Challenges in Design of Multicenter Trials: End points assessed longitudinally for change and monotonicity

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 ( r I ∼ 0.7–0.85) approached that in the epidemiologic cohort ( r I ∼ 0.85–0.95). Associations between pairs of end points explained 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.