NATHAN1: Assessment of Efficacy and Safety of Thioctic Acid in the Oral Treatment of Diabetic Polyneuropathy (Stage 1 or 2)

• Sponsor: MEDA Pharma GmbH & Co. KG (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00977483
• Collaborator: Clinquest, Inc. (Industry), Ergomed (Industry), Quintiles, Inc. (Industry)
• Enrollment: 460
• Locations: 38
• Arms: 2
• Duration (Months): 80.1
• Patients Per Site: 12.1
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Diabetic Polyneuropathy	Drug: Thioctic Acid; Drug: Placebo	Phase 3

Detailed 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 460 participants
• Allocation: Randomized
• Intervention Model: Single Group Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• 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
• Study Start Date: May 1, 1998
• Actual Primary Completion Date: Jan 1, 2005
• Actual Study Completion Date: Jan 1, 2005

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Drug: Thioctic Acid 600mg tablet Thioctic Acid (alpha-lipoic acid) once daily throughout the trial	Drug: Thioctic Acid; 600mg tablet once daily 4 years double-blind treatment period; Other Names: alpha-lipocic acid
Placebo Comparator: Drug: Placebo 1 tablet once daily throughout the trial	Drug: Placebo; 1 tablet once daily 4 years double-blind treatment period

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 64 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

1. TSS (feet) ≤5

2. 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))

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	´Diabetes Care Center	Birmingham	Alabama	United States	35205
2	Mayo Clinic Arizona	Scottsdale	Arizona	United States	85259
3	City of Hope National Medical Center	Duarte	California	United States	91010
4	Medical Building	Long Beach	California	United States	90805
5	UCSD Neuromuscular Research Program	San Diego	California	United States	92103
6	University of California	San Francisco	California	United States	94143-0114
7	Diabetes Research Center	Tustin	California	United States	92780
8	Loyola University Medical Center	Maywood	Illinois	United States	60153
9	Beth Israel Medical Center	Boston	Massachusetts	United States	02215
10	University of Michigan Medical Center	Ann Arbor	Michigan	United States	48019-0205
11	Health Partners Riverside Neurology Clinic	Minneapolis	Minnesota	United States	55454-1478
12	Mayo Clinic Rochester	Rochester	Minnesota	United States	55905
13	University of Missouri Dept. of Neurology	Columbia	Missouri	United States	65212
14	Creighton University Diabetes Center	Omaha	Nebraska	United States	68131
15	Lovelace Scientific Resources, Inc.	Albuquerque	New Mexico	United States	87108
16	Ney York Hospital Cornell Med Center	New York	New York	United States	10021
17	East Carolina University, School of Medicine	Greenville	North Carolina	United States	27858
18	The Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
19	Ohio State University Medical Center	Columbus	Ohio	United States	43210
20	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania	United States	15213
21	Dallas Diabetes & Endocrine Center	Dallas	Texas	United States	75230
22	University of Texas South Western Medical Center	Dallas	Texas	United States	75325-8858
23	Baylor College of Medicine	Houston	Texas	United States	77030
24	Diabetes & Glandular Disease Center	San Antonio	Texas	United States	78229-3894
25	Leonard R. Strelitz Diabetes Institutes	Norfolk	Virginia	United States	23510
26	University Clinic for Diabetes, Endocrinology and Metabolic	Zagreb		Croatia	10000
27	University Clinic of Internal Medicine	Zagreb		Croatia	10000
28	University Hospital	Hvidovre		Denmark	2650
29	Hospital Jean Verdler	Bondy Cedex		France	93143
30	Policlinic University	Napoli		Italy	80138
31	Hospital Geriatrico Diabetological Service	Padova		Italy	35137
32	Hosptal of Parma Department of Medicine	Parma		Italy	43100
33	University Hospital Utrecht Department of Internal Medicine	Utrecht		Netherlands	3584
34	Hospital del Mar Department Neurophysiology	Barcelona		Spain	08003
35	Hospital Clinico y Provincial	Barcelona		Spain	08036
36	C.H.U.S. General Hospital	Santiago de Compostela		Spain	15705
37	University Clinic	Malmö		Sweden	20602
38	Manchester Royal Infirmary Department of Medicine	Manchester		United Kingdom	M13 9WL

Sponsors and Collaborators

• MEDA Pharma GmbH & Co. KG
• Clinquest, Inc.
• Ergomed
• Quintiles, Inc.

Investigators

• Principal Investigator: Peter James Dyck, Mayo Clinic, Dept. of Neurology, 200 First Street Southwest, Rochester, MN 55905, USA

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00977483
• Other Study ID Numbers: D-20557-3011; NATHAN1; D-20557/9353000001
• First Posted: Sep 15, 2009
• Last Update Posted: Feb 7, 2022
• Last Verified: Nov 1, 2016

• Additional relevant MeSH terms: Polyneuropathies; Diabetic Neuropathies; Thioctic Acid

Study Results

No Results Posted as of Feb 7, 2022