Impact of COVID-19 pandemic on nonpharmacological pain management trials in military and veteran healthcare settings: an evaluation informed by implementation science.

The coronavirus disease (COVID-19) pandemic disrupted healthcare and clinical research, including a suite of 11 pragmatic clinical trials (PCTs), across clinics within the Department of Veterans Affairs (VA) and the Department of Defense (DOD). These PCTs were designed to evaluate an array of nonpharmacological treatments and models of care for treatment of patients with pain and co-occurring conditions. The aims of the study are to (a) describe modifications to PCTs and interventions to address the evolving pandemic and (b) describe the application of implementation science methods for evaluation of those PCT modifications. The project used a two-phase, sequential, mixed-methods design. In Phase I, we captured PCT disruptions and modifications via a Research Electronic Data Capture questionnaire, using Periodic Reflections methods as a guide. In Phase II, we utilized the Framework for Reporting Adaptations and Modifications-Expanded (FRAME) taxonomy to develop a focus group interview guide and checklist that would provide more in-depth data than Phase I. Data were analyzed using directed content analysis. Phase I revealed that all PCTs made between two and six trial modifications. Phase II, FRAME-guided analyses showed that the key goals for modifying interventions were increasing treatment feasibility and decreasing patient exposure to COVID-19, while preserving intervention core elements. Context (format) modifications led eight PCTs to modify parts of the interventions for virtual delivery. Content modifications added elements to enhance patient safety; tailored interventions for virtual delivery (counseling, exercise, mindfulness); and modified interventions involving manual therapies. Implementation science methods identified near-real-time disruptions and modifications to PCTs focused on pain management in veteran and military healthcare settings.

Active-duty personnel and veterans often report pain and seek treatment in military and veteran healthcare settings. Nondrug treatments, such as self-care, counseling, exercise, and manual therapy, are recommended for most patients with chronic pain. The COVID-19 pandemic has affected clinical trials of these nondrug treatments in military and veteran populations. In this study, we explored how 11 research teams adapted study trials on pain to address COVID-19. Team members completed online questions, brief checklists, and a one-time focus group about how they modified their trials. Each of the 11 trials made 2 to 6 changes to their studies. Most paused or delayed recruitment efforts. Many shifted parts of the study to a virtual format. Goals for adapting treatments included improved feasibility and decreased patient exposure to COVID-19. Context or format changes increased virtual delivery of study treatments. Content changes focused on patient safety, tailoring treatments for virtual delivery, and offering varied manual therapies. Provider concerns about technology and patient willingness to seek in-person care during the pandemic also were factors driving changes. These findings may support the increased use of virtual care for pain management in military and veteran health settings.

A Phase 2 Randomized, Double-Blind, Placebo-controlled Trial of Oral Camostat Mesylate for Early Treatment of COVID-19 Outpatients Showed Shorter Illness Course and Attenuation of Loss of Smell and Taste.

Importance: Early treatment of mild SARS-CoV-2 infection might lower the risk of clinical deterioration in COVID-19. Objective: To determine whether oral camostat mesylate would reduce upper respiratory SARS-CoV-2 viral load in newly diagnosed outpatients with mild COVID-19, and would lead to improvement in COVID-19 symptoms. Design: From June, 2020 to April, 2021, we conducted a randomized, double-blind, placebo-controlled phase 2 trial. Setting: Single site, academic medical center, outpatient setting in Connecticut, USA. Participants: Of 568 COVID-19 positive potential adult participants diagnosed within 3 days of study entry and assessed for eligibility, 70 were randomized and 498 were excluded (198 did not meet eligibility criteria, 37 were not interested, 265 were excluded for unknown or other reasons). The primary inclusion criteria were a positive SARS-CoV-2 nucleic acid amplification result in adults within 3 days of screening regardless of COVID-19 symptoms. Intervention: Treatment was 7 days of oral camostat mesylate, 200 mg po four times a day, or placebo. Main Outcomes and Measures: The primary outcome was reduction of 4-day log10 nasopharyngeal swab viral load by 0.5 log10 compared to placebo. The main prespecified secondary outcome was reduction in symptom scores as measured by a quantitative Likert scale instrument, Flu-PRO-Plus modified to measure changes in smell/taste measured using FLU-PRO-Plus. Results: Participants receiving camostat had statistically significant lower quantitative symptom scores (FLU-Pro-Plus) at day 6, accelerated overall symptom resolution and notably improved taste/smell, and fatigue beginning at onset of intervention in the camostat mesylate group compared to placebo. Intention-to-treat analysis demonstrated that camostat mesylate was not associated with a reduction in 4-day log10 NP viral load compared to placebo. Conclusions and relevance: The camostat group had more rapid resolution of COVID-19 symptoms and amelioration of the loss of taste and smell. Camostat compared to placebo was not associated with reduction in nasopharyngeal SARS-COV-2 viral load. Additional clinical trials are warranted to validate the role of camostat mesylate on SARS-CoV-2 infection in the treatment of mild COVID-19. Trial registration: Clinicaltrials.gov, NCT04353284 (04/20/20)(https://clinicaltrials.gov/ct2/show/NCT04353284?term=camostat+%2C+yale&draw=2&rank=1).

