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

ABSTRACT 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.

Incentives and payments in pragmatic clinical trials: Scientific, ethical, and policy considerations

Pragmatic clinical trials are increasingly used to generate knowledge about real-world clinical interventions. However, they involve some distinctive ethical and regulatory challenges. In this article, we examine a set of issues related to incentives and other payments to patients in pragmatic clinical trials. Although many of the ethical concerns related to incentives and payments in explanatory trials pertain to pragmatic clinical trials, the pragmatic features may introduce additional challenges. These include those related to the risk of incentives and payments undermining the scientific validity and social value of pragmatic clinical trials, the sources of data used in pragmatic clinical trials, and when the pragmatic clinical trials are conducted under waivers of consent. Based on our examination of these matters, we offer some preliminary recommendations regarding incentives and payments in pragmatic clinical trials, recognizing that additional data and experiences are needed to refine them.

Assessing Creatine Supplementation for Neuroprotection against Perinatal Hypoxic-Ischaemic Encephalopathy: A Systematic Review of Perinatal and Adult Pre-Clinical Studies

There is an important unmet need to develop interventions that improve outcomes of hypoxic-ischaemic encephalopathy (HIE). Creatine has emerged as a promising neuroprotective agent. Our objective was to systematically evaluate the preclinical animal studies that used creatine for perinatal neuroprotection, and to identify knowledge gaps that need to be addressed before creatine can be considered for pragmatic clinical trials for HIE. Methods: We reviewed preclinical studies up to 20 September 2021 using PubMed, EMBASE and OVID MEDLINE databases. The SYRCLE risk of bias assessment tool was utilized. Results: Seventeen studies were identified. Dietary creatine was the most common administration route. Cerebral creatine loading was age-dependent with near term/term-equivalent studies reporting higher increases in creatine/phosphocreatine compared to adolescent-adult equivalent studies. Most studies did not control for sex, study long-term histological and functional outcomes, or test creatine post-HI. None of the perinatal studies that suggested benefit directly controlled core body temperature (a known confounder) and many did not clearly state controlling for potential study bias. Conclusion: Creatine is a promising neuroprotective intervention for HIE. However, this systematic review reveals key knowledge gaps and improvements to preclinical studies that must be addressed before creatine can be trailed for neuroprotection of the human fetus/neonate.

113 Simplifying consent - Use of the novel integrated consent model in paediatric clinical research

Primary Subject area Hospital Paediatrics Background Obtaining informed consent from patients to participate in clinical research has traditionally been a cumbersome process, often requiring lengthy documentation and the involvement of trained research staff. Moreover, this process can be a burden to the patient/family. As a result, progress in paediatric research and enabling continual improvement in care has been slow. In the last decade, research ethicists have proposed a new “integrated consent model” (ICM) for obtaining informed consent for pragmatic clinical trials that compare standard-of-care interventions, where there is clinical equipoise. In most cases of ICM, only a brief discussion with verbal consent is required, along with a handout on study purpose, risks, benefits, and procedures. This allows for a more condensed consent process, which maximizes clarity and minimizes information overload. ICM also allows the patient/family to maintain prospective autonomy and decision-making, as compared with deferred or waived consent. The ICM model allows staff in the circle of care to obtain consent, which minimizes the stress of meeting an additional person. To our knowledge, ICM has not yet been used in the paediatric population. Objectives The objective of this abstract is to report on the utility of ICM in a non-randomized clinical trial carried out in the inpatient setting of a tertiary children’s hospital. Design/Methods We compared two widely accepted standards of care for maintaining peripheral intravenous catheter patency in a cohort of children, namely continuous infusion (“to keep the vein open” or TKVO) versus saline lock (SL). The ICM process was reviewed and approved by REB. Nurses in the circle of care received a study package that included an REB approved “consent script” to be read to the patient/family, a single page information sheet, and instructions on documenting the obtained verbal consent in the patient’s chart (Graphic 1). Results With ICM, 79% of participants were recruited into the trial by a nurse. Patient recruitment was completed 4 months ahead of the predicted schedule (Figure 1). Nursing, research, and medical staff were satisfied with ICM and found it easy to administer. ICM occurred smoothly and quickly for patients/families, with no interference with their medical care and practically no disruption to their daily schedule. Conclusion ICM is a practical alternative to laborious traditional consent models, is associated with higher patient recruitment rates, and is less burdensome for the patient/family. Paediatricians should be aware of the utility of this novel consent model.

