IntroductionA reliable and valid clinical tool to capture symptoms and signs of diabetic sensorimotor polyneuropathy (DSP) for use in clinical research trials is urgently needed. The validated Toronto Clinical Neuropathy Score (TCNS) was modified to improve sensitivity to early DSP changes. We aimed to assess the reproducibility of this modified tool, the mTCNS and to determine its validity relative to the precursor TCNS.MethodsSixty-five patients (six Type 1, 59 Type 2 diabetes) with diabetes duration 13 ± 8 years were accrued from four study sites and examined on 2 days for internal consistency and inter- and intra-rater reliability of the mTCNS. In the absence of a single quantitative gold-standard measure for DSP, results of the mTCNS were compared with the precursor TCNS for the purpose of estimating validity.ResultsInternal consistency of the two domains within the mTCNS was good (Cronbach's alpha 0.78). Very good inter-rater reliability for the mTCNS was demonstrated by an intra-class correlation coefficient for the mTCNS of 0.87 (95% confidence interval, 0.79–0.91), which was similar in magnitude to that of the TCNS (0.83; 95% confidence interval, 0.75–0.89). Intra-rater reliability testing of the mTCNS showed moderate to good correlation for individual symptoms and sensory tests (Cohen's kappa values of 0.54–0.73). The mTCNS shared moderate correlation with the precursor TCNS (Pearson correlation coefficient, 0.58).DiscussionThe mTCNS, a clinical score with higher face validity for tracking mild to moderate DSP, has sufficient reliability and validity relative to its precursor TCNS for use in clinical research.

OBJECTIVEAldose reductase inhibitors (ARIs) are potential disease modifiers for diabetes complications. We aimed to determine whether ranirestat, an ARI, could slow or reverse the course of diabetic sensorimotor polyneuropathy (DSP).RESEARCH DESIGN AND METHODSA total of 549 patients with DSP were randomly assigned to treatment with placebo or 10, 20, or 40 mg/day ranirestat for 52 weeks in this multicenter, double-blind study. Efficacy was evaluated by nerve conduction studies, the modified Toronto Clinical Neuropathy Score (mTCNS), and quantitative sensory tests (QSTs).RESULTSAt week 52, the summed sensory (bilateral sural plus proximal median sensory) nerve conduction velocity (NCV) did not show significant changes from baseline (2.0 m/s for placebo compared with 3.2–3.8 m/s for ranirestat). Significant improvement in the summed motor (peroneal, tibial, and median) NCV was observed with 20 and 40 mg/day ranirestat treatment at week 12 (P ≤ 0.05) and at weeks 24 and 36 and in peroneal motor NCV at weeks 36 and 52 (P ≤ 0.05) for the 20 mg/day ranirestat group. The mTCNS and QST results did not differ among the groups during the study. Ranirestat was well tolerated with no pertinent differences in drug-related adverse events or in effects on clinical laboratory parameters, vital signs, or electrocardiograms among the four groups.CONCLUSIONSTreatment with ranirestat appears to have an effect on motor nerve function in mild to moderate DSP, but the results of this study failed to show a statistically significant difference in sensory nerve function relative to placebo.

Drug trials for negative symptoms in schizophrenia select patients based on the severity and stability of negative symptoms, using criteria which are not suitable for trials of acute exacerbation of schizophrenia. Here we present a method to prognostically enrich for subjects having a predefined factor structure in PANSS and apply it to the measurement of negative symptoms specifically in trials of acute schizophrenia. A vector of 1335 elements based on between- and within-item variances, covariances and differences of PANSS items was created to calculate an index of heterogeneity and to enrich for a predetermined symptom construct in PANSS. Using pre-randomization PANSS scores across N=4,876 subjects in 13 trials of acute schizophrenia, we demonstrate an ability to select for a subpopulation having the greatest amount of variance explained across the 7-items of the Marder PANSS negative symptom (MPNS) construct. Network analyses on subjects enriched for MPNS construct confirm that negative symptoms were most influential in overall psychopathology, distinct from subjects without the MPNS construct. As expected for D2 antagonists, drug-placebo differences on negative symptoms with lurasidone was not specific to the subpopulation having the MPNS construct. In contrast, the novel TAAR1 agonist ulotaront demonstrated specific improvements in negative symptoms which were greatest in the MPNS subpopulation. These results demonstrate the utility of a novel prognostic enrichment strategy that can address heterogeneity in clinical trials, where patients can be selected on the basis of a greater likelihood of having the measured symptom construct (negative symptoms) related to the disorder (schizophrenia).