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Published online May 18, 2007
Diabetes Care 30:2619-2625, 2007
DOI: 10.2337/dc06-2479
© 2007 by the American Diabetes Association
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Pathophysiology/Complications
Original Article

Challenges in Design of Multicenter Trials

End points assessed longitudinally for change and monotonicity

Peter J. Dyck, MD1, Jane E. Norell, BS1, Hans Tritschler, PHD2, Klemens Schuette, MSC3, Rustem Samigullin, MD2, Dan Ziegler, MD4, Edward J. Bastyr, III, MD5,6, William J. Litchy, MD1 and Peter C. O'Brien, PHD7,*

1 Peripheral Neuropathy Research Laboratories, Mayo Clinic College of Medicine, Rochester, Minnesota
2 Viatris, Bad Homburg, Germany
3 Ergomed, Frankfurt am Main, Germany
4 German Diabetes Clinic, German Diabetes Center, Leibniz Institute at the Heinrich Heine University, Düsseldorf, Germany
5 Lilly Research Laboratories, Indianapolis, Indiana
6 Indiana University School of Medicine, Indianapolis, Indiana
7 Division of Biostatistics, Mayo Clinic College of Medicine, Rochester, Minnesota

Address correspondence and reprint requests to Dr. Peter J. Dyck, Mayo Clinic, 200 First St., SW, Rochester, MN 55905. E-mail: dyck.peter{at}mayo.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
 References
 
OBJECTIVE—Assessing clinimetric performance of diabetic sensorimotor polyneuropathy (DSPN) end points in single and multicenter trials.

RESEARCH DESIGN AND METHODS—Assessed were placebo-treated patients with DSPN in the Viatris and Eli Lilly trials and an epidemiologic cohort.

RESULTS—Test reproducibility in clinical trial cohorts (rI ~ 0.7–0.85) approached that in the epidemiologic cohort (rI ~ 0.85–0.95). Associations between pairs of end points explained <10% of the variability of data (sometimes 15–35%), being higher in the epidemiologic cohort and the Viatris trial than in the Lilly trial. Most end points did not show monotonic worsening over 4 years. However, sural nerve amplitude and peroneal motor conduction velocity did. A nerve conduction score ({Sigma} 5 NC nds [5 attributes of nerve conduction expressed as normal deviates]) did not show monotonic worsening in established DSPN. In the epidemiologic cohort followed for 9.5 years, monotonic worsening of small magnitude occurred for sural amplitude, vibration detection threshold, and especially for composite quantitative sensation.

CONCLUSIONS—The main reason why it is difficult to demonstrate monotonic worsening of neuropathic end points appears to be a very slow worsening of DSPN, a placebo effect for symptoms and signs, and measurement noise. Demonstrating disease progression in controlled trials of DSPN is more likely when 1) patients with developing rather than established DSPN are selected, 2) type 1 diabetic patients are preferentially recruited, 3) patients are selected who cannot or will not achieve ideal glycemic control, 4) end points chosen are known to show monotonic worsening, and 5) a restricted number of centers and expert examiners (trained, certified, using standard approaches, and reference values and interactive surveillance of tests) are used.

Abbreviations: DCCT, Diabetes Control and Complications Trial • DSPN, diabetic sensorimotor polyneuropathy • NC, nerve conduction • NIS(LL), neuropathy impairment score of lower limbs • NSC, neuropathy symptom and change score • QST, quantitative sensation test


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
 References
 
Rigorous control of glycemia retards or ameliorates diabetic sensorimotor polyneuropathy (DSPN), but long and expensive trials are needed (1–4). No adjuvant treatment, in addition to glycemic control, has achieved sufficient efficacy, considering side effects, to obtain regulatory approval (e.g., by the Food and Drug Administration) (5–13). This contrasts to interventions ameliorating sensory symptoms of pain or autonomic symptoms (gastric atony, diarrhea, and sexual dysfunction) receiving approval (14–20). Therefore, we ask, are controlled clinical trials of ancillary treatments doable, which end points should be used, and how long and rigorous do the trials need to be? Assuming that adjuvant efficacious treatments exist, why has it been so difficult to demonstrate efficacy? Possibilities are 1) interventions are not efficacious; 2) present diabetes care inhibits development of complications; 3) other diabetic complications (hypertension, hyperlipidemia, renal disease, and other) with possible adverse effects on DSPN (21) are now managed better; 4) the wrong kind, stage, or duration of DSPN is studied; 5) end points chosen are insufficiently sensitive, specific, monotonic (measuring a consistent trend of worsening or improvement with time), or generalizable (for study at many medical centers); 6) excessive recruitment of type 2 diabetic patients showing little change with time and excessive variability of measured end points; 7) both placebo and treated patients receive better than usual medical treatment (e.g., of hyperglycemia) while in the trial; and 8) studies are insufficiently powered.

