Assessment of Efficacy and Safety of Thioctic Acid in the Oral Treatment of Diabetic Polyneuropathy (Stage 1 or 2)

Stage 1 or 2a diabetic (poly)neuropathy (DNP) (Appendix 3) in patients with diabetes
mellitus (type I or II); neuropathy impairment score of the lower limbs, enlarged by 7
objective items (NISLL+7) ≥ 97.5 percentile (corresponding to 4.43 score points); total
symptoms score of the feet (TSSfeet) ≤ 5.

Inclusion Criteria:

1. Signed Informed Consent. Patients must have willingness and complete competence to
cooperate and language barriers must not preclude adequate understanding

2. Diabetes mellitus (Type I or II), as defined by the American Diabetes Association
1997, lasting > 1 year

3. Males or females 18 to 64 years (older patients are excluded because of age-related
changes in reflexes, quantitative sensory testing endpoints, and nerve conduction
endpoints)

4. Patient must have a symmetric sensory-motor peripheral polyneuropathy attributable to
diabetes mellitus following a thorough evaluation for other causes of neuropathy
determined by performing complete medical and neurological examinations including
physical and neurological history, history of medications, history of exposure to
other toxins, and laboratory studies

5. Severity of diabetic polyneuropathy must be Stage 1 or 2a

6. Insulin regimen, weight, diet, and activity level must be relatively stable in the
opinion of the investigator (for example, HbA1C must not vary by more than ± 2 Vol.%
within 6 months preceding the study i.e. if the index measure = 10% the range would
be 8-12%)

7. NIS[LL]+7 tests ≥ 97.5 percentiles (corresponding to 4.43 transformed score points)

8. NIS[LL] ≥ 2 points (NIS[LL] is based on questions 17-24, 28, 29, 34, 35, and 37 of
the NIS)

9. One of the following:

- an abnormality of nerve conduction attributes in two separate nerves, i.e. ≥99th
percentile for DL or ≤1st percentile for NCV or amplitude or

- an abnormality of HRDB, i.e. ≤ 1st percentile

10. TSS (feet) ≤5

11. Females must either be surgically sterilised (tubal ligation, bilateral oophorectomy,
or hysterectomy) or at least 1 year postmenopausal or practicing an acceptable method
of contraception, including oral contraceptives with a stable regimen for at least
two months, depo-medroxyprogesterone, a barrier method alone (diaphragm, condoms, or
contraceptive sponge with spermicidals), or an IUD that has been in place for at
least two months

Exclusion Criteria:

1. Patients with proximal asymmetric neuropathy, cranial neuropathies, truncal
radiculopathy, pan dysautonomia, diabetic plexopathies, or acute or active
mononeuropathies (including cranial neuropathies, post-herpetic neuralgias, etc.),
the presence of which might obscure accurate assessment of severity of the diabetic
polyneuropathy under assessment, with the exception of carpal tunnel syndrome (CTS)
or tardy ulnar neuropathy (TUN) or both

2. Neuropathy of any cause other than diabetes mellitus which might interfere with the
assessment of the severity of dPNP Other neurologic diseases that may produce
weakness, sensory loss, or autonomic symptoms or test abnormality which might
interfere with the assessment of the severity of dPNP Myopathy of any cause which
might interfere with the assessment of the severity of dPNP

3. Peripheral vascular disease severe enough to cause intermittent claudication or
ischemic ulcers or limb ischemia

4. Patients with a history of ophthalmological findings suggesting a high risk for
visual loss i.e., significant maculopathy or proliferative retinopathy

5. Psychiatric, psychological, or behavioural symptoms that would interfere with the
patient's ability to participate in the trial

6. Patients with any active neoplastic disease except basal cell carcinoma

7. Patients with atrial fibrillation unless controlled and stabilised by medication
(changed to this criterion by Amendment 1)

8. Patients with clinically significant cardiac, pulmonary, gastrointestinal,
hematologic, or endocrine disease (other than diabetes) that may confound
interpretation of the study results or prevent the patient from completing the study

9. Patients who have had organ transplants of any kind

10. Patients with significant hepatic or renal disease (ASAT or ALAT >2 times normal,
serum creatinine >1.8 mg/dL (>159 µmol/l) for males or >1.6 mg/dL (>141 µmol/l) for
females)

11. Patients with a recent history (within last 12 months) of drug or alcohol abuse

12. Use of any investigational drug within the last 6 months

13. History of severe or anaphylactic reaction to multiple drugs, sulfur products, or
biologic products (changed to this criterion by Amendment 1)

14. Ketoacidosis or hypoglycaemia within last 3 months resulting in hospital admission

15. Antioxidant therapy (vitamins E > 400IU, C > 200mg, and beta-Carotene > 30mg) or
pentoxyphylline within last 1 month before start of trial

16. Use of evening primrose oil or any other gamma-linolenic acid containing substance
within the last 3 months

17. Use of thioctic acid > 50mg/day within last 3 months

18. History of use of medications or vitamins known to cause peripheral neuropathy
including but not limited to use of phenytoin or carbamazepine over 15 or more years,
or use of pyridoxine > 100mg/d within the past 12 months

19. Bilateral sural nerve biopsies

20. Existing foot ulcers

21. Pregnant or lactating females

22. Continued use of medications listed in protocol 6.3.3 (first paragraph)

23. Medication non-compliance (deviation of more than ±10% of dosages to be taken (1
tablet/day))