Evaluating The Efficacy And Tolerability Of The Oral Combination Of Alpha Lipoic Acid And Vitamin B Complex Preparation In Carpal Tunnel Syndrome : a Single-center, Randomized, Double-blind, Placebo-controlled Trial.
Phase: PHASE2
Conditions: Carpal Tunnel Syndrome (CTS)
Sponsor: Universiti Putra Malaysia

 
Study Title: 
 
Evaluating The Efficacy And Tolerability Of The Oral Combination Of Alpha Lipoic 
Acid And Vitamin B Complex Preparation In Carpal Tunnel Syndrome: a single center, 
randomized, double-blind, placebo-controlled trial. 
 
 
Protocol Development Phase 1: 17th January 2023 
Protocol Revisions Version 2 : 2nd February 2023 
Protocol Revisions Version 3 : 1st April 2023 
Study initiation date: 1st December 2023 
Study completion date: 30th  September 2024 
 
Protocol by:  
Dr. Anna Misyail Abdul Rashid 
Internal Medicine Physician and Neurologist 
Neurology Department, FPSK/HPUPM, 
Universiti Putra Malaysia. 
Version 3 :1/4/2023 
 
 

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1. Research title:  
Evaluating The Efficacy And Tolerability Of The Oral Combination Of Alpha Lipoic Acid 
And Vitamin B Complex Preparation In Carpal Tunnel Syndrome: a single center, 
randomized, double-blind, placebo-controlled trial. 
 
2. Principal investigator: 
Dr. Anna Misyail Abdul Rashid 
3. Co-investigators 
Dr. Nur Alya Zainal 
Assoc. Prof. Dr. Wan Aliaa Wan Sulaiman 
Dr. Azliza Ibrahim 
Dr. Abdul Hanif Khan Yusof Khan 
Dr. Janudin Baharin 
Dr. Collin Looi 
Pn. Musmarlina Omar 
 
4. Introduction 
Background of the study 
Carpal Tunnel Syndrome (CTS) is one of the commonest peripheral neuropathy caused by 
compression of the median nerve at the level of the wrist. The patients typically present with 
symptoms of tingling and numbness of the hand in the distribution of the median nerve, which 
may range in its clinical severity (1). Treatment for CTS ranges from non-pharmacological and 
medical for mild to moderate cases, to surgical interventions in more severe cases. It poses an 
important workplace issue, causing significant loss of time from work and high medical cost, 
approximating to almost $30,000 for each injured worker (2). 
 
Problem statement and study rationale 
For mild to moderate CTS, literature shows conflicting evidence on efficacy of non-surgical 
approach, which includes non-pharmacologic treatment such as splinting, physiotherapy and 
ultrasound; as well as medical therapy which includes oral antiepileptics, combination of 
vitamins and local steroid injections. As such, current evidence do not recommend one 
treatment over the other (2,3). Of these available treatments, many patients do not like the 
invasive nature of steroid injections and long term side effect of steroids, and thus opt for oral 

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medications. For severe CTS however, the preferred treatment is surgical treatment via carpal 
tunnel release as the response to medical therapy maybe suboptimal (2). 
 
Among the oral medications, anti-epileptic drugs such as gabapentin may cause significant side 
effect (i.e drowsiness) at a higher dose, which prevents its widespread use. As such, 
combination of vitamins and alpha lipoic acid are becoming more preferred due to its lower 
rate of side effects. We seek to determine the efficacy of Bionerv, which is an oral combination 
of alpha lipoic acid (300mg), methylcobalamin (500mcg), Vitamin B1 (39mg) and Vitamin B6 
(8mg) on mild to moderate CTS. 
  
 
5. Research Question(s) 
a. What are the socio-demographic profiles of patients with CTS in Malaysia? 
b. Are oral combination of alpha lipoic acid and vitamin B preparations for the 
treatment of CTS safe? 
c. Does oral administration of a combination of alpha lipoic acid and vitamin B 
preparations improve symptoms of CTS? 
d. Does oral administration of a combination of alpha lipoic acid and vitamin B 
preparations improve electrodiagnostic tests in patients with CTS? 
 
