/L) 
 
 
 
 
   HDL (mmol/L) 
 
 
 
 
   TG (mmol/L) 
 
 
 
 
*Significant at 0.05  
1309 
a: Paired samples T Test 
1310 
 
1311 
 
1312 
Table 12: Comparison of diabetes quality of life within intervention group(n=38) 
1313 
 
Mean (SD) 
F -statistic 
(df) 
p- valuea,* 
Baseline 
(DQoL_b) 
13 weeks 
(DqoL_6) 
12 weeks 
(DqoL_12) 
Diabetes quality 
of life (DqoL) 
 
 
 
 
 
Multiple Comparison [DqoL_b (mean(SD)]vs. [DqoL_6)(mean(SD)]  :p-value b 
                                   [DqoL_b (mean(SD)]vs. [DqoL_12 (mean(SD)] : p-valueb  
           [DqoL_6 (mean(SD)]vs. [DqoL_12 (mean(SD)]: p-valueb 
*Significant at 0.05 
1314 
a: Repeated measures ANOVA was applied  
1315 
b: Paired samples T Test 
1316 
MulivariateNormality Assumption is fulfilled. 
1317 
 
1318 
 
1319 
 
1320 
Table 13: Comparison of body mass index within intervention group(n=38) 
1321 
 
Mean (SD) 
F -statistic 
(df) 
p- valuea,* 
Baseline 
(BMI_b) 
13 weeks 
(BMI _6) 
12 weeks 
(_BMI 12) 
Body 
Mass 
Index (BMI) 
 
 
 
 
 
Multiple Comparison [BMI _b (mean(SD)]vs. [BMI_6)(mean(SD)]  :p-value b 
                                   [BMI _b (mean(SD)]vs. [BMI _12 (mean(SD)] : p-valueb  
           [BMI _6 (mean(SD)]vs. [BMI _12 (mean(SD)]: p-valueb 
*Significant at 0.05 
1322 
a: Repeated measures ANOVA was applied  
1323 
b: Paired samples T Test 
1324 
MulivariateNormality Assumption is fulfilled. 
1325 
 
1326 
 
1327 
 
1328 

37 
 
Table 14: Comparison of blood pressure within intervention group(n=38) 
1329 
 
Mean (SD) 
F -statistic 
(df) 
p- valuea,* 
Baseline 
(BP _b) 
13 weeks 
(BP_6) 
12 weeks 
(_BP 12) 
Blood pressure 
(BP) 
 
 
 
 
 
Multiple Comparison [BP _b (mean(SD)]vs. [BP_6)(mean(SD)]  :p-value b 
                                   [BP _b (mean(SD)]vs. [BP _12 (mean(SD)] : p-valueb  
           [BP _6 (mean(SD)]vs. [BP _12 (mean(SD)]: p-valueb 
*Significant at 0.05 
1330 
a: Repeated measures ANOVA was applied.  
1331 
b: Paired samples T Test 
1332 
MulivariateNormality Assumption is fulfilled. 
1333 
 
1334 
12.0 GANTT CHART  
1335 
1336 
13.0 MILESTONE  
1337 
 
Plan 
Date 
1 Proposal development  
August – November 2023 
2 Ethic submission  
Nov 2023 – Jan 2024 
3 Data collection  
 
Feb – Sept 2024 
4 Data analysis  
 
Oct – Feb 2025 
5 Report writing  
 
Mac – September 2025 
 
1338 
14.0 BUDJET 
1339 
 
1340 
 
1341 
 
1342 

38 
 
15. REFERENCES  
1343 
 
1344 
Abbott, C. A., Malik, R. A., Van Ross, E. R., Kulkarni, J. & Boulton, A. J. (2011). Prevalence and 
1345 
characteristics of painful diabetic neuropathy in a large community-based diabetic population in the 
1346 
UK. Diabetes care, 34(10), 2220-2224.  
1347 
 
