The Neurological Assessment of Thioctic Acid in Diabetic Neuropathy (NATHAN) 1 trial was a multicenter (36 centers in the U.S., Canada, and Europe [Supplementary Materials
]), randomized, double-blind, placebo-controlled, two-arm, 1:1 allocation ratio, parallel-group clinical trial using film-coated tablets containing 600 mg ALA (Thioctacid HR; MEDA Pharma, Bad Homburg, Germany) that were administered once daily or matching placebo tablets with increased amounts of cellulose and lactose that were identical in appearance in diabetic patients with mild-to-moderate DSPN (18
). The trial consisted of a 2-week screening phase, 6-week placebo run-in phase, 4-year double-blind phase, and 4-week washout phase. Approvals were obtained from the local ethics committees of all participating centers.
Inclusion criteria at the screening visit were age 18–64 years; type 1 or type 2 diabetes defined by the American Diabetes Association criteria (1997); diabetes duration ≥1 year; presence of stage 1 or 2a DSPN attributable to diabetes (18
); stable insulin regimen, weight, diet, and physical activity level as judged by the investigator; NIS–Lower Limbs and seven nerve conduction tests (NIS-LL+7) score ≥97.5th percentile (corresponding to 4.43 transformed score points); NIS-LL ≥2 points; one of two abnormalities [either 1
) abnormal nerve conduction attributes in two separate nerves ≥99th percentile for distal latency or ≤1st percentile for nerve conduction velocity or amplitude or 2
) abnormal heart rate during deep breathing (HRDB) ≤1st percentile or total symptom score (TSS) in the feet <5 points]; and being of the female sex and surgically sterilized, ≥1 year postmenopausal, or practicing an acceptable method of contraception.
Exclusion criteria were neuropathies other than DSPN; myopathy and other neurologic diseases that may might interfere with the assessment of the severity of DSPN; previous bilateral sural nerve biopsies; peripheral vascular disease with intermittent claudication; foot ulcers; high risk for visual loss; psychiatric, psychological, or behavioral symptoms that would interfere with the patient’s ability to participate in the trial; active neoplastic disease except basal cell carcinoma; uncontrolled atrial fibrillation; clinically significant cardiac, pulmonary, gastrointestinal, hematologic, or other endocrine disease; organ transplants; aspartate aminotransferase or alanine aminotransferase >2 times normal; serum creatinine >1.8 and >1.6 mg/dL for men and women, respectively; drug or alcohol abuse within the last year; use of investigational drug within the last 6 months; severe or anaphylactic reaction to multiple drugs, sulfur products, or biologic products; ketoacidosis or hypoglycemia within the last 3 months resulting in hospital admission; antioxidant therapy (>400 IU vitamin E, >200 mg vitamin C, or >30 mg/day β carotene) or pentoxyphylline within the last month; γ-linolenic acid and ALA >50 mg/day within the last 3 months; history of use of medications or vitamins known to cause peripheral neuropathy including but not limited to use of phenytoin or carbamazepine ≥15 years or use of >100 mg/day pyridoxine within the last 12 months; and use of pain medications except for standard doses of salicylates, ibuprofen, indoles, fenamates, oxicams, or pyrazoles.
The primary outcome measure was a composite score including the NIS-LL+7 suggested by Dyck et al. (16
) including 1
) vibration detection threshold, 2
) peroneal motor nerve conduction velocity (MNCV), 3
) peroneal motor nerve distal latency, 4
) peroneal compound muscle action potential (CMAP), 5
) tibial motor nerve distal latency, 6
) sural sensory nerve action potential amplitude, and 7
) change in HRDB. The primary criterion of efficacy in the confirmatory analysis was the absolute change in the NIS-LL+7 score expressed as normal deviates (nds from percentiles correcting for age and other applicable variables) between baseline (mean of visit during weeks 1 and 2 or last available value before randomization) and end point (mean of weeks 191 and 192 or last available value after randomization).