The present studies focus on the performance of neuropathy end points in a longitudinal epidemiology survey in Rochester, Minnesota (22), and in placebo arm patients of two pharmaceutical trials, the Viatris trial and the Eli Lilly trial, of mild severity DSPN in type 1 and type 2 diabetes.


   RESEARCH DESIGN AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
RESULTS
 CONCLUSIONS
 References
 
Patient cohorts studied
The three cohorts studied are dissimilar in important ways but are alike in having mild or moderate severity DSPN (stage 2B and 3 [23] are excluded), and severity of neuropathy was evaluated by the same approaches and criteria. Minimal criteria for the diagnosis of DSPN were the same: i.e., {Sigma} 5 NC nds (5 attributes of nerve conduction expressed as normal deviates) ≥95th percentile, neuropathy impairment score of lower limbs [NIS(LL)] ≥2 points, or Diabetes Control and Complications Trial (DCCT) criteria (two approaches).

The epidemiologic study patients are consenting individuals with diabetes and distal symmetric DSPN from Rochester, and later Olmsted County, Minnesota (Rochester Diabetic Neuropathy Study) (22).

The Viatris trial patients (Nathan 1, Viatris) are placebo-treated individuals from a prospective double-blind multicenter trial of oral {alpha}-lipoic acid (600 mg/day) for 4 years. A total of 38 medical centers from the U.S. and Europe participated. Entry criteria were somewhat different from the epidemiologic cohort: 1) the neuropathy impairment score of lower limbs + 7 tests (NIS[LL] + 7 tests) ≥97.5th percentile; 2) NIS(LL) ≥2 points; and 3) two additional criteria: an abnormality (>99th percentile) of at least one attribute of nerve conduction (NC) in two leg nerves tested and a total symptom score ≥5 points.

The Lilly trial patients are placebo-treated individuals of two prospective double-blind multicenter trials (B7A-MC-MBCW and MBBP) of LY 333531 (a specific protein kinase C-ß inhibitor) for the symptoms of DSPN during a 1-year period. The criteria for study entry were as follows: diagnosis of DSPN, neuropathic symptoms (a symptom score >6 points), vibration detection threshold of the great toe using CASE IV ≥95th percentile, a sural nerve sensory amplitude ≥1 µV, and an A1C level <12%. A total of 71 medical centers from six countries (in the U.S., Europe, Middle East, and Asia) participated.

Personnel and performance of tests
The same clinical instruments, end points, instructions, and reference values were used for the epidemiologic cohort, the Viatris trial, and the Lilly trial. All tests were to be done independently, without taking previous or concurrent examination and test results into account.

In the epidemiologic cohort, one of us (P.J.D.) performed all clinical evaluations. In the Viatris and Lilly trials, trained and certified (for the study) neurologists or diabetologists did the examinations. Nerve conductions were performed by neurologists or electromyography technicians under the supervision of physicians. Quantitative sensation testing was done by technicians using CASE IV (a computer-based system using standard and calibrated stimuli, predetermined and validated algorithms of testing, and null stimuli and reference values [percentiles and normal deviates] from the Rochester Diabetic Neuropathy Study cohort of healthy subjects) (24,25).

All neurological evaluation sheets (Clinical Neuropathy Assessment, see below) were sent to a central reading and quality assurance center to interactively recognize omissions and errors, to electronically calculate scores, and to enter data into an electronic database (26).