1348 
Abubaker, S. A., Alonazy, A. M. & Abdulrahman, A. (2022). Effect of Alpha-Lipoic Acid in the Treatment 
1349 
of Diabetic Neuropathy: A Systematic Review. Cureus, 14(6), e25750. doi: 10.7759/cureus.25750 
1350 
 
1351 
Agathos, E., Tentolouris, A., Eleftheriadou, I., Katsaouni, P., Nemtzas, I., Petrou, A., . . . Tentolouris, N. 
1352 
(2018). Effect of alpha-lipoic acid on symptoms and quality of life in patients with painful diabetic 
1353 
neuropathy. J Int Med Res, 46(5), 1779-1790. doi: 10.1177/0300060518756540 
1354 
 
1355 
Altun, I. & Kurutas, E. B. (2016). Vitamin B complex and vitamin B12 levels after peripheral nerve injury. 
1356 
Neural Regen Res, 11(5), 842-845. doi: 10.4103/1673-5374.177150 
1357 
 
1358 
André Pfannkuche, Ahmad Alhajjar, Antao Ming, Isabell Walter, Claudia Piehler & Mertens, P. R. 
1359 
(2020). Prevalence and risk factors of diabetic peripheral neuropathy in a diabetics cohort: Register 
1360 
initiative 
“diabetes 
and 
nerves. 
Endocrine 
and 
Metabolic 
Science, 
2020, 
1-9. 
doi: 
1361 
https://doi.org/10.1016/j.endmts.2020.100053 
1362 
 
1363 
Armstrong, D. & Lavery, L. (1998). Diabetic foot ulcers: prevention, diagnosis and classification. 
1364 
American Family Physician, 57(6), 1325-1337.  
1365 
 
1366 
Asad, A., Hameed, M. A., Khan, U. A., Ahmed, N. & Butt, M.-u.-R. A. (2010). Reliability of the 
1367 
neurological scores for assessment of sensorimotor neuropathy in type 2 diabetics. JPMA. The Journal 
1368 
of the Pakistan Medical Association, 60(3), 166-170.  
1369 
 
1370 
Association, A. D. (2020). Microvascular complications and foot care: standards of medical care in 
1371 
diabetes− 2020. Diabetes care, 43(1), 135-151.  
1372 
 
1373 
Bartkoski, S. & Day, M. (2016). Alpha-Lipoic Acid for Treatment of Diabetic Peripheral Neuropathy. Am 
1374 
Fam Physician, 93(9), 786.  
1375 
 
1376 
Bujang, M. A., Adnan, T. H., Mohd Hatta, N. K. B., Ismail, M. & Lim, C. J. (2018). A revised version of 
1377 
diabetes quality of life instrument maintaining domains for satisfaction, impact, and worry. Journal of 
1378 
diabetes research, 2018, 1-10. doi: https://doi.org/10.1155/2018/5804687 
1379 
 
1380 
Callaghan, B. C., Price, R. S. & Feldman, E. L. (2020). Distal Symmetric Polyneuropathy in 2020. JAMA, 
1381 
324(1), 90-91. doi: 10.1001/jama.2020.0700 
1382 
 
1383 
Carmichael, J., Fadavi, H., Ishibashi, F., Shore, A. C. & Tavakoli, M. (2021). Advances in screening, early 
1384 
diagnosis and accurate staging of diabetic neuropathy. Frontiers in Endocrinology, 12, 1-25.  
1385 
 
1386 
Chawla, A., Bhasin, G. & Chawla, R. (2013). Validation of neuropathy symptoms score (NSS) and 
1387 
neuropathy disability score (NDS) in the clinical diagnosis of peripheral neuropathy in middle aged 
1388 
people with diabetes. The Internet Journal of Family Practice, 12(1), 1-4.  
1389 
 