Optimizing the Impact of Pragmatic Clinical Trials for Veteran and Military Populations: Lessons From the Pain Management Collaboratory.

Pragmatic clinical trials (PCTs) are well-suited to address unmet healthcare needs, such as those arising from the dual public health crises of chronic pain and opioid misuse, recently exacerbated by the COVID-19 pandemic. These overlapping epidemics have complex, multifactorial etiologies, and PCTs can be used to investigate the effectiveness of integrated therapies that are currently available but underused. Yet individual pragmatic studies can be limited in their reach because of existing structural and cultural barriers to dissemination and implementation. The National Institutes of Health, Department of Defense, and Department of Veterans Affairs formed an interagency research partnership, the Pain Management Collaboratory. The partnership combines pragmatic trial design with collaborative tools and relationship building within a large network to advance the science and impact of nonpharmacological approaches and integrated models of care for the management of pain and common co-occurring conditions. The Pain Management Collaboratory team supports 11 large-scale, multisite PCTs in veteran and military health systems with a focus on team science with the shared aim that the "whole is greater than the sum of the parts." Herein, we describe this integrated approach and lessons learned, including incentivizing all parties; proactively offering frequent opportunities for problem-solving; engaging stakeholders during all stages of research; and navigating competing research priorities. We also articulate several specific strategies and their practical implications for advancing pain management in active clinical, "real-world," settings.

Stakeholder Engagement in Pragmatic Clinical Trials: Emphasizing Relationships to Improve Pain Management Delivery and Outcomes.

BACKGROUND: The NIH-DOD-VA Pain Management Collaboratory (PMC) supports 11 pragmatic clinical trials (PCTs) on nonpharmacological approaches to management of pain and co-occurring conditions in U.S. military and veteran health organizations. The Stakeholder Engagement Work Group is supported by a separately funded Coordinating Center and was formed with the goal of developing respectful and productive partnerships that will maximize the ability to generate trustworthy, internally valid findings directly relevant to veterans and military service members with pain, front-line primary care clinicians and health care teams, and health system leaders. The Stakeholder Engagement Work Group provides a forum to promote success of the PCTs in which principal investigators and/or their designees discuss various stakeholder engagement strategies, address challenges, and share experiences. Herein, we communicate features of meaningful stakeholder engagement in the design and implementation of pain management pragmatic trials, across the PMC. DESIGN: Our collective experiences suggest that an optimal stakeholder-engaged research project involves understanding the following: i) Who are research stakeholders in PMC trials? ii) How do investigators ensure that stakeholders represent the interests of a study's target treatment population, including individuals from underrepresented groups?, and iii) How can sustained stakeholder relationships help overcome implementation challenges over the course of a PCT? SUMMARY: Our experiences outline the role of stakeholders in pain research and may inform future pragmatic trial researchers regarding methods to engage stakeholders effectively.

Extended-Release Guanfacine Does Not Show a Large Effect on Tic Severity in Children with Chronic Tic Disorders.

