Clinical trial NCT00977483: Assessment of Efficacy and Safety of Thioctic Acid in the Oral Treatment of Diabetic Polyneuropathy (Stage 1 or 2)
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Diabetic Polyneuropathy
Lead sponsor: Viatris Inc.
Sponsor class: INDUSTRY
Collaborators: name: Clinquest, Inc.
name: Ergomed
name: Quintiles, Inc.
First posted: 2009-09-15
Enrollment: 460
Sex: ALL
Minimum age (years): 18
Maximum age (years): 64
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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

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.

Eligibility criteria: 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))

Primary outcomes:
measure: 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
timeFrame: 4 years
Secondary outcomes:
measure: 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.
timeFrame: 4 years
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: ´Diabetes Care Center
state: Alabama
city: Scottsdale
country: United States
facility: Mayo Clinic Arizona
state: Arizona
city: Duarte
country: United States
facility: City of Hope National Medical Center
state: California
city: Long Beach
country: United States
facility: Medical Building
state: California
city: San Diego
country: United States
facility: UCSD Neuromuscular Research Program
state: California
city: San Francisco
country: United States
facility: University of California
state: California
city: Tustin
country: United States
facility: Diabetes Research Center
state: California
city: Maywood
country: United States
facility: Loyola University Medical Center
state: Illinois
city: Boston
country: United States
facility: Beth Israel Medical Center
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Medical Center
state: Michigan
city: Minneapolis
country: United States
facility: Health Partners Riverside Neurology Clinic
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic Rochester
state: Minnesota
city: Columbia
country: United States
facility: University of Missouri Dept. of Neurology
state: Missouri
city: Omaha
country: United States
facility: Creighton University Diabetes Center
state: Nebraska
city: Albuquerque
country: United States
facility: Lovelace Scientific Resources, Inc.
state: New Mexico
city: New York
country: United States
facility: Ney York Hospital Cornell Med Center
state: New York
city: Greenville
country: United States
facility: East Carolina University, School of Medicine
state: North Carolina
city: Cleveland
country: United States
facility: The Cleveland Clinic Foundation
state: Ohio
city: Columbus
country: United States
facility: Ohio State University Medical Center
state: Ohio
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Dallas
country: United States
facility: Dallas Diabetes & Endocrine Center
state: Texas
city: Dallas
country: United States
facility: University of Texas South Western Medical Center
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: San Antonio
country: United States
facility: Diabetes & Glandular Disease Center
state: Texas
city: Norfolk
country: United States
facility: Leonard R. Strelitz Diabetes Institutes
state: Virginia
city: Zagreb
country: Croatia
facility: University Clinic for Diabetes, Endocrinology and Metabolic
city: Zagreb
country: Croatia
facility: University Clinic of Internal Medicine
city: Hvidovre
country: Denmark
facility: University Hospital
city: Bondy Cedex
country: France
facility: Hospital Jean Verdler
city: Napoli
country: Italy
facility: Policlinic University
city: Padova
country: Italy
facility: Hospital Geriatrico Diabetological Service
city: Parma
country: Italy
facility: Hosptal of Parma Department of Medicine
city: Utrecht
country: Netherlands
facility: University Hospital Utrecht Department of Internal Medicine
city: Barcelona
country: Spain
facility: Hospital del Mar Department Neurophysiology
city: Barcelona
country: Spain
facility: Hospital Clinico y Provincial
city: Santiago de Compostela
country: Spain
facility: C.H.U.S. General Hospital
city: Malmö
country: Sweden
facility: University Clinic
city: Manchester
country: United Kingdom
facility: Manchester Royal Infirmary Department of Medicine
Study officials:
affiliation: Mayo Clinic, Dept. of Neurology, 200 First Street Southwest, Rochester, MN 55905, USA
name: Peter James Dyck
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.