6. Research objectives and hypotheses 
General objective 
a. To determine the oral efficacy of a combination of alpha lipoic acid and vitamin B 
preparations in treatment of mild to moderate CTS. 
 
Specific objectives  
a. To describe the socio-demographic profile of patients with mild to moderate CTS 
in Malaysia. 
b. To examine the efficacy of oral combination of alpha lipoic acid and vitamin B in 
reducing symptoms of mild to moderate CTS. 
c. To determine if treatment with of oral combination of alpha lipoic acid and vitamin 
B is associated with improvement of NCS in patients with mild to moderate CTS. 

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d. To evaluate tolerability of oral combination of alpha lipoic acid and vitamin B in 
patients with mild to moderate CTS 
 
 
7. Literature review 
CTS is due to local compression of the median nerve, causing conduction blocks within large 
myelinated nerve fibers. It reduces capillary blood flow to the median nerve through the 
swelling of the synovial tissue of the tendon, commonly at the level of the wrist (4). The 
reduction of blood flow in the endoneural capillary system then induces alteration in the nerve 
structure that is provoked by endoneural edema, venous congestion, ischemia, and subsequent 
metabolic abnormalities (5). It has been proposed that ischemia/reperfusion injury of the 
median nerve results in oxidative stress and inﬂammation of the subsynovial connective tissue, 
which play an important role in the evolution of idiopathic CTS.  
 
Common associations include metabolic causes such as diabetic mellitus, hypothyroidism, 
rheumatoid arthritis and pregnancy; although up to 60% of cases may be idiopathic (6). The 
clinical severity of CTS may vary from numbness and tingling; to pain sensation in the 
distribution of the median nerve. Although CTS is a clinical diagnosis, NCS is often carried 
out to determine the severity of CTS as well as to have a quantitative measure of the 
physiological function of the median nerve, that is able to guide direction if treatment and 
provide prognosis for patients (7). 
 
Mild to moderate CTS is usually treated conservatively, either with non-pharmacologic 
treatments (i.e : splinting, electrotherapy, physiotherapy) or medical treatment with oral anti-
epileptics, analgesia, steroids or even local steroid injections. Although local steroid injections 
may reduce inflammation and is hypothesized to reduce local edema and subsequently 
compression neuropathy,  systemic review fails to show sustained long term effect as compared 
to other treatment modalities (6). In contrast, severe CTS is usually treated surgically with 
carpal tunnel release (8). 
 
The long term side effects from steroids, that includes Cushing’s syndrome, resistant 
hypertension, acne and osteoporosis has caused clinicians to shy away from these medications, 
especially considering the chronic nature of  CTS. There has been a recent interest in using oral 

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antiepileptics such as gabapentin by means of its efficacy in modulation of neuropathic pain of 
other etiology. However, results of randomized controlled trials failed to show sustained 
efficacy with regards to symptom control in CTS (2,9).  
 
As such, the pharmacological treatment of CTS has been directed to neuroprotection, aiming 
to limit the injury and damage to the median nerve. Previously, vitamin preparations such 
vitamin B6 preparations were proven to mitigate neuronal problems as well as bridging 
anaesthesia to decrease pain threshold. However existing studies yield heterogenous outcomes, 
mainly due to limitations of study design and small sample size (9,10). 
 
Of late, alpha lipoic acid (ALA) has gained interest due to its powerful scavenging activity,  to 
metabolic support of nerve cells, as well as modulation of neurotrophic cytokines release. All 
together, these mechanisms reduce inflammation, improve functioning of the nerve fibers and 
promote neuroprotection and neuroregeneration (11,12). In a study involving rats, 
administration of ALA has shown to reduce infarct size, thus demonstrating its 
neuroproliferative and neurorestorative benefits. In this study, treatment with ALA increased 
proliferative cell lineage by 5 fold (13). Another  study established neuroprotective property of 
ALA by means of increased expression of  the proliferating cell nuclear antigen, which is a key 
regulatory protein for DNA repair. This study also exhibited anti-apoptotic of ALA against 
neurotoxicity which is a key aspect in cellular functioning (14). 
 