OBJECTIVE: To evaluate the tolerability, safety, and preliminary efficacy of extended-release guanfacine in children with chronic tic disorders, including Tourette's disorder (collectively referred to as CTD). METHODS: This was a multisite, 8-week, randomized, double-blind, placebo-controlled trial. The primary outcome measure was the Yale Global Tic Severity Scale (YGTSS) total score. Key secondary outcomes included the Improvement item of Clinical Global Impressions-Improvement (CGI-I) scale and the Tic Symptom Self-report (TSSR). Adverse events were monitored at each visit. RESULTS: Thirty-four subjects (23 boys and 11 girls) of ages 6 to 17 years (mean = 11.1 ± 3.1) with CTD were randomly assigned to extended-release guanfacine (n = 16) or placebo (n = 18). At baseline, the mean YGTSS total score was 26.3 ± 6.6 for the guanfacine group versus 27.7 ± 8.7 for the placebo group. Within the guanfacine group (mean final daily dose of 2.6 ± 1.1 mg, n = 14), the mean YGTSS total score declined to 23.6 ± 6.42 [t(15) = 1.84, p = 0.08; effect size = 0.35]. The results were similar in the placebo group with a score of 24.7 ± 10.54 at week 8 [t(17) = 1.83, p = 0.08; effect size = 0.38]. There was no significant difference in the rate of positive response on the CGI-I between the guanfacine group and placebo (19% [3/16] vs. 22% [4/18], p = 1.0). The most common adverse events were fatigue, drowsiness, dry mouth, headache, and irritability. Two subjects in the guanfacine group discontinued early-one because of an adverse event (depressed mood) and one because of lack of efficacy; two subjects in the placebo group discontinued because of lack of efficacy. CONCLUSIONS: This pilot study did not confirm a clinically meaningful effect size within the guanfacine group. These results do not support the launch of a larger efficacy trial for tics in children and adolescents with CTD.

Moderators and predictors of response to behavior therapy for tics in Tourette syndrome.

OBJECTIVE: To examine moderators and predictors of response to behavior therapy for tics in children and adults with Tourette syndrome and chronic tic disorders. METHODS: Data from 2 10-week, multisite studies (1 in children and 1 in adults; total n = 248) comparing comprehensive behavioral intervention for tics (CBIT) to psychoeducation and supportive therapy (PST) were combined for moderator analyses. Participants (177 male, 71 female) had a mean age of 21.5 ± 13.9 years (range 9-69). Demographic and clinical characteristics, baseline tic-suppressing medication, and co-occurring psychiatric disorders were tested as potential moderators for CBIT vs PST or predictors of outcome regardless of treatment assignment. Main outcomes measures were the Yale Global Tic Severity Scale Total Tic score and the Clinical Global Impression-Improvement score assessed by masked evaluators. RESULTS: The presence of tic medication significantly moderated response to CBIT vs PST (p = 0.01). Participants showed tic reduction after CBIT regardless of tic medication status, but only participants receiving tic medication showed reduction of tics after PST. Co-occurring psychiatric disorders, age, sex, family functioning, tic characteristics, and treatment expectancy did not moderate response. Across both treatments, greater tic severity (p = 0.005) and positive participant expectancy (p = 0.01) predicted greater tic improvement. Anxiety disorders (p = 0.042) and premonitory urge severity (p = 0.005) predicted lower tic reduction. CONCLUSIONS: Presence of co-occurring attention-deficit/hyperactivity disorder, obsessive-compulsive disorder, or anxiety disorders did not moderate response to CBIT. Although participants on tic medication showed improvement after CBIT, the difference between CBIT and PST was greater for participants who were not on tic-suppressing medication. CLINICALTRIALSGOV IDENTIFIERS: The child and adult CBIT studies are listed on clinical trials.gov (NCT00218777 and NCT00231985, respectively). CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that CBIT is effective in reducing tic severity across subgroups of patients with chronic tic disorders, although the difference between treatments was smaller for participants on tic-suppressing medications, suggesting reduced efficacy in this subgroup.

Detecting a clinically meaningful change in tic severity in Tourette syndrome: a comparison of three methods.

OBJECTIVE: To compare three statistical strategies for classifying positive treatment response based on a dimensional measure (Yale Global Tic Severity Scale [YGTSS]) and a categorical measure (Clinical Global Impression-Improvement [CGI-I] scale). METHOD: Subjects (N=232; 69.4% male; ages 9-69years) with Tourette syndrome or chronic tic disorder participated in one of two 10-week, randomized controlled trials comparing behavioral treatment to supportive therapy. The YGTSS and CGI-I were rated by clinicians blind to treatment assignment. We examined the percent reduction in the YGTSS-Total Tic Score (TTS) against Much Improved or Very Much Improved on the CGI-I, computed a signal detection analysis (SDA) and built a mixture model to classify dimensional response based on the change in the YGTSS-TTS. RESULTS: A 25% decrease on the YGTSS-TTS predicted positive response on the CGI-I during the trial. The SDA showed that a 25% reduction in the YGTSS-TTS provided optimal sensitivity (87%) and specificity (84%) for predicting positive response. Using a mixture model without consideration of the CGI-I, the dimensional response was defined by 23% (or greater) reduction on the YGTSS-TTS. The odds ratio (OR) of positive response (OR=5.68, 95% CI=[2.99, 10.78]) on the CGI-I for behavioral intervention was greater than the dimensional response (OR=2.86, 95% CI=[1.65, 4.99]). CONCLUSION: A 25% reduction on the YGTSS-TTS is highly predictive of positive response by all three analytic methods. For trained raters, however, tic severity alone does not drive the classification of positive response. Clinicaltrials.gov identifiers: NCT00218777; NCT00231985.