Use of standard and independent tests
In the epidemiologic cohort, all evaluations were performed independently without availability of earlier or concurrent tests. In the Viatris trial, ~40% of respondents reported that they had always, or sometimes, reviewed previous or concurrent medical information or tests, probably improving the estimate of reproducibility and associations. Information was not available for the Lilly trial.

Analyses
Neuropathy impairment was expressed as NIS(LL) points and symptoms as neuropathy symptom and change score (NSC) severity points. Individual attributes of nerve conduction were recorded as measured values and as normal deviates (nds) (from percentiles correcting for age and other applicable variables) (25). The composite nerve conduction score ({Sigma} 5 NC nds) consists of peroneal nerve amplitude, velocity and distal latency, tibial distal latency, and sural amplitude. The normal deviates of the measurable (when amplitude is 0, velocity and latency cannot be estimated) attributes of the five attributes listed above were summed, divided by the number of measurable attributes and multiplied by 5. Results of quantitative sensation tests (QST) and reduction of heart rate with deep breathing were given as normal deviates (from percentiles corrected for applicable variables).

For reproducibility, intraclass correlations were used. For concordance between tests, Spearman rank-order correlations were used. For change with time, neuropathic end points were regressed on time and the derived slope was tested for statistical significance.

Study limitation
Factors that might affect results of any trial, and therefore the extent to which results from others might be disparate from ours, include 1) methods of data analyses used, including adjustment using normative values and whether classic or Bayesian statistics are used; 2) restriction on enrollments, defining the population to which inferences are to be made; and 3) the nature of any drug effect, including the magnitude of any effect and whether the effect is to show deterioration or to reverse decline.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
CONCLUSIONS
 References
 
Demographic and disease characteristics
In patients from the untreated (the epidemiologic study) and placebo arm (the Viatris and Lilly trials), glycemic control (A1C ~8–9%) was not ideal (Table 1). All patients studied had mild-severity DSPN. However, by the criteria of the median values of NIS(LL), {Sigma} 5 NC nds, {Sigma} 3 QST tests nds, and heart rate with deep breathing nds, the Viatris trial cohort was most severe, followed by the Lilly trial and then by the epidemiologic cohort. By the criteria of symptoms (NSC severity) and {Sigma} DCCT criteria (summated values giving equal weights for decreased ankle reflexes, clinical vibration of toes, and neuropathic symptoms [from NSC]), the order of most to least severe was the Lilly trial, the Viatris trial, and the epidemiologic cohorts.


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  		Table 1— Clinical characteristics of patients in the Rochester, Viatris, and Lilly cohorts at first evaluation using inclusion criteria of {Sigma} 5 NC tests ≥95th percentile

 
Reproducibility of nerve tests
Reproducibility of neuropathy end points could only be assessed for the Viatris trial and the Lilly trial. Generally, reproducibility was in the range of rI = 0.7–0.85 (Table 2), somewhat lower than previously published values mainly from the epidemiologic cohort.


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  		Table 2— Reproducibility of neuropathic end point measurements at onset of Viatris and Lilly controlled clinical trials of DSPN

 
Concordance (r2 as percentages) between pairs of neuropathy end points
There is considerable variability of associations between pairs of end points and among cohorts (Table 3). For many pairs of end points, the percent variability explained by the data are <10%; but for others, it was in the range of 15–35%. For the epidemiologic cohort, the Viatris trial, and the Lilly trial, neurological signs (NIS[LL]) were correlated with symptoms to a substantial degree, i.e., 6, 12, and 15% at the first and 15, 24, and 16% at the last examination, respectively. By comparison, {Sigma} 5 NC and NIS(LL) had values of 11, 17, and 0% and 14, 19, and 1%, respectively—a low correlation in the Lilly trial at both examinations. The mean values of the percent correlations were similar between the epidemiologic cohort and the Viatris trial at first and at last evaluations. It was lower for the Lilly trial cohort. In all cases, mean correlations were higher at the last examination than at the first examination.


