Challenges in Design of Multicenter Trials

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 (r I ϳ 0.7-0.85) approached that in the epidemiologic cohort (r I ϳ 0. 85-0.95). Associations between pairs of end points explained Ͻ10% 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 (⌺ 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. Diabetes Care 30:2619-2625, 2007R igorous 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,...

Corneal confocal microscopy best identifies the development and progression of neuropathy in patients with type 1 diabetes

“…Progression of neuropathy is difficult to monitor, and this has been suggested to contribute to an inability to prove efficacy of novel treatments 1 . One strategy to demonstrate monotonic worsening is selection of cohorts without neuropathy at enrolment 1 .…”

“…One strategy to demonstrate monotonic worsening is selection of cohorts without neuropathy at enrolment 1 . Past studies, including analyses on the same cohort described here, have defined an absence of neuropathy at enrolment using a composite score of signs and symptoms.…”

Diabetic Peripheral Neuropathy: Should a Chaperone Accompany Our Therapeutic Approach?

“…LA did not significantly improve nerve conduction attributes but did improve some scores of small-fiber neuropathy and muscular function. It is important to note that the lack of efficacy in the NATHAN 1 trial seems to arise from the lack of further decline of nerve conduction deficits in the placebo-treated group during the study (Ziegler et al, 2011), an inherent challenge to trial design in DPN (Dyck et al, 2007). LA is approved for treating DPN in Germany (Gooch and Podwall, 2004) and is commercially available as a dietary supplement in the United States.…”

Whither Clinical Research in Diabetic Sensorimotor Peripheral Neuropathy?

“…Many currently selected end points, including quantitative sensory testing and composite clinical scores, rely on patient responses and are therefore prone to variability. Electrophysiological measures, however, especially sural nerve amplitudes and peroneal nerve conduction velocities, performed well in recent studies (11,12).…”

“…In the current issue of Diabetes Care, Dyck et al (12) further debate the challenges in selecting appropriate end points in clinical trials of new agents for DPN. Assessed were the performances of end points in the placebo arms of two large pharmaceutical trials (one of 4-years' and the other of 1-year's duration) and the 10-year Rochester DPN epidemiological study.…”