Challenges in Design of Multicenter Trials

End points assessed longitudinally for change and monotonicity

  1. Peter J. Dyck, MD1,
  2. Jane E. Norell, BS1,
  3. Hans Tritschler, PHD2,
  4. Klemens Schuette, MSC3,
  5. Rustem Samigullin, MD2,
  6. Dan Ziegler, MD4,
  7. Edward J. Bastyr III, MD56,
  8. William J. Litchy, MD1 and
  9. Peter C. O'Brien, PHD7*
  1. 1Peripheral Neuropathy Research Laboratories, Mayo Clinic College of Medicine, Rochester, Minnesota
  2. 2Viatris, Bad Homburg, Germany
  3. 3Ergomed, Frankfurt am Main, Germany
  4. 4German Diabetes Clinic, German Diabetes Center, Leibniz Institute at the Heinrich Heine University, Düsseldorf, Germany
  5. 5Lilly Research Laboratories, Indianapolis, Indiana
  6. 6Indiana University School of Medicine, Indianapolis, Indiana
  7. 7Division of Biostatistics, Mayo Clinic College of Medicine, Rochester, Minnesota
  1. 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

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 (Σ 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.

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.

  • 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.

    • Accepted May 9, 2007.
    • Received January 12, 2007.
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  1. Published online before print May 18, 2007, doi: 10.2337/dc06-2479 Diabetes Care October 2007 vol. 30 no. 10 2619-2625
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