title: Challenges in design of multicenter trials: end points assessed longitudinally for change and monotonicity.
abstract: OBJECTIVE
  Assessing clinimetric performance of diabetic sensorimotor polyneuropathy (DSPN) end points in single and multicenter trials.
  
  
  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 (r(I) approximately 0.7-0.85) approached that in the epidemiologic cohort (r(I) approximately 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.
authors.affiliation: Peripheral Neuropathy Research Laboratories, Mayo Clinic College of Medicine, 200 First St., SW, Rochester, MN 55905, USA. dyck.peter@mayo.edu
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Dyck
authors.forename: Jane E
authors.initials: JE
authors.lastname: Norell
authors.forename: Hans
authors.initials: H
authors.lastname: Tritschler
authors.forename: Klemens
authors.initials: K
authors.lastname: Schuette
authors.forename: Rustem
authors.initials: R
authors.lastname: Samigullin
authors.forename: Dan
authors.initials: D
authors.lastname: Ziegler
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Bastyr
authors.forename: William J
authors.initials: WJ
authors.lastname: Litchy
authors.forename: Peter C
authors.initials: PC
authors.lastname: O'Brien
mesh_terms: D000328:Adult; D000368:Aged; D000701:Analgesics, Opioid / Q000627:therapeutic use; D015331:Cohort Studies; D003929:Diabetic Neuropathies / Q000188:drug therapy / Q000503:physiopathology*; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D015337:Multicenter Studies as Topic / Q000379:methods*; D010919:Placebos; D015203:Reproducibility of Results; D012107:Research Design; D016896:Treatment Outcome
chemical_list: D000701:Analgesics, Opioid; D010919:Placebos