This has led to the hypothesis of improved outcome if the medications are combined in a single  
preparation. As such, Bionerv was developed as a combination drug (Alpha Lipoic Acid 
(300mg), Methylcobalamin (500mcg), Vitamin B1 (39mg) and Vitamin B6 (8mg)) to simplify 
administration for patients. We would like to determine the efficacy of oral combination of 
alpha lipoic acid and vitamin B preparations versus placebo; with regards to symptom control 
and improvement on NCS parameters. Both groups are allowed to undergo physiotherapy 
which includes splinting, ultrasound and other non-pharmacologic treatment, as determined 
necessary by the clinician. The concomitant treatment that the patient is receiving is also 
recorded. 
 
 
 

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8. Conceptual framework  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Intervention : Bionerv 
Alpha 
Lipoic 
Acid 
(300mg), 
Methylcobalamin 
(500mcg), 
Vitamin B1 (39mg) and Vitamin 
B6 (8mg); two tablets once daily. 
Placebo 
: 
Maltodextrin, 
Microcrystalline 
Cellulose 
, 
Tricalcium Phosphate , Silicon 
Dioxide , Magnesium stearate; two 
tablets once daily. 
Independent variable 
Age 
Gender 
Anthropometric data 
(weight, height, body mass index) 
Comorbidities 
Severity of CTS 
Laterality of CTS 
Primary outcome 
Electrodiagnostic improvement of median 
nerve on NCS: 
i-
Distal sensory latency (DSL) 
ii-
Sensory action potential 
(SNAP) 
iii-
Conduction velocity (CV) 
iv-
Distal motor latency (DML) 
v-
Compound Motor Action 
Potential (CMAP) 
Secondary outcome 
Tolerability of oral combination of alpha 
lipoic acid and vitamin B preparations 
Boston Carpal Tunnel Questionnaires 
(BCTQ)  
i-symptom severity scale (SSS) 
ii-functional status scale (FSS) 
Pain score (Visual analogue scale; VAS) 
Quality of life score (SF 36 questionnaire) 

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9. Research methodology 
This is a single center, randomized, double-blind, placebo-controlled trial conducted in 
University Putra Malaysia Teaching Hospital (HPUPM).  
Study period : 6 months 
Date of first subject enrolment :1st December 2023 
Date of last subject completed: 30th September 2024 
Target population : patients with symptoms of CTS 
Sampling frame : all patients referred to Neurology Department for clinical and 
electrodiagnostic examination of CTS. 
Sampling unit : patients with mild to moderate CTS 
Sampling method : universal sampling  
 
All patients that presented to Neurology Clinic or Neurophysiology Laboratory with symptoms 
of hand numbness/tingling or pain in the median nerve distribution undergo a thorough physical 
examination based on current international guideline for diagnosis and assessment of CTS (15). 
This includes : 
• Personal characteristics (eg, age, sex, weight, height, body mass index) 
• Range of motion of hand/wrist 
• Observation of deformity, swelling, atrophy, skin trophic changes 
• Manual muscle testing of the upper extremity (eg, examine for muscular atrophy, 
especially in the thenar muscle group), pinch/grip strength 
• Sensory examination  
• Provocative tests (eg, Phalen test, Tinel sign, median nerve compression test, reverse 
Phalen test) 
 
These patients then undergo an NCS, to determine the severity of CTS. The NCS will be carried 
out using the machine Natus, USA, Synergy on Nicolet EDX NCS EMG EP System. The NCS 
protocol follows the American Academy of Neurology/American Association of 
Neuromuscular and Electrodiagnostic Medicine/American Academy of Physical Medicine and 
Rehabilitation (AAN/AANEM/AAPMR) guidelines for diagnosis of CTS (15), which includes 
electrodiagnostic examination of : 
 

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• Sensory NCS studies to the median nerve with distal latency compared to the ulnar and 
radial nerve 
• Median motor nerve conduction studies 
 
If the clinical and NCS studies fulfil the diagnosis of CTS and fits the inclusion criteria for the 
study, they undergo randomisation into the treatment group or the control group. The treatment 
group will receive oral combination of alpha lipoic acid and vitamin B preparations, while the 
control group will receive a placebo. The treatment will be carried out for 6 months.  
 
