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

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

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

Study Overview

• Status: Completed
• Conditions: Diabetic Polyneuropathy
• Intervention / Treatment: Drug: Thioctic Acid; Drug: Placebo

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 Type: Interventional
• Enrollment (Actual): 460
• Phase: Phase 3

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 60 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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

Outcome Measure	Time Frame
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

Collaborators and Investigators

• Sponsor: MEDA Pharma GmbH & Co. KG
• Collaborators: Quintiles, Inc.; Ergomed; Clinquest, Inc.
• Investigators: Principal Investigator: Peter James Dyck, Mayo Clinic, Dept. of Neurology, 200 First Street Southwest, Rochester, MN 55905, USA

Publications and helpful links

General Publications

• Ziegler D, Low PA, Litchy WJ, Boulton AJ, Vinik AI, Freeman R, Samigullin R, Tritschler H, Munzel U, Maus J, Schutte K, Dyck PJ. Efficacy and safety of antioxidant treatment with alpha-lipoic acid over 4 years in diabetic polyneuropathy: the NATHAN 1 trial. Diabetes Care. 2011 Sep;34(9):2054-60. doi: 10.2337/dc11-0503. Epub 2011 Jul 20.

Study record dates

Study Major Dates

• Study Start: May 1, 1998
• Primary Completion (Actual): January 1, 2005
• Study Completion (Actual): January 1, 2005

Study Registration Dates

• First Submitted: September 14, 2009
• First Submitted That Met QC Criteria: September 14, 2009
• First Posted (Estimate): September 15, 2009

Study Record Updates

• Last Update Posted (Actual): February 7, 2022
• Last Update Submitted That Met QC Criteria: February 4, 2022
• Last Verified: November 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Endocrine System Diseases; Diabetes Complications; Diabetes Mellitus; Neuromuscular Diseases; Peripheral Nervous System Diseases; Polyneuropathies; Diabetic Neuropathies; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Protective Agents; Micronutrients; Vitamins; Antioxidants; Vitamin B Complex; Thioctic Acid
• Other Study ID Numbers: D-20557-3011; NATHAN1; D-20557/9353000001