Secondary outcome measures included the NIS, NIS-LL, Neuropathy Symptoms and Change (NSC) score, TSS, cooling detection threshold, heat pain response slope (0.5–5.0), tibial nerve CMAP and MNCV, sural sensory nerve action potential latency, and sensory nerve conduction velocity (SNCV). In a response/progression analysis after 2 and 4 years, a clinically meaningful response was defined as a decrease in NIS or NIS-LL by ≥2 points, respectively, while clinically meaningful progression was defined as an increase in NIS or NIS-LL by ≥2 points, respectively (16
Duplicate measurements of these measures within 1 week were performed at baseline, after 2 years, and after 4 years, whereas single measurements were carried out at screening and after 6 months, 1 year, and 3 years except for the NIS and NSC, which were assessed as single assessments at screening and thereafter at 6-month intervals, and the TSS and foot inspection, assessed at 3-month intervals.
The NIS is the sum score of examinations of muscle weakness, reflex loss, touch pressure, vibration, joint position and motion, and pinprick of index finger and great toe and is scored for both sides of the body (19
). The NSC scores (number, severity, and change) are derived from answers to 38 questions (muscle weakness, questions 1–19; sensation, questions 20–29; and autonomic symptoms, questions 30–38) (7
). Experienced, trained, and certified (by P.J.D. and colleagues) physicians evaluated the NIS and NSC. Study physicians had participated in training sessions and actual examination of patients under observation using a formal certification process. The nerve conduction, quantitative sensory tests (QSTs), and autonomic tests were performed by trained and certified personnel (by P.A.L., W.J.L., P.J.D., and colleagues). All results were interactively evaluated by the Reading and Quality Assurance Centers (at Mayo Clinic and Health Partners). Eligibility, baseline conditions, wave forms, stimulus response patterns, and test values were also assessed.
Safety measures included monitoring of adverse events, vital signs, weight, 12-lead resting electrocardiogram, chest X-ray at baseline, concomitant medication, global assessment of tolerability, and physical examination. Laboratory tests including blood chemistry, hematology, blood glucose, and HbA1c were performed at screening, baseline, and 2-month (1st year), 3-month (2nd year), and 6-month (3rd year) intervals.
Screened patients were assigned a unique five-digit number. Randomized patients were additionally assigned a four-digit randomization number at baseline. Patients were assigned to the two treatment groups according to a randomization list generated by the Biostatistics Department of MEDA Pharma. The random allocation was balanced using an undisclosed block size of six. The investigators and the monitor received sealed envelopes to enable decoding the individual blinded treatment in case of emergency.
The following hypothesis was tested: H0:μT = μP vs. H1:μT≠μP, where μT and μP denote the mean change in NIS-LL+7 tests from baseline to end point in the ALA and placebo groups, respectively. A two-way ANOVA including the factors treatment and center was performed. Variances were allowed to differ between treatments. Degrees of freedom were derived according to Kenward-Rogers. A 95% CI for the treatment difference based on least squares (LS) estimates from the model without interactions was calculated. A second model including treatment and center interaction was fitted explanatorily.
An interim analysis was performed as soon as the 2-year data of most subjects were available. The complete table part of the study had been provided to and assessed by an independent supervisory committee. The decision on continuation of the study was based on the confirmatory test of the primary variable. At P
< 0.005, the study would have been stopped. To ensure a global type 1 error of 5%, the error level for the final analysis was set to α2 = 0.0452 according to the Šidák (20
Depending on the structure of data, either contingency tables [n (%)] or descriptive statistics (n, mean, SD, median, range, quartiles) were presented for time courses and changes from baseline. Secondary end points were analyzed by applying a Wilcoxon Mann-Whitney test.
Adverse events were coded according to the World Health Organization-Adverse Reactions Terminology (ART). Global incidences on preferred term and body system class level were calculated based on different causality filters. Vital and laboratory variables were screened for notable individual and trend-like changes.
Sample size calculation.
We used a conservative approach to suggest that treatment with ALA may prevent worsening of DSPN but not necessarily cause improvement (16
). A clinically meaningful treatment difference of 2.0 nds for the changes from baseline for NIS-LL+7 tests and statistical error probabilities α = 0.05 and β = 0.1 were assumed. Based on a two-sided t
test, the following scenarios for SDs and sample size per group (n
) were considered: SD 3.57, n
= 68; SD 4, n
= 86; SD 5, n
= 133; SD 6, n
= 191; SD 7, n
= 211. To account for a relatively high dropout rate expected in this long-term study, randomization of 250 patients per arm was proposed. Analysis of the intention-to-treat population was primary for all efficacy variables. Homogeneity of baseline characteristics was investigated by exploratory statistical tests based on the intention-to-treat population on selected baseline variables.