Effect Size of Rituximab on Pulmonary Function in the Treatment of Connective-Tissue Disease-Related Interstitial Lung Disease: A Systematic Review and Meta-Analysis

BACKGROUND: Rituximab (RTX) has been previously reported as directed treatment in patients with connective-tissue disease-related interstitial lung diseases (CTD-ILD). A systematic assessment of treatment effect size on pulmonary function outcomes and related adverse effects in patients with CTD-ILD has not been previously reported.METHODS: We performed a systematic review and meta-analysis of published reports from PubMed, Embase, and Cochrane Libraries. Randomized and non-randomized controlled trials, case-control, cohort, and case series (with five or more cases) containing individual pulmonary function data and adverse effects were included. Study endpoints were pre and post treatment change in percent predicted forced vital capacity (FVC %) and diffusion capacity for carbon monoxide (DLCO%), along with reported drug-related adverse events. RESULTS: Twenty studies totaling 411 patients were identified with 14 included in the meta-analysis of pulmonary function and six in the descriptive review. Random effects meta-analysis of pre and post-treatment pulmonary function findings demonstrated increases in FVC% (n =296) (mean difference (MD) 4.57%, [95% CI 2.63-6.51]) and DLCO% (n = 246) (MD 5.0% [95% CI 2.71-7.29]) after RTX treatment. RTX treatment-related adverse effects were reported in 13.6% of the pooled cohort. CONCLUSIONS: A systematic assessment of post-treatment effect size suggests a potential role for RTX in stabilizing or improving lung function in patients with CTD-ILD, with a modest but not insignificant adverse effect profile.

Increasing Precision without Altering Treatment Effects: Repeated Measures Designs in Survey Experiments

The use of survey experiments has surged in political science. The most common design is the between-subjects design in which the outcome is only measured posttreatment. This design relies heavily on recruiting a large number of subjects to precisely estimate treatment effects. Alternative designs that involve repeated measurements of the dependent variable promise greater precision, but they are rarely used out of fears that these designs will yield different results than a standard design (e.g., due to consistency pressures). Across six studies, we assess this conventional wisdom by testing experimental designs against each other. Contrary to common fears, repeated measures designs tend to yield the same results as more common designs while substantially increasing precision. These designs also offer new insights into treatment effect size and heterogeneity. We conclude by encouraging researchers to adopt repeated measures designs and providing guidelines for when and how to use them.

Repeatability and sensitivity to change of non-invasive end points in PAH: the RESPIRE study

End points that are repeatable and sensitive to change are important in pulmonary arterial hypertension (PAH) for clinical practice and trials of new therapies. In 42 patients with PAH, test–retest repeatability was assessed using the intraclass correlation coefficient and treatment effect size using Cohen’s d statistic. Intraclass correlation coefficients demonstrated excellent repeatability for MRI, 6 min walk test and log to base 10 N-terminal pro-brain natriuretic peptide (log10NT-proBNP). The treatment effect size for MRI-derived right ventricular ejection fraction was large (Cohen’s d 0.81), whereas the effect size for the 6 min walk test (Cohen’s d 0.22) and log10NT-proBNP (Cohen’s d 0.20) were fair. This study supports further evaluation of MRI as a non-invasive end point for clinical assessment and PAH therapy trials.Trial registration number NCT03841344.

How Much Value Would a Treatment for Alzheimer’s Disease Offer? Cost-Effectiveness Thresholds for Pricing a Disease-Modifying Therapy

Background:: Recent trials suggest that disease-modifying therapy (DMT) for Alzheimer’s disease may become available soon. With the expected high price and a large patient pool, the budget impact will be substantial. Objective: We explore combinations of effectiveness and price under which a DMT is cost-effective. Method: We used an open-source model to conduct two-way scenario analyses for both payer and societal perspectives, varying price, and treatment effect size simultaneously. The analysis generates cost-effectiveness threshold prices over a potential range of DMT effectiveness in patients aged 65+ with mild cognitive impairment due to Alzheimer’s disease in the US. Results: Under the willingness-to-pay a threshold of $150,000 per quality-adjusted life year and assuming 30% risk reduction relative to the standard of care, the maximum cost-effective price of a DMT per patient per year is ~$22,000 and ~$15,000 from societal and payer perspectives, respectively. Conclusion: Joint variation of price and treatment effect size can help assess the cost-effectiveness of a potential Alzheimer’s disease treatment.