Treatment group will receive oral combination of alpha lipoic acid and vitamin B. 
Composition: Alpha Lipoic Acid (300mg), Methylcobalamin (500mcg), Vitamin B1 (39mg) 
and Vitamin B6 (8mg), 2 tablets taken once daily (Bionerv). 
 
Control group will receive placebo drug. Composition: Maltodextrin, Microcrystalline 
Cellulose , Tricalcium Phosphate , Silicon Dioxide , Magnesium stearate, 2 tablets taken once 
daily. 
 
Inclusion and exclusion criteria 
Inclusion criteria 
• Age more than 18 years old 
• Subjects with symptoms and physical examination of CTS 
• Fulfil the electrodiagnostic criteria of mild to moderate CTS, defined based on the 
Padua Scale (16): 
o Minimal : abnormal segmental and comparative tests only  
o Mild : abnormal digit/wrist sensory nerve conduction velocity (SNCV) and 
normal distal motor latency (DML) 
o Moderate : abnormal digit/wrist sensory nerve conduction velocity (SNCV) and 
abnormal distal motor latency (DML)  
 
Exclusion criteria 
• Pregnant or breast feeding women 
• Patients with history of trauma in the dominant hand 
• Patients with symptoms of CTS but has normal NCS 

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• Patients with electrodiagnostic criteria of severe or extreme CTS as defined in the Padua 
scale (16): 
o severe : absence of sensory response (SNAP) and abnormal distal motor latency 
(DML) 
o extreme : absence of motor (CMAP) and sensory responses (SNAP)  
• Patients who are taking traditional or complementary medication for CTS 
 
 
Study procedure 
The patients were randomized to receive oral combination of alpha lipoic acid and 
vitamin B; Bionerv (alpha lipoic acid; 300mg, methylcobalamin; 500mcg, vitamin B1; 
39mg and vitamin B6; 8mg), 2 tablets once daily or placebo drug (maltodextrin, 
microcrystalline cellulose, tricalcium phosphate, silicon gioxide, magnesium stearate) 2 
tablets once daily.  
 
During visit 1, a thorough history and physical examination were done, and demographic 
data was collected. Afterward, the patients were required to answer three sets of self-
administered questionnaires: Boston Carpal Tunnel Questionnaire (BCTQ), Visual 
analogue score (VAS) and SF-36. The BCTQ is a specific questionnaire for assessing 
CTS that consists of two distinct scales, the Symptom Specific Scale (SSS) which has 11 
items and the Functional Status Scale (FSS) containing 8 items. Each scale generates a 
final score ranging from 1 to 5, with a higher score indicating greater disability and poor 
symptoms control. BCTQ is a reliable questionnaire to assess CTS owing to its high 
cross-cultural adaptation and multilingual validity and reliability (17-18). The VAS is a 
visual scale with 0 scored as “no pain” and 10 as “worst pain imaginable” and serves as 
an excellent tool for pain score with excellent validity and reproducibility (19-20). The 
SF-36 is a quality-of-life questionnaire that comprises of 36 questions covering eight 
domains of health which are; Physical Functioning (PF), Role Limitations due to Physical 
Health, Role Limitations (RL) due to Emotional Problems (RE), energy/fatigue, 
emotional well-being, social functioning, pain, and general health (GH) where a higher 
score indicates a better outcome (21). After the administration of these questionnaires, 
they will be subjected for a nerve conduction study (NCS) to determine the severity of 
CTS. The NCS were performed by the same trained personnel to ensure consistency and 

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accuracy. A Patient-Reported Questionnaire to monitor any side effects were used to 
assess the tolerability of the drugs. 
The patients were reassessed at Visit 2 (3 months post-treatment) and Visit 3 (6 months 
post-treatment). During each visit, they underwent physical examination, NCS, and were 
required to complete the three sets of questionnaires (BCTQ, VAS, and SF-36). They 
were also required to fill in the form regarding the side effects of the treatments. The 
investigators made a phone call and sent reminder message at the 6th and 18th week to 
ensure compliance, medication adequacy and follow up review. During the study, patients 
were allowed to undergo the standard of care treatment at our center such as 
physiotherapy. 
 