1390 
Chiles, N. S., Phillips, C. L., Volpato, S., Bandinelli, S., Ferrucci, L., Guralnik, J. M. & Patel, K. V. (2014). 
1391 
Diabetes, peripheral neuropathy, and lower-extremity function. J Diabetes Complications, 28(1), 91-
1392 
95. doi: 10.1016/j.jdiacomp.2013.08.007 
1393 

39 
 
 
1394 
Darivemula, S., Nagoor, K., Patan, S. K., Reddy, N. B., Deepthi, C. S. & Chittooru, C. S. (2019). Prevalence 
1395 
and Its Associated Determinants of Diabetic Peripheral Neuropathy (DPN) in Individuals Having Type-
1396 
2 Diabetes Mellitus in Rural South India. Indian J Community Med, 44(2), 88-91. doi: 
1397 
10.4103/ijcm.IJCM_207_18 
1398 
 
1399 
Debele, G. R., Kuse, S. A., Kefeni, B. T., Geda, A., Jifar, W. W., Kitila, K. M. & Hajure, M. (2023). Why too 
1400 
soon? Predictors of time to diabetic peripheral neuropathy among newly diagnosed diabetes mellitus 
1401 
patients: a multicenter follow-up study at health-care setting of Ethiopia. Arch Public Health, 81(1), 
1402 
186. doi: 10.1186/s13690-023-01202-3 
1403 
 
1404 
El-Nahas, M. R., Elkannishy, G., Abdelhafez, H., Elkhamisy, E. T. & El-Sehrawy, A. A. (2020). Oral Alpha 
1405 
Lipoic Acid Treatment for Symptomatic Diabetic Peripheral Neuropathy: A Randomized Double-
1406 
Blinded Placebo-Controlled Study. Endocr Metab Immune Disord Drug Targets, 20(9), 1531-1534. doi: 
1407 
10.2174/1871530320666200506081407 
1408 
 
1409 
Farah, S. & Yammine, K. (2022). A systematic review on the efficacy of vitamin B supplementation on 
1410 
diabetic peripheral neuropathy. Nutr Rev, 80(5), 1340-1355. doi: 10.1093/nutrit/nuab116 
1411 
 
1412 
Feldman, E. L., Callaghan, B. C., Pop-Busui, R., Zochodne, D. W., Wright, D. E., Bennett, D. L., . . . 
1413 
Viswanathan, V. (2019). Diabetic neuropathy. Nat Rev Dis Primers, 5(1), 42. doi: 10.1038/s41572-019-
1414 
0097-9 
1415 
 
1416 
Feldman, E. L., Stevens, M., Thomas, P., Brown, M., Canal, N. & Greene, D. (1994). A practical two-step 
1417 
quantitative clinical and electrophysiological assessment for the diagnosis and staging of diabetic 
1418 
neuropathy. Diabetes care, 17(11), 1281-1289.  
1419 
 
1420 
Fisher, L., Hessler, D. M., Polonsky, W. H. & Mullan, J. (2012). When is diabetes distress clinically 
1421 
meaningful?: establishing cut points for the Diabetes Distress Scale. Diabetes Care, 35(2), 259-264. 
1422 
doi: 10.2337/dc11-1572 
1423 
 
1424 
Gilron, I., Robb, S., Tu, D., Holden, R., Towheed, T., Ziegler, D., . . . Gray, C. (2021). Double-blind, 
1425 
randomized, placebo-controlled crossover trial of alpha-lipoic acid for the treatment of fibromyalgia 
1426 
pain: the IMPALA trial. Pain, 162(2), 561-568. doi: 10.1097/j.pain.0000000000002028 
1427 
 
1428 
Gylfadottir, S. S., Christensen, D. H., Nicolaisen, S. K., Andersen, H., Callaghan, B. C., Itani, M., . . . 
1429 
Finnerup, N. B. (2020). Diabetic polyneuropathy and pain, prevalence, and patient characteristics: a 
1430 
cross-sectional questionnaire study of 5,514 patients with recently diagnosed type 2 diabetes. Pain, 
1431 
161(3), 574-583. doi: 10.1097/j.pain.0000000000001744 
1432 
 