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  		Table 3— Percent Spearman rank-order correlations (r2) between pairs of neuropathic end points explained by the data in the Rochester (R), Viatris (V), and Lilly (L) cohorts at first and last evaluation

 
Consistency of end point worsening over time (monotonicity)
Estimates of monotonicity varied somewhat depending on criteria for diagnosis of DSPN (Table 4). Therefore, it was assessed using three criteria for the diagnosis of DSPN, i.e., NIS[LL] ≥2 points, {Sigma} 5 NC nds ≥95th, and DCCT with two or more of three criteria (two varieties). By these criteria, sural sensory nerve amplitude performed best, significantly worsening eight of a possible nine times, with the ninth time not showing a significant change. Peroneal nerve motor conduction velocity showed significant worsening in two of nine cases. Heart rate change with deep breathing showed neither worsening nor improvement. Improvement was found for ankle reflexes (significantly four of nine times); NSC(lower limbs) severity also showed significant improvement (three of nine times). Summated DCCT criteria showed significant improvement in three of nine cases. Tibial motor distal latency showed significant improvement in three cases.


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  		Table 4— Median regression slopes (b ) of various neuropathic end points over time in the Rochester, Viatris, and Lilly cohorts using different criteria for the diagnosis of polyneuropathy

 
These results were confirmed and strengthened by assessment of longitudinal data in patients in the epidemiologic cohort with DSPN for the full duration of study (median 9.5 years) (Table 5, available from the authors upon request). The end points showing consistent monotonic worsening without improvement were as follows: sural sensory amplitude, clinical vibration of toe (significant two of four times), and {Sigma} 3 QST nds (significant four of four times).

Testing for the effect of restricting entry into study by a percentile value of an end point and then following course using the same but unrestricted end point
The possible effect was tested using {Sigma} 5 NC nds in triplicate measures at baseline of the Viatris trial cohort patients. At first (of triplicate measures), only patients with {Sigma} 5 NC nds values ≥95th percentile were included and the same patients assessed at the second and third occasion—all three tests done within a week of each other. Comparing {Sigma} 5 NC nds median values of the second and third to that of the first examination, the median values were 10.4 nds, 10.7 nds (NS), and 10.2 nds (P = 0.03). Because nerve conductions in DSPN have not significantly changed in a few days, the significant improvement found at the third examination is due to restriction at first evaluation and using the same end point (without restriction) for the subsequent two evaluations.


   CONCLUSIONS
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
References
 
This study does not directly address all of the possible reasons why it has been difficult to demonstrate efficacy from adjuvant treatments of DSPN but deals with issues of reproducibility, concordance between pairs of tests, monotonicity, and the rate of worsening over prolonged times in mild DSPN. Our results show that the main reason is that DSPN worsens very slowly and that many end points are not sufficiently sensitive, accurate, representative, reproducible, and especially monotonic to reliably recognize the small worsening occurring over a period of 4 years. The magnitude of worsening measured over a period of 4 years was very small and was not accompanied by increased neurological signs or symptoms, both showing improvement (albeit small) rather than worsening. One possible explanation for why only a slight deterioration was observed might be our use of the commonly used practice in controlled clinical trials to "carry last observations forward" with the consequence of underestimating actual deterioration. Here, it was not the reason for the low rate of worsening, since results were essentially unchanged with deletion of "carried forward" data. Because this slow rate of worsening was found for all three cohorts and had also been observed previously in DCCT studies (1,2), we attribute it to very slow worsening of DSPN.

Assuming that DSPN worsens very slowly and that adjuvant treatments are unlikely to improve nerve function to a greater degree than from euglycemia, end points needed to detect a difference between treatment and placebo must have excellent clinimetric characteristics. If, on the other hand, an adjuvant treatment causes a greater improvement than that from institution of euglycemia, one assumes that present monitoring approaches or analyses would be able to recognize and track improvement. Many of the end points studied were reasonably reproducible and concordant. By the criteria of monotonicity, some of the end points performed poorly. This was especially true for symptoms and neurological signs, which typically showed significant improvement rather than worsening. The failure of these clinical measures to perform well raises a serious question about the adequacy of the recently published research case definition of polyneuropathy (27). The end points that performed best were sural nerve amplitude and to a lesser degree peroneal motor conduction velocity, both showing monotonic worsening. This worsening is all the more meaningful, as we had corrected for the influence of change in age and weight. Considering the epidemiologic cohort patients with DSPN followed for the full duration of study (median 9.5 years), sural nerve amplitude continued to show significant monotonic worsening three of four times. By contrast, peroneal motor conduction velocity did not show monotonic worsening. The composite score ({Sigma} 3 QST nds) showed monotonic worsening four of four times.