Exploring the manifestations of anxiety in children with autism spectrum disorders.

This study explores the manifestation and measurement of anxiety symptoms in 415 children with ASDs on a 20-item, parent-rated, DSM-IV referenced anxiety scale. In both high and low-functioning children (IQ above vs. below 70), commonly endorsed items assessed restlessness, tension and sleep difficulties. Items requiring verbal expression of worry by the child were rarely endorsed. Higher anxiety was associated with functional language, IQ above 70 and higher scores on several other behavioral measures. Four underlying factors emerged: Generalized Anxiety, Separation Anxiety, Social Anxiety and Over-arousal. Our findings extend our understanding of anxiety across IQ in ASD and provide guidance for improving anxiety outcome measurement.

Altered immunoglobulin profiles in children with Tourette syndrome.

BACKGROUND: Post-infectious autoimmunity and immune deficiency have been implicated in the pathogenesis of Tourette syndrome (TS). We asked here whether B cell immunity of patients with TS differs from healthy subjects. METHODS: In two independent cross-sectional samples, we compared serum levels of IgG1, IgG2, IgG3, IgG4, IgM, IgA, and IgE in 21 patients with TS from Yale University (17 males, 4 females, 8-16 years) versus 21 healthy controls (13 males, 8 females, 7-17 years); and in 53 patients with TS from Groningen University (45 males, 8 females, 6-18 years) versus 53 healthy controls (22 males, 31 females, 6-18 years), respectively. We also investigated correlations between Ig concentrations and symptom severity. In 13 additional patients (9 males, 4 females, age range 9-14), we established Ig profiles at time points before, during, and after symptom exacerbations. RESULTS: IgG3 levels were significantly lower in Yale patients compared to healthy children (medians 0.28 versus 0.49 mg/ml, p=.04), while levels of IgG2, IgG4, and IgM in patients were lower at trend-level significance (p≤.10). Decreased IgG3 (medians 0.45 versus 0.52 mg/ml; p=.05) and IgM (medians 0.30 versus 0.38 mg/ml; p=.04) levels were replicated in the Groningen patients. Ig levels did not correlate with symptom severity. There was a trend-level elevation of IgG1 during symptom exacerbations (p=.09). CONCLUSION: These pilot data indicate that at least some patients with TS have decreased serum IgG3, and possibly also IgM levels, though only few subjects had fully expressed Ig immunodeficiency. Whether these changes are related to TS pathogenesis needs to be investigated.

Decreased numbers of regulatory T cells suggest impaired immune tolerance in children with tourette syndrome: a preliminary study.

BACKGROUND: Post-streptococcal autoimmune inflammation of basal ganglia was suggested to be an etiological factor in some cases of Tourette syndrome (TS). Since regulatory T (T reg) cells play a major role in preventing autoimmunity, we hypothesized that a defect in T reg cells may be present in children with TS. We also postulated that group A beta hemolytic streptococcal infections could promote autoimmune responses by releasing exotoxins (streptococcal pyrogenic exotoxins [SPE]). METHODS: We analyzed peripheral blood of TS patients and healthy age-matched control subjects by fluorescence-activated cell sorting (FACS) on multiple occasions and determined the numbers of CD4(+)CD25(+)CD69(-) T reg cells. Further, we quantified the number of CD4(+) and CD8(+) lymphocytes with regard to Vbeta chains to which SPEs are known to bind. RESULTS: A significant decrease in T reg cells was observed in patients with moderate to severe TS symptoms compared with healthy age-matched control children. A decrease in T reg cell number was also noted during symptom exacerbations in five out of six patients. Further, we found a significant decrease in numbers of CD8(+)Vbeta18(+) T cells in moderate to severe TS patients. CONCLUSIONS: These data support our hypothesis that at least some TS patients may have a decreased capacity to inhibit autoreactive lymphocytes through a deficit in T reg cells. Interactions of host T cell immunity and microbial factors may also contribute to the pathogenesis of TS.

Adulthood outcome of tic and obsessive-compulsive symptom severity in children with Tourette syndrome.