1433 
Herman, W., Pop-Busui, R., Braffett, B., Martin, C., Cleary, P., Albers, J., . . . Group, D. E. R. (2012). Use 
1434 
of the Michigan Neuropathy Screening Instrument as a measure of distal symmetrical peripheral 
1435 
neuropathy in Type 1 diabetes: results from the Diabetes Control and Complications 
1436 
Trial/Epidemiology of Diabetes Interventions and Complications. Diabetic medicine, 29(7), 937-944.  
1437 
 
1438 
Jacobson, A. M., Groot, M. D. & Samson, J. A. (1994). The evaluation of two measures of quality of life 
1439 
in patients with type I and type II diabetes. Diabetes care, 17(4), 267-274.  
1440 
 
1441 
Jadhao, P., Swain, J., Das, S., Mangaraj, S. & Sravya, S. L. (2024). Prevalence and Predictors of Diabetic 
1442 
Peripheral Neuropathy in Newly Diagnosed Type 2 Diabetes Mellitus Patients. Curr Diabetes Rev. doi: 
1443 
10.2174/0115733998282818240125110248 
1444 

40 
 
 
1445 
Jensen, T. S., Karlsson, P., Gylfadottir, S. S., Andersen, S. T., Bennett, D. L., Tankisi, H., . . . Callaghan, B. 
1446 
C. (2021). Painful and non-painful diabetic neuropathy, diagnostic challenges and implications for 
1447 
future management. Brain, 144(6), 1632-1645. doi: 10.1093/brain/awab079 
1448 
 
1449 
Juster-Switlyk, K. & Smith, A. G. (2016). Updates in diabetic peripheral neuropathy. F1000Res, 5. doi: 
1450 
10.12688/f1000research.7898.1 
1451 
 
1452 
Kamel, S. R., Hamdy, M., Abo Omar, H. A., Kamal, A., Ali, L. H. & Abd Elkarim, A. H. (2015). Clinical 
1453 
diagnosis of distal diabetic polyneuropathy using neurological examination scores: correlation with 
1454 
nerve conduction studies. Egyptian Rheumatology and Rehabilitation, 42, 128-136.  
1455 
 
1456 
Khan, H., Singh, T. G., Dahiya, R. S. & Abdel-Daim, M. M. (2022). alpha-Lipoic Acid, an Organosulfur 
1457 
Biomolecule a Novel Therapeutic Agent for Neurodegenerative Disorders: An Mechanistic 
1458 
Perspective. Neurochem Res, 47(7), 1853-1864. doi: 10.1007/s11064-022-03598-w 
1459 
 
1460 
Khdour, M. R. (2020). Treatment of diabetic peripheral neuropathy: a review. J Pharm Pharmacol, 
1461 
72(7), 863-872. doi: 10.1111/jphp.13241 
1462 
 
1463 
Kioskli, K., Scott, W., Winkley, K., Kylakos, S. & McCracken, L. M. (2019). Psychosocial Factors in Painful 
1464 
Diabetic Neuropathy: A Systematic Review of Treatment Trials and Survey Studies. Pain Med, 20(9), 
1465 
1756-1773. doi: 10.1093/pm/pnz071 
1466 
 
1467 
Kisozi, T., Mutebi, E., Kisekka, M., Lhatoo, S., Sajatovic, M., Kaddumukasa, M., . . . Katabira, E. (2017). 
1468 
Prevalence, severity and factors associated with peripheral neuropathy among newly diagnosed 
1469 
diabetic patients attending Mulago hospital: a cross-sectional study. African health sciences, 17(2), 
1470 
463-473.  
1471 
 