What inferences about the conduct of future therapeutic trials of DSPN can be drawn from the present analysis, and are multicenter trials doable? Several important insights about how to improve future trials can be inferred. First, since near euglycemia prevents or ameliorates DSPN, success is more likely if patients who cannot, or will not, achieve good chronic glycemic control are included. Second, end points should be chosen differing on whether patients without or with DSPN are to be recruited for study—composite scores of NC and heart rate with deep breathing emphasized for the former and the two attributes of NC and composite score of QSTs identified here for the latter. Third, studies will need to be done for long times to show a treatment effect. Perhaps the best stage of DSPN for conduct of trials is patients on the verge of developing DSPN. These patients showed monotonic worsening of composite scores of nerve conduction and, to a lesser degree, of heart rate variability with deep breathing (28). Type 1 diabetic patients are preferable to type 2 diabetic patients because there is less variability of normal test results due to their younger age and because polyneuropathy worsens to a greater degree in type 1 diabetes (25,29). However, we acknowledge that selection of other patients, other stages of complication, or other methods of analyses may be shown to improve study performance unlike that shown here.

The monotonic improvement of clinical signs and symptoms in placebo arm trial patients of controlled clinical trials demonstrated here is of concern, especially in light of their historical use in DSPN (30,31) and their importance in the recently published case definition of polyneuropathy (27). We judge the observed improvement we observed in the placebo arm of trials is mainly due to a placebo effect. Measures of neurological signs and symptoms, although good enough to demonstrate a large therapeutic response (e.g., in immune neuropathies [32,33]), are not as able to do so in DSPN with low rates of worsening.

Finally, we note that restricting entry into study by use of a percentile abnormality of an end point and then using the same end point to measure change may result in a spurious estimate of improvement. Therefore, it is advisable to either incorporate a run-in phase and subsequent baseline measurements for analyses or use different criteria for entry into study than used for purposes of follow-up.


   Acknowledgments
 
The work was supported in part from grants received from the National Institute of Neurologic Disorders and Stroke (NS36797).

The authors thank patients and investigators of the Viatris and Eli Lilly trials, patients in the Rochester Diabetic Neuropathy Study, and Vicki Clark and Mary Lou Hunziker for their help.

Additional contributing authors are Vladimir Skljarevski, MD, Eli Lilly and Co., Indianapolis, Indiana; and Phillip A. Low, MD, P. James B. Dyck, MD, Christopher J. Klein, MD (Peripheral Neuropathy Research Laboratories), and L. Joseph Melton, III, MD (Division of Epidemiology), Mayo Clinic College of Medicine, Rochester, Minnesota.


   Footnotes
 
Published ahead of print at http://care.diabetesjournals.org on 18 May 2007. DOI: 10.2337/dc06-2479.

* See the ACKNOWLEDGMENTS for additional contributing authors. Back

A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received for publication January 12, 2007. Accepted for publication May 9, 2007.


