Assessment of Efficacy and Safety of Thioctic Acid in the Oral Treatment of Symptomatic Diabetic Neuropathy (SYDNEY 2)
Study Details
Study Description
Brief Summary
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Detailed Description
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.
Study Design
Outcome Measures
Primary Outcome Measures
Eligibility Criteria
Criteria
Inclusion Criteria:
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Diabetes mellitus (Type I or II), as defined by the American Diabetes Association, 1997, lasting 1 year.
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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.
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HbA1C < 10%.
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TSS > 7.5 points.
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NISLL > 2 points.
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Pain sensation (according to pin-prick sensitivity test) absent or decreased (NIS item 35 1).
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Age range: 18 to 74 years. Inclusion criteria prior to randomisation
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The TSS must be > 5 points
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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.
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At least 1 of the 4 symptoms of the TSS must have occurred continuously over the last 3 months.
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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:
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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.
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Neuropathy of any cause other than diabetes mellitus which might interfere with the assessment of the severity of dPNP.
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Other neurologic diseases that may produce weakness, sensory loss, or autonomic symptoms or test abnormality.
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Myopathy of any cause.
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Peripheral vascular disease severe enough to cause intermittent claudication or ischemic ulcers or limb ischemia.
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Patients with proliferating retinopathy requiring immediately therapy and impending blindness.
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Psychiatric, psychological, or behavioural symptoms that would interfere with the patient's ability to participate in the trial.
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Patients with any active neoplastic disease except basal cell carcinoma.
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Patients with atrial fibrillation unless controlled and stabilised by medication.
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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.
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Patients who have had organ transplants of any kind.
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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).
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Patients with a recent history (within last 12 months) of drug or alcohol abuse.
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Use of any investigational drug (participation in a clinical trial) within last 1 month.
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History of severe or anaphylactic reaction to drugs, sulfur or biologic products.
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Recent (within last 3 months) ketoacidosis or hypoglycaemia, necessitating hospital admission.
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Antioxidant therapy (vitamins E > 400 IU, C > 200 mg, and beta-Carotene > 30 mg) or pentoxyphylline within last 1 month before start of trial.
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Use of thioctic acid (> 50 mg), evening primrose oil or any other gamma-linolenic acid containing substance within the last 3 months.
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Continued use of medications listed in section 6.2.3.
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Bilateral sural nerve biopsies.
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Existing foot ulcers.
Safety concerns:
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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.
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History of allergic reaction to the study medication or its excipients.
Administrative reasons:
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Informed Consent is not signed or the patient has not complete competence to co-operate.
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Any language barriers that can affect adequate understanding.
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Anticipated non-availability for study visits/procedures.
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Vulnerable subjects (such as persons kept in detention)
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Wolfson Medical Center, Diabetes Unit | Holon | Israel | 58100 | |
| 2 | Haddassah Medical Center Ein Kerem, Diabetes Unit | Jerusalem | Israel | 91120 | |
| 3 | Chair of Nervous Diseases of IM Sechenov Moscow Medical Academy at City Clinical Hospital | Moscow | Russian Federation | 119048 | |
| 4 | Chair of Endocrinology and Diabetology of Russian Medical Academy of Postgraduate Education at Central Clinical Hospital of Ministry of Communication RF | Moscow | Russian Federation | 125315 | |
| 5 | Federal Centre of Medical Social Expertise and Rehabilitation of Invalids, Centre Diabetic Food | Moscow | Russian Federation | 127486 |
Sponsors and Collaborators
- MEDA Pharma GmbH & Co. KG
Investigators
- Principal Investigator: Dan Ziegler, Prof., German Diabetes Research Institute, Heinrich Heine University, Auf'm Hennekamp 65, D-40225 Düsseldorf, Germany
Study Documents (Full-Text)
None provided.More Information
Publications
- Ametov AS, Barinov A, Dyck PJ, Hermann R, Kozlova N, Litchy WJ, Low PA, Nehrdich D, Novosadova M, O'Brien PC, Reljanovic M, Samigullin R, Schuette K, Strokov I, Tritschler HJ, Wessel K, Yakhno N, Ziegler D; SYDNEY Trial Study Group. The sensory symptoms of diabetic polyneuropathy are improved with alpha-lipoic acid: the SYDNEY trial. Diabetes Care. 2003 Mar;26(3):770-6. Erratum in: Diabetes Care. 2003 Jul;26(7):2227.
- Cameron NE, Cotter MA, Archibald V, Dines KC, Maxfield EK. Anti-oxidant and pro-oxidant effects on nerve conduction velocity, endoneurial blood flow and oxygen tension in non-diabetic and streptozotocin-diabetic rats. Diabetologia. 1994 May;37(5):449-59.