1472 
Lee, P. Y., Hani, S. S., Cheng, Y. G., Zainuddin, Z., Singh, H. & Loh, K. W. (2022). The proportion of 
1473 
undiagnosed diabetic peripheral neuropathy and its associated factors among patients with T2DM 
1474 
attending urban health clinics in Selangor. Malays Fam Physician, 17(1), 36-43. doi: 10.51866/oa1297 
1475 
 
1476 
Li-Ying, G., Shahrom, E. E., Ganesan, C. C., Vethakkan, S. R. & Khean-Jin, G. (2017). The prevalence and 
1477 
associated factors of neuropathic pain symptoms in a cohort of multi-ethnic Malaysian patients with 
1478 
diabetes mellitus. Neurology Asia, 22(4), 325-331.  
1479 
 
1480 
Liu, F., Zhang, Y., Yang, M., Liu, B., Shen, Y. D., Jia, W. P. & Xiang, K. S. (2007). [Curative effect of alpha-
1481 
lipoic acid on peripheral neuropathy in type 2 diabetes: a clinical study]. Zhonghua Yi Xue Za Zhi, 
1482 
87(38), 2706-2709.  
1483 
 
1484 
Lu, Y., Xing, P., Cai, X., Luo, D., Li, R., Lloyd, C., . . . Li, M. (2020). Prevalence and Risk Factors for Diabetic 
1485 
Peripheral Neuropathy in Type 2 Diabetic Patients From 14 Countries: Estimates of the INTERPRET-DD 
1486 
Study. Front Public Health, 8, 534372. doi: 10.3389/fpubh.2020.534372 
1487 
 
1488 
Malaysia, M. o. h. (2020). Clinical Practice Guidelines on Management of Type 2 Diabetes Mellitus 
1489 
 (6th Edition), Available at: https://mems.my/cpg-management-of-type-2-diabetes-mellitus-6th-
1490 
edition/.  
1491 
 
1492 
Mimi, O., Teng, C. L. & Chia, Y. C. (2003). The prevalence of diabetic peripheral neuropathy in an 
1493 
outpatient setting. Med J Malaysia, 58(4), 533-538.  
1494 
 
1495 

41 
 
Mousavi, S. M., Shab-Bidar, S., Kord-Varkaneh, H., Khorshidi, M. & Djafarian, K. (2019). Effect of alpha-
1496 
lipoic acid supplementation on lipid profile: A systematic review and meta-analysis of controlled 
1497 
clinical trials. Nutrition, 59, 121-130. doi: 10.1016/j.nut.2018.08.004 
1498 
 
1499 
Nagamatsu, M., Nickander, K. K., Schmelzer, J. D., Raya, A., Wittrock, D. A., Tritschler, H. & Low, P. A. 
1500 
(1995). Lipoic acid improves nerve blood flow, reduces oxidative stress, and improves distal nerve 
1501 
conduction in experimental diabetic neuropathy. Diabetes Care, 18(8), 1160-1167. doi: 
1502 
10.2337/diacare.18.8.1160 
1503 
 
1504 
Organization, W. H. (2020). Diagnosis and Management of Type 2 Diabetes.  
1505 
 
1506 
Papanas, N. & Ziegler, D. (2014). Efficacy of alpha-lipoic acid in diabetic neuropathy. Expert Opin 
1507 
Pharmacother, 15(18), 2721-2731. doi: 10.1517/14656566.2014.972935 
1508 
 
1509 
Perkins, B. A., Olaleye, D., Zinman, B. & Bril, V. (2001). Simple screening tests for peripheral neuropathy 
1510 
in the diabetes clinic. Diabetes care, 24(2), 250-256.  
1511 
 
1512 
Pop-Busui, R., Boulton, A. J., Feldman, E. L., Bril, V., Freeman, R., Malik, R. A., . . . Ziegler, D. (2017a). 
1513 
Diabetic neuropathy: a position statement by the American Diabetes Association. Diabetes care, 40(1), 
1514 
136.  
1515 
 
