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We are appreciative of the many useful comments of the discussants, particularly with regard to additional important areas for methodological research. Most of these comments stand on their own, requiring [...]

Background: Despite adolescents and young adults being the most frequent users of cannabis, all information on cannabis drug testing interpretation is based on data from adults.Aims: This study aimed to define the time course of urinary 11-nor-9-carboxy-tetrahydrocannabinol (THCCOOH) excretion among 70 adolescent and young adult cannabis users during 1 month of biochemically-verified cannabis abstinence.Methods: Urine specimens were collected at non-abstinent baseline and after 2, 3, 8, 15, 21 and 28 days of abstinence. Specimens were tested for THCCOOH with a 'rapid' immunoassay drug test and a confirmatory assay using liquid chromatography-tandem mass spectrometry, with a 5 ng/mL limit of quantitation. Elimination rate was tested using a population pharmacokinetics model.Results/outcomes: Participants had an average of 26 days of abstinence (SD = 6). Initial creatinine-adjusted THCCOOH concentration (CN-THCCOOH) was 148 ng/mg (SD = 157). Half-life was 2 days (SD = 5), with a 10-day window of detection (estimated range: 4-80 days). At the final timepoint and among those with > 25 days of abstinence (n = 62), 40% (n = 25) had THCCOOH concentrations > 5 ng/mL (i.e. detectable on confirmatory assay) and 19% (n = 12) were 'positive' per federal drug testing guidelines (i.e. values greater than 50 ng/mL on the screening immunoassay and 15 ng/mL on the confirmatory assay). More frequent past month cannabis use was associated with higher baseline CN-THCCOOH concentrations, but not with rate of elimination. Nested five-fold cross-validation suggested high model reliability and predictive validity.Conclusions/interpretation: Findings underscore that, as with adults, detectable cannabinoid metabolites do not necessarily indicate recent use in adolescents and young adults. Algorithms that account for THCCOOH levels, assessed longitudinally and time between specimen collections are best equipped to confirm abstinence.Clinical Trial Registration: NCT03276221; https://clinicaltrials.gov/ct2/show/NCT03276221?term=Randi+Schuster&rank=1. [ABSTRACT FROM AUTHOR]

Objective: To conduct a phase-II trial using a ranking and selection paradigm where multiple treatments are compared with limited sample size and the best is chosen for a subsequent efficacy trial versus placebo. This strategy can find an effective treatment faster than traditional strategy of conducting larger trials against placebo. Methods: Sixty amyotrophic lateral sclerosis (ALS) participants were randomized 1:1:1 to creatine 30 g/day (CRE), tamoxifen 40 mg/day (T40), or tamoxifen 80 mg/day (T80), with matching placebo. The primary outcome was 38-week change in ALS Functional Rating Scale-Revised (ALSFRS-R), analyzed in a repeated-measures ANOVA. Secondary outcomes included slow vital capacity (SVC), quantitative muscle strength, early drug discontinuation (EDD), adverse events (AEs), and survival. Results: CRE participants experienced higher rates of drug-related AEs (82% vs. 43% T40, 47% T80) and EDD (50% vs. 24% T40, 29% T80). T80 participants experienced slower adjusted mean decline in ALSFRS-R in points/month (–0.80 vs. –0.84 T40, –0.85 CRE) and quantitative muscle strength but not in SVC and higher rates of mortality. Conclusion: Efficacy of T80 ranked numerically superior to CRE and T40 with respect to ALSFRS-R decline. Following the selection paradigm, T80 would be chosen to test against placebo. The approach was not designed to distinguish among treatments that are nearly equally effective or ineffective. If treatments are equivalent, then under the paradigm, it does not matter which treatment is selected. Newer approaches for increasing trial efficiency, including an adaptive platform trial design, may mitigate limitations of the selection design. [ABSTRACT FROM AUTHOR]

Objective: Linking emergency medical services (EMS) electronic patient care reports (ePCRs) to emergency department (ED) records can provide clinicians access to vital information that can alter management. It can also create rich databases for research and quality improvement. Unfortunately, previous attempts at ePCR and ED record linkage have had limited success. In this study, we use supervised machine learning to derive and validate an automated record linkage algorithm between EMS ePCRs and ED records.Materials and Methods: All consecutive ePCRs from a single EMS provider between June 2013 and June 2015 were included. A primary reviewer matched ePCRs to a list of ED patients to create a gold standard. Age, gender, last name, first name, social security number, and date of birth were extracted. Data were randomly split into 80% training and 20% test datasets. We derived missing indicators, identical indicators, edit distances, and percent differences. A multivariate logistic regression model was trained using 5-fold cross-validation, using label k-fold, L2 regularization, and class reweighting.Results: A total of 14 032 ePCRs were included in the study. Interrater reliability between the primary and secondary reviewer had a kappa of 0.9. The algorithm had a sensitivity of 99.4%, a positive predictive value of 99.9%, and an area under the receiver-operating characteristic curve of 0.99 in both the training and test datasets. Date-of-birth match had the highest odds ratio of 16.9, followed by last name match (10.6). Social security number match had an odds ratio of 3.8.Conclusions: We were able to successfully derive and validate a record linkage algorithm from a single EMS ePCR provider to our hospital EMR. [ABSTRACT FROM AUTHOR]

