Safety and Efficacy of Topiramate in Individuals With Cryptogenic Sensory Peripheral Neuropathy With Metabolic Syndrome: The TopCSPN Randomized Clinical Trial.

Importance: Cryptogenic sensory peripheral neuropathy (CSPN) is highly prevalent and often disabling due to neuropathic pain. Metabolic syndrome and its components increase neuropathy risk. Diet and exercise have shown promise but are limited by poor adherence. Objective: To determine whether topiramate can slow decline in intraepidermal nerve fiber density (IENFD) and/or neuropathy-specific quality of life measured using the Norfolk Quality of Life-Diabetic Neuropathy (NQOL-DN) scale. Design, Setting, and Participants: Topiramate as a Disease-Modifying Therapy for CSPN (TopCSPN) was a double-blind, placebo-controlled, randomized clinical trial conducted between February 2018 and October 2021. TopCSPN was performed at 20 sites in the National Institutes of Health-funded Network for Excellence in Neurosciences Clinical Trials (NeuroNEXT). Individuals with CSPN and metabolic syndrome aged 18 to 80 years were screened and randomly assigned by body mass index (<30 vs ≥30), which is calculated as weight in kilograms divided by height in meters squared. Patients were excluded if they had poorly controlled diabetes, prior topiramate treatment, recurrent nephrolithiasis, type 1 diabetes, use of insulin within 3 months before screening, history of foot ulceration, planned bariatric surgery, history of alcohol or drug overuse in the 2 years before screening, family history of a hereditary neuropathy, or an alternative neuropathy cause. Interventions: Participants received topiramate or matched placebo titrated to a maximum-tolerated dose of 100 mg per day. Main Outcomes and Measures: IENFD and NQOL-DN score were co-primary outcome measures. A positive study was defined as efficacy in both or efficacy in one and noninferiority in the other. Results: A total of 211 individuals were screened, and 132 were randomly assigned to treatment groups: 66 in the topiramate group and 66 in the placebo group. Age and sex were similar between groups (topiramate: mean [SD] age, 61 (10) years; 38 male [58%]; placebo: mean [SD] age, 62 (11) years; 44 male [67%]). The difference in change in IENFD and NQOL-DN score was noninferior but not superior in the intention-to-treat (ITT) analysis (IENFD, 0.21 fibers/mm per year; 95% CI, -0.43 to ∞ fibers/mm per year and NQOL-DN score, -1.52 points per year; 95% CI, -∞ to 1.19 points per year). A per-protocol analysis excluding noncompliant participants based on serum topiramate levels and those with major protocol deviations demonstrated superiority in NQOL-DN score (-3.69 points per year; 95% CI, -∞ to -0.73 points per year). Patients treated with topiramate had a mean (SD) annual change in IENFD of 0.56 fibers/mm per year relative to placebo (95% CI, -0.21 to ∞ fibers/mm per year). Although IENFD was stable in the topiramate group compared with a decline consistent with expected natural history, this difference did not demonstrate superiority. Conclusion and Relevance: Topiramate did not slow IENFD decline or affect NQOL-DN score in the primary ITT analysis. Some participants were intolerant of topiramate. NQOL-DN score was superior among those compliant based on serum levels and without major protocol deviations. Trial Registration: ClinicalTrials.gov Identifier: NCT02878798.

Prospective biomarker study in newly diagnosed glioblastoma: Cyto-C clinical trial.

BACKGROUND: Glioblastoma (GBM) has a 5-year survival rate of 3%-5%. GBM treatment includes maximal resection followed by radiotherapy with concomitant and adjuvant temozolomide (TMZ). Cytochrome C oxidase (CcO) is a mitochondrial enzyme involved in the mechanism of resistance to TMZ. In a prior retrospective trial, CcO activity in GBMs inversely correlated with clinical outcome. The current Cyto-C study was designed to prospectively evaluate and validate the prognostic value of tumor CcO activity in patients with newly diagnosed primary GBM, and compared to the known prognostic value of MGMT promoter methylation status. METHODS: This multi-institutional, blinded, prospective biomarker study enrolled 152 patients with newly diagnosed GBM who were to undergo surgical resection and would be candidates for standard of care. The primary end point was overall survival (OS) time, and the secondary end point was progression-free survival (PFS) time. Tumor CcO activity and MGMT promoter methylation status were assayed in a centralized laboratory. RESULTS: OS and PFS did not differ by high or low tumor CcO activity, and the prognostic validity of MGMT promoter methylation was confirmed. Notably, a planned exploratory analysis suggested that the combination of low CcO activity and MGMT promoter methylation in tumors may be predictive of long-term survival. CONCLUSIONS: Tumor CcO activity alone was not confirmed as a prognostic marker in GBM patients. However, the combination of low CcO activity and methylated MGMT promoter may reveal a subgroup of GBM patients with improved long-term survival that warrants further evaluation. Our work also demonstrates the importance of performing large, multi-institutional, prospective studies to validate biomarkers. We also discuss lessons learned in assembling such studies.

