Title

A study to evaluate the effect of Alpha Lipoic acid on neuropathic symptoms and inhibition of Platelet aggregation in diabetic neuropathy patients on Gabapentin /Pregabalin.

Protocol number: CPT/ALA /02                Version No: 03               Dated: 17.04.2021

Objective

Primary Objectives:

1. To evaluate the effect of alpha lipoic acid on VPT.

2. To evaluate the effect of alpha lipoic acid on platelet aggregation.

Secondary Objectives:

1.To evaluate the effect of alpha lipoic acid on neuropathic symptoms

2. To evaluate the effect on quality of life

3. To evaluate the effect on Neuron specific enolase

4. To evaluate the effect on Malondialdehyde (MDA), Nitric oxide (NO), Glutathione

   (GSH) and high sensitivity c reactive protein (hs CRP)

5. To evaluate the effect of Alpha lipoic acid on lipid profile

6. To evaluate Safety of the study drugs

Rationale

·      Distal symmetric polyneuropathy (DSPN) has been recognized as a major complication of Diabetes. Thirty to 90% of patients with diabetes have peripheral neuropathy. It has been linked that an increased free-radical production along with defective antioxidant mechanisms can generate DSPN. Oxidative stress-inflammation pathways are activated in DSPN. Most guidelines suggest tricyclic agents (TCAs), serotonin–norepinephrine reuptake inhibitors (SNRIs) or γ- aminobutyric acid (GABA) analogues (gabapentin or pregabalin) as first-line agents followed by opioids and topical treatments. Among these Pregabalin and Gabapentin are most commonly used drugs.

·      But these drugs have many    side effects like somnolence, dizziness, peripheral edema, weight gain, physical or psychological dependence etc. with Pregabalin and dizziness, lack    of coordination, abnormal eye movements, constipation etc. with Gabapentin.

·      Alpha lipoic acid (ALA) is a potent antioxidant, it is known to prevent pancreatic beta cell destruction, increase glucose uptake and its antioxidant effect is useful in delaying the development of DSPN. Neuroprotective and also pain-relieving effects of ALA therapy have been reported in the literature. In animal studies ALA showed reduction in Neuron Specific Enolase (NSE) levels which is an indicator of neuronal injury. It is safe in end stage renal failure as well as in liver disease.

·      A retrospective study in 443 diabetic patients evaluated the switching from the   

pathogenetic treatment option of α-lipoic acid to symptomatic treatment of neuropathic pain - Gabapentin. They concluded that switching from long-term treatment with α-lipoic acid to central analgesic drugs such as gabapentin in painful diabetic neuropathy was associated with considerably higher rates of side effects, frequencies of outpatient visits and daily costs of treatment. The ex vivo and in vitro experiments showed that ALA exerted antiplatelet activity. ALA inhibited platelet aggregation by all pathways of aggregation. Adenosine diphosphate (ADP) and Arachidonic acid (ARA) pathways are most sensitive to ALA activity.  

·      Hence the present study is planned to evaluate effect of ALA, a known antioxidant, on VPT, neuropathic symptoms, NSE levels and platelet activity in diabetic neuropathy patients.

Population

Diabetic neuropathy Patients

Design

Prospective, Randomized, double blind, placebo controlled, parallel study.  

Methodology

After EC approval and obtaining informed consent from the patients fulfilling inclusion criteria, they will be randomized to either of the two groups: 1. Alpha lipoic acid 600mg once daily as add on to Gabapentin/Pregabalin for 3 months and 2. Identical Placebo once daily as add on to Gabapentin/Pregabalin for 3 months. Following parameters will be evaluated at different time points as mentioned in part 7 point 1 and 2  

Statistics

Statistical analysis will be performed using the SPSS Software. Data will be presented as mean ± SD for primary outcome variable and oxidative stress markers will be analysed by repeated measures ANOVA for within group analysis and unpaired t- test for between group analysis. Level of significance will be kept at p < 0.05. Intention to treat analysis will be applied.  Data from the last visit will be carried forward to the end of the study in case of drop out discontinued patients.