Background/Aims: For single arm trials, a treatment is evaluated by comparing an outcome estimate to historically reported outcome estimates. Such a historically controlled trial is often analyzed as if the estimates from previous trials were known without variation and there is no trial-to-trial variation in their estimands. We develop a test of treatment efficacy and sample size calculation for historically controlled trials that considers these sources of variation. Methods: We fit a Bayesian hierarchical model, providing a sample from the posterior predictive distribution of the outcome estimand of a new trial, which, along with the standard error of the estimate, can be used to calculate the probability that the estimate exceeds a threshold. We then calculate criteria for statistical significance as a function of the standard error of the new trial and calculate sample size as a function of difference to be detected. We apply these methods to clinical trials for amyotrophic lateral sclerosis using data from the placebo groups of 16 trials. Results: We find that when attempting to detect the small to moderate effect sizes usually assumed in amyotrophic lateral sclerosis clinical trials, historically controlled trials would require a greater total number of patients than concurrently controlled trials, and only when an effect size is extraordinarily large is a historically controlled trial a reasonable alternative. We also show that utilizing patient level data for the prognostic covariates can reduce the sample size required for a historically controlled trial. Conclusion: This article quantifies when historically controlled trials would not provide any sample size advantage, despite dispensing with a control group. [ABSTRACT FROM AUTHOR]

Introduction: RNS60 is a novel immune-modulatory agent that has shown neuroprotective effects in amytrophic lateral sclerosis (ALS) preclinical models. RNS60 is administered by weekly intravenous infusion and daily nebulization. The objective of this pilot open-label trial was to test the feasibility, safety, and tolerability of long-term RNS60 administration in ALS patients.Methods: The planned treatment duration was 23 weeks and the primary outcomes were safety and tolerability. Secondary outcomes included PBR28 positron emission tomography (PET) imaging and plasma biomarkers of inflammation.Results: Sixteen participants with ALS received RNS60 and 13 (81%) completed 23 weeks of RNS60 treatment. There were no serious adverse events and no participants withdrew from the trial due to drug-related adverse events. There were no significant changes in the biomarkers.Discussion: Long-term RNS60 administration was safe and well-tolerated. A large, multicenter, phase II trial of RNS60 is currently enrolling participants to test the effects of RNS60 on ALS biomarkers and disease progression. Muscle Nerve 59:303-308, 2019. [ABSTRACT FROM AUTHOR]

Clinical trials are often designed to compare treatments on the basis of multiple outcomes. For the analysis of the treatment comparison from such a trial, in 1999, the Finkelstein-Schoenfeld test was proposed, which was a generalization of the Gehan-Wilcoxon test based on pairwise comparison of patients on a primary outcome when possible but otherwise on a secondary outcome. In 2012, Pocock and colleagues suggested an estimate based on this concept, the Win Ratio, which summarized the ratio of the number of patients who fared better versus worse on the experimental arm. However, in 2016, Oakes noted that the Win Ratio could be a function of the distribution of follow-up times of the trial. The aim of this paper is to propose an approach to representing the Win Ratio graphically in such a way that the effect of time on the estimate would be apparent. In addition, the methods are used to display the contribution of each endpoint to the composite. We apply the methods to clinical trials in cancer, cardiology, and neurology. Software is available named winRatioAnalysis in CRAN. [ABSTRACT FROM AUTHOR]

Objective: Evaluate the safety and tolerability of resistance and endurance exercise in ALS participants as measured by their ability to complete this six-month study. Methods: Participants were randomized to Resistance, Endurance, or Stretching/Range of Motion (SROM the exercise regimen prescribed for most ALS patients) exercises. All exercises were performed at home with an individualized regimen designed by a physical therapist trained in ALS management. Primary outcome measures were tolerability of the exercises at 24 weeks defined by 50% of participants completing at least 50% of the prescribed exercise regimen. Secondary outcome measures included the ALSFRS-R, pulmonary FVC, and other measures of ALS function. Results: At 12 and 24 weeks, all three exercise regimens were tolerated according to our pre-specified criteria. Compliance to the prescribed exercise regimen was the highest in the resistance and SROM arms of the study. All three forms of exercise were considered safe as there were no differences in the rates of disease progression among groups. There were no differences in the secondary outcome measures and feasibility for evaluating these measures was successful. In a post-hoc analysis, there was a trend towards fewer falls in the Resistance and Endurance groups. Conclusions: This study demonstrates that SROM, resistance, and endurance exercise are all safe to be performed with the specified regimen without any worsening of outcomes as related to ALS function. All three forms of exercise were tolerated with resistance and SROM exercises showing the highest compliance over the 24 week-period. [ABSTRACT FROM AUTHOR]

