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Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT00977483
Other study ID # D-20557-3011
Secondary ID NATHAN1D-20557/9
Status Completed
Phase Phase 3
First received
Last updated
Start date May 1998
Est. completion date January 2005

Study information

Verified date November 2016
Source Viatris Inc.
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

To assess clinical efficacy and safety of long-term orally administered thioctic acid in the treatment of diabetic polyneuropathy.


Description:

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.


Recruitment information / eligibility

Status Completed
Enrollment 460
Est. completion date January 2005
Est. primary completion date January 2005
Accepts healthy volunteers No
Gender All
Age group 18 Years to 64 Years
Eligibility 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))

Study Design


Intervention

Drug:
Thioctic Acid
600mg tablet once daily 4 years double-blind treatment period
Placebo
1 tablet once daily 4 years double-blind treatment period

Locations

Country Name City State
Croatia University Clinic for Diabetes, Endocrinology and Metabolic Zagreb
Croatia University Clinic of Internal Medicine Zagreb
Denmark University Hospital Hvidovre
France Hospital Jean Verdler Bondy Cedex
Italy Policlinic University Napoli
Italy Hospital Geriatrico Diabetological Service Padova
Italy Hosptal of Parma Department of Medicine Parma
Netherlands University Hospital Utrecht Department of Internal Medicine Utrecht
Spain Hospital Clinico y Provincial Barcelona
Spain Hospital del Mar Department Neurophysiology Barcelona
Spain C.H.U.S. General Hospital Santiago de Compostela
Sweden University Clinic Malmö
United Kingdom Manchester Royal Infirmary Department of Medicine Manchester
United States Lovelace Scientific Resources, Inc. Albuquerque New Mexico
United States University of Michigan Medical Center Ann Arbor Michigan
United States ´Diabetes Care Center Birmingham Alabama
United States Beth Israel Medical Center Boston Massachusetts
United States The Cleveland Clinic Foundation Cleveland Ohio
United States University of Missouri Dept. of Neurology Columbia Missouri
United States Ohio State University Medical Center Columbus Ohio
United States Dallas Diabetes & Endocrine Center Dallas Texas
United States University of Texas South Western Medical Center Dallas Texas
United States City of Hope National Medical Center Duarte California
United States East Carolina University, School of Medicine Greenville North Carolina
United States Baylor College of Medicine Houston Texas
United States Medical Building Long Beach California
United States Loyola University Medical Center Maywood Illinois
United States Health Partners Riverside Neurology Clinic Minneapolis Minnesota
United States Ney York Hospital Cornell Med Center New York New York
United States Leonard R. Strelitz Diabetes Institutes Norfolk Virginia
United States Creighton University Diabetes Center Omaha Nebraska
United States University of Pittsburgh Medical Center Pittsburgh Pennsylvania
United States Mayo Clinic Rochester Rochester Minnesota
United States Diabetes & Glandular Disease Center San Antonio Texas
United States UCSD Neuromuscular Research Program San Diego California
United States University of California San Francisco California
United States Mayo Clinic Arizona Scottsdale Arizona
United States Diabetes Research Center Tustin California

Sponsors (4)

Lead Sponsor Collaborator
MEDA Pharma GmbH & Co. KG Clinquest, Inc., Ergomed, Quintiles, Inc.

Countries where clinical trial is conducted

United States,  Croatia,  Denmark,  France,  Italy,  Netherlands,  Spain,  Sweden,  United Kingdom, 

Outcome

Type Measure Description Time frame Safety issue
Primary Primary efficacy variable: Absolute change in the neuropathy impairment score lower limbs enlarged by 7 objective items (NISLL+7) between baseline (mean of Visit 0.3 and 0.4 or last available value before randomisation, respectively) and endpoint 4 years
Secondary NIS, NSC, TSS, LLF, QST, VDT, CDT and HP, QAE by means of the HRDB, amplitude CMAP, DL and MNCV on peroneal and tibial nerves, amplitude SNAP and latency on sural nerve, foot inspection, efficacy. 4 years
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