1516 
Pop-Busui, R., Boulton, A. J., Feldman, E. L., Bril, V., Freeman, R., Malik, R. A., . . . Ziegler, D. (2017b). 
1517 
Diabetic Neuropathy: A Position Statement by the American Diabetes Association. Diabetes Care, 
1518 
40(1), 136-154. doi: 10.2337/dc16-2042 
1519 
 
1520 
Reis de Matos, M., Santos-Bezerra, D. P., Dias Cavalcante, C. d. G., Xavier de Carvalho, J., Leite, J., 
1521 
Neves, J. A. J., . . . Correa-Giannella, M. L. (2020). Distal symmetric and cardiovascular autonomic 
1522 
neuropathies in Brazilian individuals with type 2 diabetes followed in a primary health care unit: a 
1523 
cross-sectional study. International journal of environmental research and public health, 17(9), 1-9.  
1524 
 
1525 
Reljanovic, M., Reichel, G., Rett, K., Lobisch, M., Schuette, K., Moller, W., . . . Mehnert, H. (1999). 
1526 
Treatment of diabetic polyneuropathy with the antioxidant thioctic acid (alpha-lipoic acid): a two year 
1527 
multicenter randomized double-blind placebo-controlled trial (ALADIN II). Alpha Lipoic Acid in Diabetic 
1528 
Neuropathy. Free Radic Res, 31(3), 171-179. doi: 10.1080/10715769900300721 
1529 
 
1530 
Ruhnau, K. J., Meissner, H. P., Finn, J. R., Reljanovic, M., Lobisch, M., Schutte, K., . . . Ziegler, D. (1999). 
1531 
Effects of 3-week oral treatment with the antioxidant thioctic acid (alpha-lipoic acid) in symptomatic 
1532 
diabetic polyneuropathy. Diabet Med, 16(12), 1040-1043. doi: 10.1046/j.1464-5491.1999.00190.x 
1533 
 
1534 
Salehi, B., Berkay Yilmaz, Y., Antika, G., Boyunegmez Tumer, T., Fawzi Mahomoodally, M., Lobine, D., 
1535 
. . . Sharifi-Rad, J. (2019). Insights on the Use of alpha-Lipoic Acid for Therapeutic Purposes. 
1536 
Biomolecules, 9(8). doi: 10.3390/biom9080356 
1537 
 
1538 
Sola, S., Mir, M. Q., Cheema, F. A., Khan-Merchant, N., Menon, R. G., Parthasarathy, S. & Khan, B. V. 
1539 
(2005). Irbesartan and lipoic acid improve endothelial function and reduce markers of inflammation 
1540 
in the metabolic syndrome: results of the Irbesartan and Lipoic Acid in Endothelial Dysfunction 
1541 
(ISLAND) study. Circulation, 111(3), 343-348. doi: 10.1161/01.CIR.0000153272.48711.B9 
1542 
 
1543 
Tan, L. S. (2010). The clinical use of the 10 g monofilament and its limitations: a review. Diabetes 
1544 
research and clinical practice, 90(1), 1-7.  
1545 
 
1546 

42 
 
Tankova, T., Koev, D. & Dakovska, L. (2004). Alpha-lipoic acid in the treatment of autonomic diabetic 
1547 
neuropathy (controlled, randomized, open-label study). Rom J Intern Med, 42(2), 457-464.  
1548 
 
1549 
Tesfaye, S., Vileikyte, L., Rayman, G., Sindrup, S. H., Perkins, B. A., Baconja, M., . . . Toronto Expert 
1550 
Panel on Diabetic, N. (2011). Painful diabetic peripheral neuropathy: consensus recommendations on 
1551 
diagnosis, assessment and management. Diabetes Metab Res Rev, 27(7), 629-638. doi: 
1552 
10.1002/dmrr.1225 
1553 
 
