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

NCT00977483 | Completed Phase 3 DMC

• 3 other identifiers: D-20557-3011NATHAN1D-20557/9353000001
• Study Type: interventional
• Target: 460
• Locations: 9 countries
• Sites: 38

Brief Summary

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

Conditions

Diabetic Polyneuropathy

Outcome Measures

Primary Outcomes (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 Outcomes (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

Study Arms (2)

Drug: Thioctic Acid

EXPERIMENTAL

600mg tablet Thioctic Acid (alpha-lipoic acid) once daily throughout the trial

Drug: Thioctic Acid

Drug: Placebo

PLACEBO COMPARATOR

1 tablet once daily throughout the trial

Drug: Placebo

Interventions

Thioctic Acid DRUG

600mg tablet once daily 4 years double-blind treatment period

Also known as: alpha-lipocic acid

Drug: Thioctic Acid

Placebo DRUG

1 tablet once daily 4 years double-blind treatment period

Drug: Placebo

Eligibility Criteria

• Age: 18 Years - 64 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Signed Informed Consent. Patients must have willingness and complete competence to cooperate and language barriers must not preclude adequate understanding
• Diabetes mellitus (Type I or II), as defined by the American Diabetes Association 1997, lasting \> 1 year
• 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)
• 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
• Severity of diabetic polyneuropathy must be Stage 1 or 2a
• 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%)
• NIS\[LL\]+7 tests ≥ 97.5 percentiles (corresponding to 4.43 transformed score points)
• NIS\[LL\] ≥ 2 points (NIS\[LL\] is based on questions 17-24, 28, 29, 34, 35, and 37 of the NIS)
• 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
• TSS (feet) ≤5
• 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

You may not qualify if:

• 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
• 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
• Peripheral vascular disease severe enough to cause intermittent claudication or ischemic ulcers or limb ischemia
• Patients with a history of ophthalmological findings suggesting a high risk for visual loss i.e., significant maculopathy or proliferative retinopathy
• Psychiatric, psychological, or behavioural symptoms that would interfere with the patient's ability to participate in the trial
• Patients with any active neoplastic disease except basal cell carcinoma
• Patients with atrial fibrillation unless controlled and stabilised by medication (changed to this criterion by Amendment 1)
• 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
• Patients who have had organ transplants of any kind
• 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)
• Patients with a recent history (within last 12 months) of drug or alcohol abuse
• Use of any investigational drug within the last 6 months
• History of severe or anaphylactic reaction to multiple drugs, sulfur products, or biologic products (changed to this criterion by Amendment 1)
• Ketoacidosis or hypoglycaemia within last 3 months resulting in hospital admission
• Antioxidant therapy (vitamins E \> 400IU, C \> 200mg, and beta-Carotene \> 30mg) or pentoxyphylline within last 1 month before start of trial

Sponsors & Collaborators

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

Study Sites (38)

´Diabetes Care Center

Birmingham, Alabama, 35205, United States

Location

Mayo Clinic Arizona

Scottsdale, Arizona, 85259, United States

Location

City of Hope National Medical Center

Duarte, California, 91010, United States

Location

Medical Building

Long Beach, California, 90805, United States

Location

UCSD Neuromuscular Research Program

San Diego, California, 92103, United States

Location

University of California

San Francisco, California, 94143-0114, United States

Location

Diabetes Research Center

Tustin, California, 92780, United States

Location

Loyola University Medical Center

Maywood, Illinois, 60153, United States

Location

Beth Israel Medical Center

Boston, Massachusetts, 02215, United States

Location

University of Michigan Medical Center

Ann Arbor, Michigan, 48019-0205, United States

Location

Health Partners Riverside Neurology Clinic

Minneapolis, Minnesota, 55454-1478, United States

Location

Mayo Clinic Rochester

Rochester, Minnesota, 55905, United States

Location

University of Missouri Dept. of Neurology

Columbia, Missouri, 65212, United States

Location

Creighton University Diabetes Center

Omaha, Nebraska, 68131, United States

Location

Lovelace Scientific Resources, Inc.

Albuquerque, New Mexico, 87108, United States

Location

Ney York Hospital Cornell Med Center

New York, New York, 10021, United States

Location

East Carolina University, School of Medicine

Greenville, North Carolina, 27858, United States

Location

The Cleveland Clinic Foundation

Cleveland, Ohio, 44195, United States

Location

Ohio State University Medical Center

Columbus, Ohio, 43210, United States

Location

University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, 15213, United States

Location

Dallas Diabetes & Endocrine Center

Dallas, Texas, 75230, United States

Location

University of Texas South Western Medical Center

Dallas, Texas, 75325-8858, United States

Location

Baylor College of Medicine

Houston, Texas, 77030, United States

Location

Diabetes & Glandular Disease Center

San Antonio, Texas, 78229-3894, United States

Location

Leonard R. Strelitz Diabetes Institutes

Norfolk, Virginia, 23510, United States

Location

University Clinic for Diabetes, Endocrinology and Metabolic

Zagreb, 10000, Croatia

Location

University Clinic of Internal Medicine

Zagreb, 10000, Croatia

Location

University Hospital

Hvidovre, 2650, Denmark

Location

Hospital Jean Verdler

Bondy, 93143, France

Location

Policlinic University

Napoli, 80138, Italy

Location

Hospital Geriatrico Diabetological Service

Padua, 35137, Italy

Location

Hosptal of Parma Department of Medicine

Parma, 43100, Italy

Location

University Hospital Utrecht Department of Internal Medicine

Utrecht, 3584, Netherlands

Location

Hospital del Mar Department Neurophysiology

Barcelona, 08003, Spain

Location

Hospital Clinico y Provincial

Barcelona, 08036, Spain

Location

C.H.U.S. General Hospital

Santiago de Compostela, 15705, Spain

Location

University Clinic

Malmo, 20602, Sweden

Location

Manchester Royal Infirmary Department of Medicine

Manchester, M13 9WL, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 21775755 DERIVED

MeSH Terms

Conditions

Diabetic Neuropathies

Interventions

Thioctic Acid

Condition Hierarchy (Ancestors)

Peripheral Nervous System Diseases; Neuromuscular Diseases; Nervous System Diseases; Diabetes Complications; Diabetes Mellitus; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Carboxylic Acids; Organic Chemicals; Thiophenes; Sulfur Compounds; Coenzymes; Enzymes and Coenzymes; Fatty Acids; Lipids

Study Officials

• Peter James Dyck

  Mayo Clinic, Dept. of Neurology, 200 First Street Southwest, Rochester, MN 55905, USA

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY

Study Record Dates

• First Submitted: September 14, 2009
• First Posted: September 15, 2009
• Study Start: May 1, 1998
• Primary Completion: January 1, 2005
• Study Completion: January 1, 2005
• Last Updated: February 7, 2022

Record last verified: 2016-11

Locations

US (25); DK (1); IT (3); ES (3); FR (1); CR (2); GB (1); NL (1); SE (1)