  
 
 
 
Fig. 1 The visual analogue scale (VAS). 
 
The quality of life questionnaires have become of recent interest. Although the BCTQ and VAS 
score are able to scale functional disability and pain, they are not constructed to determine the 
quality of life which encompasses emotional and social domains of everyday function. The SF 
36 measures two distinct physical and mental dimension. It also can good validity and 
reproducibility and is useful in our clinical setting (22). 
 
Randomisation 
Patients’ randomisation is done by an independent statistician using a random number 
generating programme (www.randomizer.org) into two groups (treatment and placebo) using 
mixed block randomization technique at the ratio of 1:1 i.e. group A and group B. The 
independent statistician will then code the treatment and the placebo into group A and group B. 
The written allocation of assignment for each participant with an identification number (code) 
was sealed in a brown opaque envelope. This envelope will be opened by the researcher on 
recruitment of a participant. The key coding to the allocation will be revealed by the 
independent statistician at the completion of the study. An independent statistician will label 
the treatment and placebo group as either group ‘A’ or group ‘B’. 
 
The participants are assigned to either treatment or placebo arm in a parallel intervention mode. 

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The principle of random allocation is employed to assign the participants to an intervention (i.e. 
treatment) and a control (i.e. placebo arm). To achieve an unbiased comparison group and to 
have a balanced randomization, permuted block randomization with a varying block size is used 
for the study. The sample size estimated for the study is 76. Hence, there are 19 blocks with a 
block size of four participants each and one-to- one allocation ratio is used. Random sequence 
generation is done with the help of a Research Randomizer, an online random number generator 
(Urbaniak & Plous, 2014). An external member, who is not directly involved in the study, 
generates the sequence. To have a strict implementation of the generated random sequence, the 
concealed allocation is achieved using sequentially numbered, opaque and sealed envelopes 
(SNOSEs).  An   aluminium   foil   is   kept   inside   the   envelope to prevent possible chances 
of deciphering. An external member, who is not directly involved in the study, would prepare 
the SNOSEs. 
 
The final code is only known to the statistician and the document will be stored in a secure 
locked safe. The following information will be recorded during the randomization; study ID 
(assigned during the study initiation), investigator password (assigned during the initiation), 
subjects screening status, date of informed consent signed by subject, subject’s ID no (e.g., Last 
4 digits of IC), upon successful randomization, the subjects will be assigned randomization 
number and treatment. The subject’s ID no. and randomization no. will be documented on the 
Patient Enrolment Log and Patient Identification List. 
 
Blinding and emergency unblinding procedures 
The participants and outcome assessor of the study is blinded about the allocation status of the 
participants. In the setting of an adverse event (AE), for which knowledge of the identity of the 
test drug is necessary to manage the subject's condition, the sealed emergency code key for that 
subject may be broken and the test drug identified by the medical monitor. The medical monitor 
will have a set of sealed emergency code keys (one for each subject) kept in a secured location 
and he/she will be accessible at all times by telephone. The medical monitor is medical officer 
who is working in the hospital. He/she is familiar with hospital system and is also aware of the 
study protocol. Should emergency unblinding be required, the investigator will call the medical 
monitor who will break the emergency code key for that subject, identify the test coil and inform 
the investigator. A detailed report with the date and reason for identifying the study drug will 

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be prepared by the medical monitor and attached to the case report form. This report must be 
signed by the medical monitor and the investigator. All unused sealed code keys will be 
accounted for at the end of the study. 
Except in the case of emergency, the treatment blind will be maintained until all subjects have 
completed the treatment and the database has been cleaned and locked. Any broken code will 
be clearly justified and explained by a comment on the case report form, along with the date on 
which the code was broken. 
 