   References
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
 References
 

  1. DCCT Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329:977–986, 1993[Abstract/Free Full Text]
  2. DCCT Research Group: Effect of intensive diabetes treatment on nerve conduction in the Diabetes Control and Complications Trial. Ann Neurol 38:869, 1995[Medline]
  3. Amthor K-F, Dahl-Jorgensen K, Berg TJ, Skard Heier M, Sandvik L, Aagenaes O, Hanssen KF: The effect of 8 years of strict glycaemic control on peripheral nerve function in IDDM patients: the Oslo Study. Diabetologia 37:579–584, 1994[Medline]
  4. Service FJ, Rizza RA, Daube JR, O'Brien PC, Dyck PJ: Near normoglycaemia improved nerve conduction and vibration sensation in diabetic neuropathy. Diabetologia 28:722–727, 1985[Medline]
  5. Ziegler D, Reljanovic M, Mehnert H, Gries FA: Alpha-lipoic acid in the treatment of diabetic polyneuropathy in Germany: current evidence from clinical trials. Exp Clin Endocrinol Diabetes 107:421–430, 1999[Medline]
  6. Keen H, Payan J, Allawi J, Walker J, Jamal GA, Weir AI, Henderson LM, Bissessar EA, Watkins PJ, Sampson M, Gale EAM, Scarpello JHB, Boddie HG, Hardy KJ, Thomas PK, Misra P, Halonen J-P: Treatment of diabetic neuropathy with gamma-linolenic acid: the Gamma-Linolenic Acid Multicenter Trial Group. Diabetes Care 16:8–15, 1993[Abstract]
  7. Apfel SC, Kessler JA, Adornato BT, Litchy WJ, Sanders C, Rask CA: Recombinant human nerve growth factor in the treatment of diabetic polyneuropathy. Neurology 51:695–702, 1998[Abstract/Free Full Text]
  8. The Sorbinil Retinopathy Trial: neuropathy results: Sorbinil Retinopathy Trial Research Group. Neurology 43:1141–1149, 1993[Abstract/Free Full Text]
  9. Apfel SC, Schwartz S, Adornato BT, Freeman R, Biton V, Rendell M, Vinik A, Giuliani M, Stevens JC, Barbano R, Dyck PJ: Efficacy and safety of recombinant human nerve growth factor in patients with diabetic polyneuropathy: a randomized controlled trial. JAMA 284:2215–2221, 2000[Abstract/Free Full Text]
  10. Greene DA, Arezzo JC, Brown MB: Effect of aldose reductase inhibition on nerve conduction and morphometry in diabetic neuropathy: Zenarestat Study Group. Neurology 53:580–591, 1999[Abstract/Free Full Text]
  11. Nicolucci A, Carinci F, Cavaliere D, Scorpiglione N, Belfiglio M, Labbrozzi D, Mari E, Benedetti MM, Tognoni G, Liberati A: A meta-analysis of trials on aldose reductase inhibitors in diabetic peripheral neuropathy: the Italian Study Group: The St. Vincent Declaration. Diabet Med 13:1017–1026, 1996[Medline]
  12. Abbott CA, Vileikyte L, Williamson S, Carrington AL, Boulton AJ: Multicenter study of the incidence of and predictive risk factors for diabetic neuropathic foot ulceration. Diabetes Care 21:1071–1075, 1998[Abstract]
  13. Ziegler D: New drugs to prevent or treat diabetic polyneuropathy. International Diabetes Monitor 13:1–10, 2001
  14. Rull JA, Quibrera R, Gonzalez-Millan H, Lozano Castaneda O: Symptomatic treatment of peripheral diabetic neuropathy with carbamazepine (Tegretol): double blind crossover trial. Diabetologia 5:215–218, 1969[Medline]
  15. Sindrup SH: Antidepressants in the treatment of diabetic neuropathy symptoms: pharmacodynamic, -kinetic, and -genetic aspects. Dan Med Bull 41:66–78, 1994[Medline]
  16. Sindrup SH, Jensen TS: Efficacy of pharmacological treatments of neuropathic pain: an update and effect related to mechanism of drug action. Pain 83:389–400, 1999[Medline]
  17. Backonja M, Beydoun A, Edwards KR, Schwartz SL, Fonseca V, Hes M, LaMoreaux L, Garofalo E: Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: a randomized controlled trial. JAMA 280:1831–1836, 1998[Abstract/Free Full Text]
  18. Davies HT, Crombie IK, Lonsdale M, Macrae WA: Consensus and contention in the treatment of chronic nerve-damage pain. Pain 47:191–196, 1991[Medline]
