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

Diabetic Polyneuropathy Clinical Trial

— NATHAN1  

Official title:

Assessment of Efficacy and Safety of Thioctic Acid in the Oral Treatment of Diabetic Polyneuropathy (Stage 1 or 2) NATHAN1 A Randomized, Placebo-controlled, Double-blind Multi-centre Trial With 2 Parallel Groups

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
• 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
• 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))

Related Conditions & MeSH terms

• Diabetic Neuropathies
• Diabetic Polyneuropathy
• Polyneuropathies

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