- Cameron NE, Cotter MA. The relationship of vascular changes to metabolic factors in diabetes mellitus and their role in the development of peripheral nerve complications. Diabetes Metab Rev. 1994 Oct;10(3):189-224. Review.
- Collins SL, Moore RA, McQuayHJ, Wiffen P. Antidepressants and anticonvulsants for diabetic neuropathy and postherpetic neuralgia: a quantitative systematic review. J Pain Symptom Manage. 2000 Dec;20(6):449-58. Review.
- Dyck PJ, Karnes JL, O'Brien PC, Litchy WJ, Low PA, Melton LJ 3rd. The Rochester Diabetic Neuropathy Study: reassessment of tests and criteria for diagnosis and staged severity. Neurology. 1992 Jun;42(6):1164-70.
- Dyck PJ, Kratz KM, Lehman KA, Karnes JL, Melton LJ 3rd, O'Brien PC, Litchy WJ, Windebank AJ, Smith BE, Low PA, et al. The Rochester Diabetic Neuropathy Study: design, criteria for types of neuropathy, selection bias, and reproducibility of neuropathic tests. Neurology. 1991 Jun;41(6):799-807.
- Inzucchi SE. Oral antihyperglycemic therapy for type 2 diabetes: scientific review. JAMA. 2002 Jan 16;287(3):360-72. Review.
- Jarvis B, Coukell AJ. Mexiletine. A review of its therapeutic use in painful diabetic neuropathy. Drugs. 1998 Oct;56(4):691-707. Review.
- Nagamatsu M, Nickander KK, Schmelzer JD, Raya A, Wittrock DA, Tritschler H, Low PA. Lipoic acid improves nerve blood flow, reduces oxidative stress, and improves distal nerve conduction in experimental diabetic neuropathy. Diabetes Care. 1995 Aug;18(8):1160-7.
- Rains C, Bryson HM. Topical capsaicin. A review of its pharmacological properties and therapeutic potential in post-herpetic neuralgia, diabetic neuropathy and osteoarthritis. Drugs Aging. 1995 Oct;7(4):317-28. Review.
- Reljanovic M, Reichel G, Rett K, Lobisch M, Schuette K, Möller W, Tritschler HJ, Mehnert H. Treatment of diabetic polyneuropathy with the antioxidant thioctic acid (alpha-lipoic acid): a two year multicenter randomized double-blind placebo-controlled trial (ALADIN II). Alpha Lipoic Acid in Diabetic Neuropathy. Free Radic Res. 1999 Sep;31(3):171-9.
- Ruhnau KJ, Meissner HP, Finn JR, Reljanovic M, Lobisch M, Schütte K, Nehrdich D, Tritschler HJ, Mehnert H, Ziegler D. Effects of 3-week oral treatment with the antioxidant thioctic acid (alpha-lipoic acid) in symptomatic diabetic polyneuropathy. Diabet Med. 1999 Dec;16(12):1040-3.
- Smith AR, Shenvi SV, Widlansky M, Suh JH, Hagen TM. Lipoic acid as a potential therapy for chronic diseases associated with oxidative stress. Curr Med Chem. 2004 May;11(9):1135-46. Review.
- Strokov IA, Kozlova NA, Mozolevskiĭ IuV, Miasoedov SP, Iakhno NN. [The efficacy of the intravenous administration of the trometamol salt of thioctic (alpha-lipoic) acid in diabetic neuropathy]. Zh Nevrol Psikhiatr Im S S Korsakova. 1999;99(6):18-22. Russian.
- Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. BMJ. 1998 Sep 12;317(7160):703-13. Erratum in: BMJ 1999 Jan 2;318(7175):29.
- Wang PH, Lau J, Chalmers TC. Meta-analysis of effects of intensive blood-glucose control on late complications of type I diabetes. Lancet. 1993 May 22;341(8856):1306-9.
- Ziegler D, Hanefeld M, Ruhnau KJ, Hasche H, Lobisch M, Schütte K, Kerum G, Malessa R. Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a 7-month multicenter randomized controlled trial (ALADIN III Study). ALADIN III Study Group. Alpha-Lipoic Acid in Diabetic Neuropathy. Diabetes Care. 1999 Aug;22(8):1296-301.
- Ziegler D, Hanefeld M, Ruhnau KJ, Meissner HP, Lobisch M, Schütte K, Gries FA. Treatment of symptomatic diabetic peripheral neuropathy with the anti-oxidant alpha-lipoic acid. A 3-week multicentre randomized controlled trial (ALADIN Study). Diabetologia. 1995 Dec;38(12):1425-33.
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