Assessment of Efficacy and Safety of Thioctic Acid in the Oral Treatment of Symptomatic Diabetic Neuropathy (SYDNEY 2)

The primary objective of the trial is to determine the optimal dose of orally (tablet) administered thioctic acid in the treatment of symptoms of diabetic polyneuropathy (dPNP). It is expected that at least one of the three dosages to be tested (600, 1200, or 1800 mg tablets) of orally administered thioctic acid improves the symptoms of dPNP as compared to placebo.

Secondary objectives are evaluations of other variables pertinent to dPNP, safety, and tolerability.

Following a screening visit, patients will receive placebo oral for 7 days. Eligible patients with chronic symptoms will then randomly be assigned to one of 4 treatment groups and treated with trial medication for 5 weeks.

Eligibility Criteria:
Inclusion Criteria:

1. Diabetes mellitus (Type I or II), as defined by the American Diabetes Association, 1997, lasting 1 year.
2. Patient must have a symmetric sensory-motor peripheral polyneuropathy of at least stage 2 attributable to diabetes mellitus following a thorough evaluation for other causes of neuropathy.
3. HbA1C \< 10%.
4. TSS \> 7.5 points.
5. NISLL \> 2 points.
6. Pain sensation (according to pin-prick sensitivity test) absent or decreased (NIS item 35 1).
7. Age range: 18 to 74 years. Inclusion criteria prior to randomisation
8. The TSS must be \> 5 points
9. The TSS range (maximum TSS minus minimum TSS during the run-in phase) must be less than 3 points to avoid inclusion of patients with rapidly oscillating symptoms.
10. At least 1 of the 4 symptoms of the TSS must have occurred continuously over the last 3 months.
11. Lack of compliance, i.e. below 85% or above 115% (Accordingly, 6 daily doses taken of the 7 daily doses scheduled for Phase A would be acceptable).

Exclusion Criteria:

Lack of suitability for the trial:

1. Proximal asymmetric neuropathy, cranial neuropathies, truncal radiculopathy, diabetic plexopathies, or acute or active mononeuropathies (including cranial neuropathies, post-herpes neuralgias, etc.), 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.
3. Other neurologic diseases that may produce weakness, sensory loss, or autonomic symptoms or test abnormality.
4. Myopathy of any cause.
5. Peripheral vascular disease severe enough to cause intermittent claudication or ischemic ulcers or limb ischemia.
6. Patients with proliferating retinopathy requiring immediately therapy and impending blindness.
7. Psychiatric, psychological, or behavioural symptoms that would interfere with the patient's ability to participate in the trial.
8. Patients with any active neoplastic disease except basal cell carcinoma.
9. Patients with atrial fibrillation unless controlled and stabilised by medication.
10. Patients with clinically significant cardiac, pulmonary, gastrointestinal, haematological, or endocrine disease (other than diabetes) that may confound interpretation of the study results or prevent the patient from completing the study.
11. Patients who have had organ transplants of any kind.
12. Patients with significant hepatic or renal disease (ASAT, ALAT or GGT \>2 times normal, serum creatinine \>1.8 mg/dL (\>159 mmol/l) for males or \>1.6 mg/dL (\>141 mmol/l) for females).
13. Patients with a recent history (within last 12 months) of drug or alcohol abuse.
14. Use of any investigational drug (participation in a clinical trial) within last 1 month.
15. History of severe or anaphylactic reaction to drugs, sulfur or biologic products.
16. Recent (within last 3 months) ketoacidosis or hypoglycaemia, necessitating hospital admission.
17. Antioxidant therapy (vitamins E \> 400 IU, C \> 200 mg, and beta-Carotene \> 30 mg) or pentoxyphylline within last 1 month before start of trial.
18. Use of thioctic acid (\> 50 mg), evening primrose oil or any other gamma-linolenic acid containing substance within the last 3 months.
19. Continued use of medications listed in section 6.2.3.
20. Bilateral sural nerve biopsies.
21. Existing foot ulcers.

    Safety concerns:
22. Pregnant or lactating females: Pregnancy as evidenced by positive b-hCG-test at screening visit or by testing performed at the study site on demand, or women of child-bearing potential not using adequate contraception.
23. History of allergic reaction to the study medication or its excipients.

    Administrative reasons:
24. Informed Consent is not signed or the patient has not complete competence to co-operate.
25. Any language barriers that can affect adequate understanding.
26. Anticipated non-availability for study visits/procedures.
27. Vulnerable subjects (such as persons kept in detention)