Introduction: Urate has been identified as a predictor of amyotrophic lateral sclerosis (ALS) survival in some but not all studies. Here we leverage the recent expansion of the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database to study the association between urate levels and ALS survival.Methods: Pooled data of 1,736 ALS participants from the PRO-ACT database were analyzed. Cox proportional hazards regression models were used to evaluate associations between urate levels at trial entry and survival.Results: After adjustment for potential confounders (i.e., creatinine and body mass index), there was an 11% reduction in risk of reaching a survival endpoint during the study with each 1-mg/dL increase in uric acid levels (adjusted hazard ratio 0.89, 95% confidence interval 0.82-0.97, P < 0.01).Discussion: Our pooled analysis provides further support for urate as a prognostic factor for survival in ALS and confirms the utility of the PRO-ACT database as a powerful resource for ALS epidemiological research. Muscle Nerve 57: 430-434, 2018. [ABSTRACT FROM AUTHOR]

Background Cytokine-based drugs are currently being explored as alternative cancer immunotherapies. While the cytokine interleukin-18 (IL-18) has immunostimulatory effects, it is negatively regulated by a secreted high-affinity binding protein, IL-18BP, that functions as an immune checkpoint that limits IL-18's efficacy as a cancer therapeutic. A modified version of IL-18, termed "decoy-resistant" or DR-18, that can avoid trapping by IL-18BP while still maintaining its immune signaling potential, has recently been developed. DR-18 has shown promising preclinical activity in melanoma and colorectal murine models, including potential synergy with anti-PD-1 therapy, and is currently in Phase I trials. In this study, we aim to test the efficacy and determine the cellular mechanism of action of DR-18 in combination with immune checkpoint inhibitors (ICIs) in immunocompetent preclinical models of renal cell carcinoma (RCC), with the goal of establishing the basis for testing these combinations in early phase clinical trials. Methods We engrafted tumors subcutaneously using two different syngeneic, immunocompetent murine RCC models: Renca and RAG. Mice were treated with single-agent DR-18 and combinations of DR-18 with single- and dual-agent anti-PD-1 and anti-CTLA-4. Tumor growth and survival were monitored. In the Renca model, plasma was collected at early time-points and cytokine/chemokine levels were profiled using a 31-plex discovery assay. Single-cell RNA and TCR sequencing was also performed on Renca tumors. Additionally, immune cell depletion studies were conducted in the Renca model with antibodies targeting CD8, CD4, NK cells, and interferon-gamma. Results In the Renca model, DR-18 monotherapy modestly inhibited tumor growth and prolonged survival. The effects were comparable to single- and dual-agent ICIs. Adding PD-1 blockade to DR-18 did not enhance efficacy whereas the addition of anti-CTLA-4 to DR-18 significantly increased anti-tumor effects. Triple-therapy (DR-18 plus anti-PD-1 plus anti-CTLA-4) did not further inhibit tumor growth or prolong survival compared to the doublet (DR-18 plus anti-CTLA-4). The RAG model was more sensitive to ICIs but produced similar results, again showing modest anti-tumor activity of single-agent DR-18 and enhanced benefit of combining with anti-CTLA-4 but not anti-PD-1. Cytokine/chemokine profiling revealed significantly elevated levels of IP-10 (CXCL10) and MIG (CXCL9) after one cycle of DR-18 plus anti-CTLA-4 compared to control and single-agent treatments, suggesting that these chemokines may be key early mediators of the anti-tumor immune response. Single-cell transcriptomic analysis demonstrated changes in intra-tumoral T cell, macrophage, and granulocyte populations with DR-18 plus anti-CTLA-4 relative to other regimens, including enrichment of CD8+ precursor and terminally exhausted T cells and a neutrophil population associated with interferon signaling. Additionally, single-cell TCR analysis showed a reduction in intra-tumoral clonotype diversity with DR-18 plus anti-CTLA-4 compared to other treatments. Immune cell depletion studies identified CD8+ T cells, NK cells, and interferon-gamma, but not CD4+ T cells, as equally required for efficacy of DR-18 plus anti-CTLA-4. Conclusions In this study, we identify DR-18, an IL-18-based drug engineered with resistance to a secreted decoy-receptor protein, in combination with anti-CTLA-4 as having enhanced anti-tumor activity in preclinical models of RCC. This regimen was associated with a more pro-inflammatory immune microenvironment. Further investigation is ongoing to elucidate the cellular mechanism of action of this regimen more fully and lay the groundwork for clinical testing of DR-18-based combination therapy in RCC. In the future, testing novel partner agents outside of anti-PD-1/CTLA-4 and using RCC models of ICI-resistance could be particularly informative and clinically relevant. [ABSTRACT FROM AUTHOR]