Why Ecological Momentary Assessment Surveys Go Incomplete: When It Happens and How It Impacts Data.

BACKGROUND: Ecological momentary assessment (EMA) often requires respondents to complete surveys in the moment to report real-time experiences. Because EMA may seem disruptive or intrusive, respondents may not complete surveys as directed in certain circumstances. PURPOSE: This article aims to determine the effect of environmental characteristics on the likelihood of instances where respondents do not complete EMA surveys (referred to as survey incompletion), and to estimate the impact of survey incompletion on EMA self-report data. RESEARCH DESIGN: An observational study. STUDY SAMPLE: Ten adults hearing aid (HA) users. DATA COLLECTION AND ANALYSIS: Experienced, bilateral HA users were recruited and fit with study HAs. The study HAs were equipped with real-time data loggers, an algorithm that logged the data generated by HAs (e.g., overall sound level, environment classification, and feature status including microphone mode and amount of gain reduction). The study HAs were also connected via Bluetooth to a smartphone app, which collected the real-time data logging data as well as presented the participants with EMA surveys about their listening environments and experiences. The participants were sent out to wear the HAs and complete surveys for 1 week. Real-time data logging was triggered when participants completed surveys and when participants ignored or snoozed surveys. Data logging data were used to estimate the effect of environmental characteristics on the likelihood of survey incompletion, and to predict participants' responses to survey questions in the instances of survey incompletion. RESULTS: Across the 10 participants, 715 surveys were completed and survey incompletion occurred 228 times. Mixed effects logistic regression models indicated that survey incompletion was more likely to happen in the environments that were less quiet and contained more speech, noise, and machine sounds, and in the environments wherein directional microphones and noise reduction algorithms were enabled. The results of survey response prediction further indicated that the participants could have reported more challenging environments and more listening difficulty in the instances of survey incompletion. However, the difference in the distribution of survey responses between the observed responses and the combined observed and predicted responses was small. CONCLUSION: The present study indicates that EMA survey incompletion occurs systematically. Although survey incompletion could bias EMA self-report data, the impact is likely to be small.

Comparison of In-Situ and Retrospective Self-Reports on Assessing Hearing Aid Outcomes.

BACKGROUND: Ecological momentary assessment (EMA) is a methodology involving repeated surveys to collect in-situ self-reports that describe respondents' current or recent experiences. Audiology literature comparing in-situ and retrospective self-reports is scarce. PURPOSE: To compare the sensitivity of in-situ and retrospective self-reports in detecting the outcome difference between hearing aid technologies, and to determine the association between in-situ and retrospective self-reports. RESEARCH DESIGN: An observational study. STUDY SAMPLE: Thirty-nine older adults with hearing loss. DATA COLLECTION AND ANALYSIS: The study was part of a larger clinical trial that compared the outcomes of a prototype hearing aid (denoted as HA1) and a commercially available device (HA2). In each trial condition, participants wore hearing aids for 4 weeks. Outcomes were measured using EMA and retrospective questionnaires. To ensure that the outcome data could be directly compared, the Glasgow Hearing Aid Benefit Profile was administered as an in-situ self-report (denoted as EMA-GHABP) and as a retrospective questionnaire (retro-GHABP). Linear mixed models were used to determine if the EMA- and retro-GHABP could detect the outcome difference between HA1 and HA2. Correlation analyses were used to examine the association between EMA- and retro-GHABP. RESULTS: For the EMA-GHABP, HA2 had significantly higher (better) scores than HA1 in the GHABP subscales of benefit, residual disability, and satisfaction (p = 0.029-0.0015). In contrast, the difference in the retro-GHABP score between HA1 and HA2 was significant only in the satisfaction subscale (p = 0.0004). The correlations between the EMA- and retro-GHABP were significant in all subscales (p = 0.0004 to <0.0001). The strength of the association ranged from weak to moderate (r = 0.28-0.58). Finally, the exit interview indicated that 29 participants (74.4%) preferred HA2 over HA1. CONCLUSION: The study suggests that in-situ self-reports collected using EMA could have a higher sensitivity than retrospective questionnaires. Therefore, EMA is worth considering in clinical trials that aim to compare the outcomes of different hearing aid technologies. The weak to moderate association between in-situ and retrospective self-reports suggests that these two types of measures assess different aspects of hearing aid outcomes.