1554 
Vallianou, N., Evangelopoulos, A. & Koutalas, P. (2009). Alpha-lipoic Acid and diabetic neuropathy. Rev 
1555 
Diabet Stud, 6(4), 230-236. doi: 10.1900/RDS.2009.6.230 
1556 
 
1557 
Won, J. C., Kwon, H.-S., Moon, S.-S., Chun, S. W., Kim, C. H., Park, I. B., . . . Park, T. S. (2020a). γ-linolenic 
1558 
acid versus α-lipoic acid for treating painful diabetic neuropathy in adults: a 12-week, double-placebo, 
1559 
randomized, noninferiority trial. Diabetes Metab J, 44(4), 542-554.  
1560 
 
1561 
Won, J. C., Kwon, H. S., Moon, S. S., Chun, S. W., Kim, C. H., Park, I. B., . . . Park, T. S. (2020b). gamma-
1562 
Linolenic Acid versus alpha-Lipoic Acid for Treating Painful Diabetic Neuropathy in Adults: A 12-Week, 
1563 
Double-Placebo, Randomized, Noninferiority Trial. Diabetes Metab J, 44(4), 542-554. doi: 
1564 
10.4093/dmj.2019.0099 
1565 
 
1566 
Yang, Z., Zhang, Y., Chen, R., Huang, Y., Ji, L., Sun, F., . . . Zhan, S. (2018). Simple tests to screen for 
1567 
diabetic peripheral neuropathy. The Cochrane Database of Systematic Reviews, 2018(7).  
1568 
 
1569 
Young, M., Boulton, A., MacLeod, A., Williams, D. & Sonksen, P. (1993). A multicentre study of the 
1570 
prevalence of diabetic peripheral neuropathy in the United Kingdom hospital clinic population. 
1571 
Diabetologia, 36, 150-154.  
1572 
 
1573 
Zhu, J., Hu, Z., Luo, Y., Liu, Y., Luo, W., Du, X., . . . Peng, S. (2023). Diabetic peripheral neuropathy: 
1574 
pathogenetic mechanisms and treatment. Front Endocrinol (Lausanne), 14, 1265372. doi: 
1575 
10.3389/fendo.2023.1265372 
1576 
 
1577 
Ziegler, D. & Gries, F. A. (1997). Alpha-lipoic acid in the treatment of diabetic peripheral and cardiac 
1578 
autonomic neuropathy. Diabetes, 46 Suppl 2, S62-66. doi: 10.2337/diab.46.2.s62 
1579 
 
1580 
Ziegler, D., Hanefeld, M., Ruhnau, K., Meissner, H., Lobisch, M., Schütte, K. & Gries, F. (1995). 
1581 
Treatment of symptomatic diabetic peripheral neuropathy with the anti-oxidant alpha-lipoic acid. A 
1582 
3-week multicentre randomized controlled trial (ALADIN Study). Diabetologia, 38(12), 1425-1433.  
1583 
 
1584 
Ziegler, D., Hanefeld, M., Ruhnau, K. J., Hasche, H., Lobisch, M., Schutte, K., . . . Malessa, R. (1999). 
1585 
Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a 7-month 
1586 
multicenter randomized controlled trial (ALADIN III Study). ALADIN III Study Group. Alpha-Lipoic Acid 
1587 
in Diabetic Neuropathy. Diabetes Care, 22(8), 1296-1301. doi: 10.2337/diacare.22.8.1296 
1588 
 
1589 
Ziegler, D., Nowak, H., Kempler, P., Vargha, P. & Low, P. A. (2004). Treatment of symptomatic diabetic 
1590 
polyneuropathy with the antioxidant alpha-lipoic acid: a meta-analysis. Diabet Med, 21(2), 114-121. 
1591 
doi: 10.1111/j.1464-5491.2004.01109.x 
1592 
 
1593 
 
1594 
 
1595 
 
1596 
 
1597