BACKGROUND: Tourette syndrome (TS) is a childhood-onset neuropsychiatric disorder that is characterized by both motor and phonic tics. One half to two thirds of children with TS experience a reduction or complete resolution of tic symptoms during adolescence. At least one third of adults with TS have comorbid obsessive-compulsive disorder (OCD). OBJECTIVES: To clarify the clinical course of tic and OCD symptoms in children with TS and determine if baseline clinical measurements in childhood are associated with future symptom severity in late adolescence and early adulthood. DESIGN: Prospective cohort study. SETTING: Yale Child Study Center tic and OCD outpatient specialty clinic. PARTICIPANTS: Forty-six children with TS who received a structured clinical evaluation prior to age 14 years. MAIN OUTCOME MEASURES: Expert-rated tic and OCD symptom severity at follow-up interview an average of 7.6 years later (range, 3.8-12.8 years). RESULTS: Eighty-five percent of subjects reported a reduction in tic symptoms during adolescence. Only increased tic severity in childhood was associated with increased tic severity at follow-up. The average age at worst-ever tic severity was 10.6 years. Forty-one percent of patients with TS reported at one time experiencing at least moderate OCD symptoms. Worst-ever OCD symptoms occurred approximately 2 years later than worst-ever tic symptoms. Increased childhood IQ was strongly associated with increased OCD severity at follow-up. CONCLUSION: Obsessive-compulsive disorder symptoms in children with TS became more severe at a later age and were more likely to persist than tic symptoms.

Adaptive, emotional, and family functioning of children with obsessive-compulsive disorder and comorbid attention deficit hyperactivity disorder.

OBJECTIVE: The purpose of the study was to examine adaptive, emotional, and family functioning in a well-characterized group of children and adolescents with obsessive-compulsive disorder (OCD) and to evaluate the influence of comorbid attention deficit hyperactivity disorder (ADHD) on the levels of impairment in various functional domains. METHOD: The study group included 287 children and adolescents (191 boys, 96 girls) ages 7-18 years. Fifty-six subjects had a diagnosis of OCD only, 43 had both OCD and ADHD, 95 had ADHD, and 93 were unaffected comparison children. Best estimate DSM-IV diagnoses were assigned on the basis of structured interviews and clinical ratings. The children's functioning was evaluated with a comprehensive battery of well-established, standardized measures, including the Vineland Adaptive Behavior Scales, parents' ratings of social and family functioning, and children's self-reports of emotional adjustment. RESULTS: The children with OCD only were more impaired than were unaffected comparison subjects in most areas of adaptive functioning and emotional adjustment. Children with OCD plus ADHD had additional difficulties in social functioning, school problems, and self-reported depression. Impairment in daily living skills, reduced number of activities, and self-reported anxiety were uniquely associated with the diagnosis of OCD. Family dysfunction was associated with ADHD but not with OCD. CONCLUSIONS: Children and adolescents with OCD are impaired in multiple domains of adaptive and emotional functioning. When comorbid ADHD is present, there is an additional burden on social, school, and family functioning.

Disruptive behavior in children with Tourette's syndrome: association with ADHD comorbidity, tic severity, and functional impairment.

OBJECTIVE: To examine the association of disruptive behavior with social, adaptive, and family functioning in Tourette's syndrome (TS) with and without comorbid attention-deficit/hyperactivity disorder (ADHD). METHOD: The sample included 207 children (144 boys and 63 girls) between the ages of 7 and 18 years. Forty-two children received a diagnosis of TS-only, 52 received a diagnosis of ADHD-only, 52 children had TS+ADHD, and there were 61 unaffected control children. Best-estimate DSM-IV diagnoses were assigned on the basis of structured interviews and clinical ratings. Dependent measures included parent and teacher ratings of disruptive behavior, parent ratings of social and family functioning, and the Vineland Adaptive Behavior Scales. RESULTS: Children with TS-only did not differ from unaffected controls on the parent ratings of aggression and delinquent behavior or on the teacher ratings of conduct problems. By contrast, children with TS+ADHD were rated significantly above unaffected controls and similar to children with ADHD-only on these indices of disruptive behavior. Hierarchical regression analyses revealed that aggression and delinquency scores added unique contributions to impairment in social and family functioning, controlling for age, gender, and diagnostic status. CONCLUSIONS: Comorbid ADHD is highly associated with disruptive behavior and functional impairment in children with TS. When disruptive behavior problems are present, there is an additional burden on children's social and family functioning.