Challenges in Design of Multicenter Trials: Endpoints Assessed Longitudinally for Change and Monotonicity

Abstract

OBJECTIVE: Assessing clinimetric performance of polyneuropathy (DSPN) endpoints in single and multicenter trials.

METHODS: Assessed were placebo treated patients with DSPN in the VIATRIS (V) and Lilly (L) trials and an epidemiologic cohort (R).

RESULTS: Test reproducibility in clinical trial cohorts (r_I ∼ 0.7 to 0.85) approached that in R (r_I ∼ 0.85 to 0.95). Associations between pairs of endpoints explained < 10% of the variability of data (sometimes 15-35%), being higher in R and V than in L. Most endpoints 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) did not show monotonic worsening in established DSPN. In R 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 endpoints appears to be 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 DM patients are preferentially recruited; 3) patients are selected who cannot or will not achieve ideal glycemic control; 4) endpoints 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.