Predictors of Treatment Response for Preschool Children With Developmental Language Disorder

Purpose Enhanced Conversational Recast treatment is an effective intervention for remediating expressive grammatical deficits in preschool-age children with developmental language disorder, but not all children respond equally well. In this study, we sought to identify which child-level variables predict response to treatment of morphological deficits. Method Predictor variables of interest, including pre-intervention test scores and target morpheme production, age, and mother's level of education (proxy for socio-economic status) were included in analyses. The sample included 105 children ( M = 5;1 [years;months]) with developmental language disorder who participated in 5 weeks of daily Enhanced Conversational Recast treatment. Classification and regression tree analysis was used to identify covariates that predicted children's generalization of their trained grammatical morpheme, as measured by treatment effect size d . Results Our analysis indicates that the Structured Photographic Expressive Language Test–Preschool 2 (SPELT-P 2) scores and the Peabody Picture Vocabulary Test–Fourth Edition scores significantly predicted the degree of benefit a child derived from Enhanced Conversational Recast treatment. Specifically, a SPELT-P 2 score above 75 (but still in the impaired range, < 87) combined with a high Peabody Picture Vocabulary Test–Fourth Edition score (> 100) yielded the largest treatment effect size, whereas a SPELT-P 2 score below 75 predicted the smallest treatment effect size. Other variables included in the model did not significantly predict treatment outcomes. Conclusions Understanding individual differences in response to treatment will allow service providers to make evidence-based decisions regarding how likely a child is to benefit from Enhanced Conversational Recast treatment and the expected magnitude of the response based on the child's background characteristics.

Phase I trial of caudate deep brain stimulation for treatment-resistant tinnitus

OBJECTIVEThe objective of this open-label, nonrandomized trial was to evaluate the efficacy and safety of bilateral caudate nucleus deep brain stimulation (DBS) for treatment-resistant tinnitus.METHODSSix participants underwent DBS electrode implantation. One participant was removed from the study for suicidality unrelated to brain stimulation. Participants underwent a stimulation optimization period that ranged from 5 to 13 months, during which the most promising stimulation parameters for tinnitus reduction for each individual were determined. These individual optimal stimulation parameters were then used during 24 weeks of continuous caudate stimulation to reach the endpoint. The primary outcome for efficacy was the Tinnitus Functional Index (TFI), and executive function (EF) safety was a composite z-score from multiple neuropsychological tests (EF score). The secondary outcome for efficacy was the Tinnitus Handicap Inventory (THI); for neuropsychiatric safety it was the Frontal Systems Behavior Scale (FrSBe), and for hearing safety it was pure tone audiometry at 0.5, 1, 2, 3, 4, and 6 kHz and word recognition score (WRS). Other monitored outcomes included surgery- and device-related adverse events (AEs). Five participants provided full analyzable data sets. Primary and secondary outcomes were based on differences in measurements between baseline and endpoint.RESULTSThe treatment effect size of caudate DBS for tinnitus was assessed by TFI [mean (SE), 23.3 (12.4)] and THI [30.8 (10.4)] scores, both of which were statistically significant (Wilcoxon signed-rank test, 1-tailed; alpha = 0.05). Based on clinically significant treatment response categorical analysis, there were 3 responders determined by TFI (≥ 13-point decrease) and 4 by THI (≥ 20-point decrease) scores. Safety outcomes according to EF score, FrSBe, audiometric thresholds, and WRS showed no significant change with continuous caudate stimulation. Surgery-related and device-related AEs were expected, transient, and reversible. There was only one serious AE, a suicide attempt unrelated to caudate neuromodulation in a participant in whom stimulation was in the off mode for 2 months prior to the event.CONCLUSIONSBilateral caudate nucleus neuromodulation by DBS for severe, refractory tinnitus in this phase I trial showed very encouraging results. Primary and secondary outcomes revealed a highly variable treatment effect size and 60%–80% treatment response rate for clinically significant benefit, and no safety concerns. The design of a phase II trial may benefit from targeting refinement for final DBS lead placement to decrease the duration of the stimulation optimization period and to increase treatment effect size uniformity.Clinical trial registration no.: NCT01988688 (clinicaltrials.gov).