Sample size estimation  
Sample size calculation was performed using the study published by Pajardi et al. Sample size 
was calculated based on improvement to limitations of everyday activity among the patients 
with CTS as the outcome parameter (1.07 ± 1.27 vs 0.83 ± 0.81). The marginal error (α) was 
set at 0.05.   
Sample size: 2 SD ^2( Zα/2 + Z β) ^2  
                            d^2 
 
SD – standard deviation = from previous studies or pilot study 
Zα/2 = Z 0.05/2 = Z 0.025 = 1.96 ( From Z table ) at 80 % power at type 1 error of 5 % 
Z β = Z 0.20 =0/842 ( From Z table ) at 80 % power 
d= effect size = difference between mean value 
 
So, the formula:  
sample size: 2 SD²( 1.96 + 0.84)² 
                             d² 
 
SD = 1.27 
Za/2 = 1.96 
Zb = 0.84 
  d² = (0.81)2 = 0.66 
 
n = 2(1.27)² ( 1.96+0.84)² 
           (0.81) ² 
 

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= 2 (1.61) (7.84) 
           0.66 
= 38 in each arm (Total 76 patients) 
 
Operational definitions 
Primary outcome measure 
The primary outcome was the electrodiagnostic improvement of the median nerve on NCS 
before the before the intervention (visit 1) and at three-months (visit 2) and six- months (visit 
3). The NCS parameters that are analysed were:  
1. Distal sensory latency; DSL (normal value for DSL <3.5ms) 
2. Sensory nerve action potential; SNAP (normal value for SNAP >2.5 µV)  
3. Conduction velocity; CV (normal value for CV >50m/s) 
4. Distal Motor Latency; DML (normal value for DSL <4ms) 
5. Compound muscle action potential; CMAP (normal value for CMAP>4.0 mV).  
 
Secondary outcomes measures 
  
• Tolerability and safety of oral combination of alpha lipoic acid and vitamin B 
preparations 
• The improvement of scores in Boston Carpal Tunnel Questionnaires (BCTQ) by the 
SSS scale prior to the intervention, at 3 months and at 6 months 
• The improvement of scores in Boston Carpal Tunnel Questionnaires (BCTQ) by the 
FSS scale prior to the intervention, at 3 months and at 6 months 
• The improvement of pain scores in VAS prior to the intervention, at 3 months and at 6 
months 
• The improvement of quality of life score SF 36 prior to the intervention, at 3 months 
and at 6 months 
 
Data collection  
Protection of human rights is the utmost priority for researchers. We obtain informed consent 
from all participants in this research. The consent process included giving full and 
comprehensible information about the research and clear assurance of their voluntary 

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participation. Beneficence is the essence of concern for the well-being of the participants 
whereby the risk of harm was the least possible.  
 
Privacy of patients are obtained in a respectful manner whereby every patient is given the 
confidence to directly disclose information to the researcher in a peaceful and non-threatening 
manner. Data collection sheets and questionnaires will not contain patients identification such 
as name, IC number, phone number, address or RN. Specific ID was used on the data collection 
sheet to ensure patient privacy. 
 
All information obtained in this study will be kept and handled in confidential manner, in 
accordance to applicable laws and regulations of the country. Data management will be 
conducted using appropriate database and validation programmes, with standard practice to 
secure information for all computer based data storage (i.e encryption and password protection). 
Data collected may be retained for re-use in further studies. The standard duration of three to 
five years with strict security of research records will be adhered and destroyed after this period 
of time. Relevant bodies such as JKEUPM will have access to the study data. 
 
