Phase IV Trial to Evaluate Efficacy of Alpha-Lipoic Acid in Treating Symptomatic Diabetic Polyneuropathy in Egypt

This is a multicenter, interventional, two-arm, parallel-group, randomized, double-blinded, placebo-controlled, phase IV trial to evaluate the efficacy and safety of ALA in the treatment of diabetic patients with symptomatic polyneuropathy in Egypt.

Patients will be randomly assigned to receive either :

* One tablet of 600 mg ALA twice a day orally for 24 weeks. Total daily dose during the study duration (24 weeks) = 1200 mg. , or
* One tablet of placebo twice a day orally for 24 weeks.
* The standard of Care (SOC) treatments will be prescribed for both study arms (Experimental and control arm) as per the routine clinical practice and following the relevant clinical guidelines. The SOC treatments include those for glycemic control and other treatments for the management of painful diabetic polyneuropathy; when needed through the course of the clinical study. As per the ADA and NICE guidelines (ADA, 2022) ("Type 2 Diabetes Adults Manag.," 2022); Pregabalin, Duloxetine, or Gabapentin are recommended as initial pharmacologic treatments for neuropathic pain in diabetes.

Estimated recruitment period: 24 weeks Estimated duration of participation: 24 weeks of treatment in addition to a screening period of approximately 1 week Visit 1: Screening/Baseline visit Visit 2: After 4 weeks ± 5 days of treatment Visit 3 (Phone call 1): After 12 weeks ± 15 days of treatment Visit 4 (Phone call 2): After 20 weeks ± 15 days of treatment Visit 5: After 24 weeks ± 15 days of treatment

• Alpha-Lipoic Acid (ALA) (Drug), also known as Thiotacid® 600 mg: Oral tablet
• Placebo (Drug), also known as Oral tablet: Microcrystalline cellulose (Ph 101) 427.5 mg, Magnesium stearate 71.25 mg, Sodium laurayl sulphate 6 mg, Croscarmellose sodium 11.25 mg, Silica, colloid anhydrous 11.25 mg, and Purified talc 30 mg.

Primary outcomes

• To compare the relative change in NCS parameters between the study arms [After four weeks of treatment]: The main objective of this study is to calculate the efficacy of alpha-lipoic acid in comparison with placebo in diabetic patients with symptomatic polyneuropathy assessed by the change in NCS parameters after 4 weeks of treatment using student t-test (Mann-Whitney test for non-parametric data) to compare relative change between treatment arm and control arm. This analysis will be comparative and will be done on eligible subjects without protocol violation and who have at least one treatment dose and an evaluable primary endpoint.

Secondary outcomes

• To compare the relative change in NCS parameters between the study arms. [After 24 weeks of treatment]: The efficacy of alpha-lipoic acid in comparison with placebo in diabetic patients with symptomatic polyneuropathy assessed by the change in NCS after 24 weeks of treatment using student t-test (Mann-Whitney test for non-parametric data) to compare relative change between treatment arm and control arm.
• To compare the relative change in NDS and Neuro-QoL between the study arms. [After 24 weeks of treatment]: The efficacy of alpha-lipoic acid in comparison with placebo in diabetic patients with symptomatic polyneuropathy as assessed by the change in NDS* total score (out of 10 = the sum of the scores for right and left sides) using student t-test (Mann-Whitney test for non-parametric data) to compare relative change between treatment and control arms.
• To compare the frequency of the need to rescue analgesic medications between the study arms [After 24 weeks of treatment]: The efficacy alpha-lipoic acid in comparison with placebo in diabetic patients with symptomatic polyneuropathy assessed by number of patients receiving rescue analgesic medications using chi square test to compare between treatment arm and control arm. This analysis will be comparative and will be done on eligible subjects without protocol violation and who have at least one treatment dose and evaluable primary endpoint
• To assess safety of Thiotacid® as per the nature and severity of the recorded adverse events. [After 24 weeks of treatment]: The safety of alpha-lipoic acid in diabetic patients with symptomatic neuropathy assessed by the number of patients experiencing AE/SAE and number of patients who discontinued study drug due to AEs. These will be described using counts/percentages with 95% CI. This analysis will be descriptive and will be conducted on all patients enrolled to the study who signed an ICF.

Sex: All, ages: 18 Years to 64 Years

Inclusion Criteria:

1. Signed informed consent form.
2. Male or female patients aged ≥ 18 and ≤ 64 years.
3. Type 2 diabetes mellitus (T2DM) patients as defined according to the American Diabetes Association (ADA) criteria with diabetes duration ≥ 1 year.
4. Hemoglobin A1c (HbA1c) ≤10%.
5. Patients with symptomatic distal symmetrical polyneuropathy (DSPN) attributable to diabetes; after a thorough evaluation for other causes of neuropathy, with evidence of polyneuropathy based on abnormal peripheral nerve function according to clinical and electrophysiological examinations.
6. Patients treated with oral antidiabetic drugs and/or insulin.
7. Patients with the treatment regimen, weight, diet, and physical activity level relatively acceptable as judged by the investigator within 1 month prior to study entry.
8. Patients with working telephone numbers.

Exclusion Criteria:

1. Female patients with child-bearing potential not using effective birth control methods including oral contraceptives with a stable regimen for at least 2 months, depo-medroxyprogesterone, a barrier method alone (diaphragm, condoms, or contraceptive sponge with spermicidals), or an intrauterine device that has been in place for at least 2 months.
2. Patients with neuropathies other than DSPN; myopathy and other neurologic diseases that might interfere with the assessment of the severity of DSPN.
3. Patients with a recent history of drug or alcohol abuse; within 1 year prior to study entry.
4. Patients with a history of peripheral vascular disease and/or foot ulcers.
5. Patients with a history of organ transplantation.
6. Patients with a history of cardiovascular, pulmonary, gastrointestinal, hematologic, or endocrine disease, or malignancy that cause neuropathic pain.
7. Hospitalization due to hypoglycemia or ketoacidosis within 3 months prior to study entry.
8. Patients with significant hepatic or renal disease \[Serum creatinine > 1.8 mg/dL for men and > 1.6 mg/dL for women, Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 3 times upper limit of normal (ULN)\].
9. Use of medications indicated for neuropathic pain relief within 15 days (washout period) prior to study entry. For analgesia, standard doses of salicylates, ibuprofen, indoles, fenamates, oxicams, or pyrazoles are allowed.
10. Use of antioxidants (including but not limited to vitamin E, vitamin C, and β-carotene) or pentoxifylline within 1 month prior to study entry.
11. Use of medications or vitamins known to cause peripheral neuropathy including but not limited to the use of phenytoin or carbamazepine over 15 or more years, or use of pyridoxine > 100 mg/d within 12 months prior to study entry.
12. Use of ≥ 50 mg ALA or use of alpha-linolenic acid-containing substances within 3 months prior to study entry.
13. Use of an investigational drug within 6 months prior to study entry.
14. Enrollment in any other clinical trial during the time of this trial.

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• Samir H Assaad Khali, PhD, Principal investigator, Alexandria University Hospital / Internal Medicine
• Mohamed R Halawa, PhD, Principal investigator, Ain-Shams University Hospital / Internal Medicine
• Nabil AF El Kafrawy, PhD, Principal investigator, Menoufia University Hospital / Internal Medicine
• Hanan M El Sotouhy Gawish, PhD, Principal investigator, Mansoura University Hospital / Internal Medicine
• Khaled ES El Hadidy, PhD, Principal investigator, Beni Suef University Hospital / Internal Medicine