  19. Harati Y, Gooch C, Swenson M, Edelman S, Greene D, Raskin P, Donofrio P, Cornblath D, Sachdeo R, Siu CO, Kamin M: Double-blind randomized trial of tramadol for the treatment of the pain of diabetic neuropathy. Neurology 50:1842–1846, 1998[Abstract]
  20. Raskin J, Pritchett YL, Wang F, D'Souza DN, Waninger AL, Iyengar S, Wernicke JF: A double-blind, randomized multicenter trial comparing duloxetine with placebo in the management of diabetic peripheral neuropathic pain. Pain Med 6:346–356, 2005[Medline]
  21. Tesfaye S, Chaturvedi N, Eaton SE, Ward JD, Manes C, Ionescu-Tirgoviste C, Witte DR, Fuller JH, Group EPCS: Vascular risk factors and diabetic neuropathy. N Engl J Med 352:341–350, 2005[Abstract/Free Full Text]
  22. Dyck PJ, Kratz KM, Lehman KA, Karnes JL, Melton LJ III, O'Brien PC, Litchy WJ, Windebank AJ, Smith BE, Low PA, Service FJ, Rizza RA, Zimmerman BR: The Rochester Diabetic Neuropathy. Study: design, criteria for types of neuropathy, selection bias, and reproducibility of neuropathic tests. Neurology 41:799–807, 1991[Abstract/Free Full Text]
  23. Dyck PJB, Dyck PJ: Diabetic polyneuropathy. In Diabetic Neuropathy. 2nd ed. Dyck PJ, Thomas PK, Eds. Philadelphia, W.B. Saunders, 1999, p. 255–278
  24. O'Brien PC, Dyck PJ: Procedures for setting normal values. Neurology 45:17–23, 1995[Free Full Text]
  25. Dyck PJ, Litchy WJ, Lehman KA, Hokanson JL, Low PA, O'Brien PC: Variables influencing neuropathic endpoints: the Rochester Diabetic Neuropathy Study of healthy subjects (RDNS-HS). Neurology 45:1115–1121, 1995[Abstract]
  26. Dyck PJ, O'Brien PC, Davies J, Klein CJ, Dyck PJB: Nerve tests expressed as percentiles, normal deviates, and composite scores. In Peripheral Neuropathy. 4th ed. Dyck PJ, Thomas PK, Eds. Philadelphia, Elsevier, 2005, p. 971–984
  27. England JD, Gronseth GS, Franklin G, Miller RG, Asbury AK, Carter GT, Cohen JA, Fisher MA, Howard JF, Kinsella LJ, Latov N, Lewis RA, Low PA, Sumner AJ: Distal symmetric polyneuropathy: a definition for clinical research: report of the American Academy of Neurology, the American Association of Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology 64:199–207, 2005[Abstract/Free Full Text]
  28. Dyck PJ, O'Brien PC, Litchy WJ, Harper CM, Klein CJ, Dyck PJB: Monotonicity of nerve tests in diabetes: subclinical nerve dysfunction precedes diagnosis of polyneuropathy. Diabetes Care 28:2192–2200, 2005[Abstract/Free Full Text]
  29. Dyck PJ, Kratz KM, Karnes JL, Litchy WJ, Klein R, Pach JM, Wilson DM, O'Brien PC, Melton LJ, Service FJ: The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort: the Rochester Diabetic Neuropathy Study. Neurology 43:817–824, 1993[Abstract/Free Full Text]
  30. Pirart J: Diabetes mellitus and its degenerative complications: a prospective study of 4,400 patients observed between 1947 and 1973: part 1. Diabetes Care 1:168–188, 1978
  31. Pirart J: Diabetes mellitus and its degenerative complications: a prospective study of 4,400 patients observed between 1947 and 1973: part 2. Diabetes Care 1:252–263, 1978
  32. Dyck PJ, Daube J, O'Brien P, Pineda A, Low PA, Windebank AJ, Swanson C: Plasma exchange in chronic inflammatory demyelinating polyradiculoneuropathy. N Engl J Med 314:461–465, 1986[Abstract]
  33. Dyck PJ, Low PA, Windebank AJ, Jaradeh SS, Gosselin S, Bourque P, Smith BE, Kratz KM, Karnes JL, Evans BA, Pineda AA, O'Brien PC, Kyle RA: Plasma exchange in polyneuropathy associated with monoclonal gammopathy of undetermined significance. N Engl J Med 325:1482–1486, 1991[Abstract]

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Whither Clinical Research in Diabetic Sensorimotor Peripheral Neuropathy?: Problems of end point selection for clinical trials
Diabetes Care, October 1, 2007; 30(10): 2752 - 2753.
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HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Diabetes Diabetes Care Clinical Diabetes Diabetes Spectrum