 
 
 
 
 
 
 
 
 
 
 

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Study flowchart  
 
 
10. Data analysis 
Analyses sets 
All randomised subjects will be included in the analysis. 
 
Baseline Comparability 
True randomisation, concealed location and adequate sample size planned for this study will 
ensure enough baseline comparability between groups (treatment and control group). 
Additionally, a table of baseline characteristics of participants in each group, without between-
group statistical comparisons will be included. This data will be analysed to determine whether 
any characteristics were imbalanced enough to have influenced the outcomes of the study 
Month 6
Visit 3
Month 3
Visit 2
Randomisation  and treatment 
allocation
Month 0
(baseline)
Visit 1 
Screening 
fulfil inclusion/exclusion criteria
Recruitment of patients
Clerking for history
Clinical examination
Nerve conduction study
Questionnaires
BCTQ
VAS
SF 36
Patient-Reported 
Questionnaire (monitor 
side effects )
Treatment 
group 
Control  
group 
Mid point assessment 
Refill prescription 
Questionnaires 
BCTQ 
VAS 
SF 36 
Patient-Reported Questionnaire 
Nerve conduction 
study 
Clinical examination 
Post treatment 
assessment 
Clinical examination 
Nerve conduction 
study 
Questionnaires 
BCTQ 
VAS 
SF 36 
Patient-Reported Questionnaire 

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Efficacy Analysis 
Analyses were performed on an intention-to-treat basis. The primary treatment comparisons of 
benefit include all eligible patients. Both eligible and ineligible patients are included in the 
analyses and compared by treatment assignment when an intent-to-treat analysis is specifically 
indicated. 
 
Safety Analysis 
The summaries of tolerability include all patients who received any study treatment; those who 
did not receive study treatment are not included in these summaries. The safety population 
comprised all randomized patients who received at least one treatment dose and was based on 
the actual treatment received. 
 
11. Ethical consideration 
The study was performed in accordance with the Declaration of Helsinki and has received ethical 
approval from Ethics Committee for Research Involving Human Subjects in University Putra Malaysia 
(Ref: JKEUPM-2022-984). 
12. Declaration of conflict of interest 
The investigators declare no conflict of interest. 
The sponsor of this study (Brego Life Sciences Sdn. Bhd.) is sponsoring the study including 
the placebo treatment and insurance coverage. The company is aware of the randomized, 
blinded and controlled nature of the study, thus understands that the results may be neutral and 
adverse events may occur. However, this should not hinder research and publication process of 
evidence based medicine.  
13. References 
1.  
Ostergaard PJ, Meyer MA, Earp BE, Meyer MA. Non-operative Treatment of Carpal 
Tunnel Syndrome. 2020;  
2.  
Keith MW, Masear V, Amadio PC, Andary M, Barth RW, Graham B, et al. Treatment 
of carpal tunnel syndrome. J Am Acad Orthop Surg. 2009;17(6):397–405.  
3.  
Jiménez del Barrio S, Bueno Gracia E, Hidalgo García C, Estébanez de Miguel E, 
Tricás Moreno JM, Rodríguez Marco S, et al. Conservative treatment in patients with 
mild to moderate carpal tunnel syndrome: A systematic review. Neurol (English Ed 
[Internet]. 2018;33(9):590–601. Available from: 

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http://dx.doi.org/10.1016/j.nrleng.2016.05.015 
4.  
Pajardi G, Bortot P, Ponti V, Novelli C. Clinical usefulness of oral supplementation 
with alpha-lipoic acid, curcumin phytosome, and B-group vitamins in patients with 
carpal tunnel syndrome undergoing surgical treatment. Evidence-based Complement 
Altern Med. 2014;2014.  
5.  
Monroy Guízar EA, García Benavides L, Ambriz Plascencia AR, Pascoe González S, 
Totsuka Sutto SE, Cardona Muñoz EG, et al. Effect of Alpha-Lipoic Acid on Clinical 
and Neurophysiologic Recovery of Carpal Tunnel Syndrome: A Double-Blind, 
Randomized Clinical Trial. J Med Food. 2018;21(5):521–6.  
6.  
Hernández-Secorún M, Montaña-Cortés R, Hidalgo-García C, Rodríguez-Sanz J, 
Corral-De-toro J, Monti-Ballano S, et al. Effectiveness of conservative treatment 
according to severity and systemic disease in carpal tunnel syndrome: A systematic 
review. Int J Environ Res Public Health. 2021;18(5):1–34.  
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