Primary anti-infective prophylaxis during routine treatment of lymphoma in the United States: A large real-world cohort analysis.

268 Background: While infectious complications contribute to considerable morbidity and mortality in patients with cancer, most scenarios lack evidence to guide optimal anti-infective prophylaxis (AIP). We evaluated a large real-world dataset to identify baseline utilization and factors associated with AIP in patients with non-Hodgkin lymphoma (NHL) treated in the US-community setting. Methods: Using the nationwide Flatiron Health de-identified electronic health record-derived database (from ≈ 280 US cancer clinics), we selected patients treated prior to 7/1/2020 with 1) R-CHOP for DLBCL, 2) bendamustine and rituximab (BR) for CLL/SLL, or 3) ibrutinib for CLL/SLL. We limited our analysis to patients treated by providers with documented prescribing of guideline recommended anti-viral prophylaxis (ppx) during proteasome inhibitor administration to ≥1 multiple myeloma patient. Our main outcome was the documented use of primary AIP defined as anti-viral and/or pneumocystis jiroveci (PJP) ppx within +/- 14 days of treatment initiation. We also report the delayed documented AIP use from day 15 to 60. We applied separate multivariable logistic regression models to each setting to examine the associations of patient-level characteristics with primary AIP (including age, sex, race, region, insurance, ECOG, year of treatment initiation). Results: A total of 3,142 (R-CHOP for DLBCL), 2,180 (BR for CLL/SLL), and 3,590 (ibrutinib for CLL/SLL) patients were included, with median age of 69, 69, and 72 years, respectively. Primary AIP was most common during BR for CLL/SLL, with 16.8% receiving any AIP (antiviral 15.6%, PJP 7.3%). Primary AIP was used in 10.5% of DLBCL patients initiating R-CHOP (antiviral 7.6%, PJP 5.6%), with the lowest utilization of AIP during ibrutinib for CLL/SLL (any 6.4%, antiviral 5.6%, PJP 2.6%). In the delayed setting, an additional 4-6% and 2-5% received viral and PJP ppx, respectively. Across all three of our multivariable analyses, higher provider rate of anti-viral ppx during proteosome inhibitor administration in MM, residing in the Midwest (vs. Northeast), and more recent treatment initiation were associated with greater odds of AIP. Other patient characteristics (age, race, ECOG) were less consistently associated with AIP across models. Furthermore, C-statistics were <0.7 in all three models (0.660-0.685), suggesting suboptimal discrimination for AIP based on patient-level characteristics alone. Conclusions: We observed low utilization of primary AIP during treatment in three common NHL settings that lack clear consensus on AIP. Variation was not well explained by measured patient characteristics, and future studies should consider provider and system attributes. Ultimately, robust evidence generation (e.g. pragmatic clinical trials) and quality improvement measures are needed to optimize ppx during routine lymphoma management.

Performance of statistical methods to address treatment non-adherence in pragmatic clinical trials with point-treatment settings: a simulation study

Introduction: The instrumental variable (IV)-based methods (e.g., two-stage least square [2SLS], two-stage residual inclusion [2SRI], and nonparametric causal bound [NPCB]) can be used to address non-adherence in pragmatic trials. These methods require assumptions, e.g., exclusion restriction, although they are known to handle unmeasured confounding. The inverse probability-weighted per-protocol [IPW-PP] method is useful in the same setting but requires different assumptions (no unmeasured confounding). Although all these methods aim to address the same problem, comprehensive simulations to compare their performance are absent in the literature. We performed extensive simulations when (1) confounding is present, (2) confounder is unmeasured but exclusion restriction is met, (3) exclusion restriction is violated, and (4) non-adherence is one-sided and differential. Method: We compared the performance in terms of bias, standard error (SE), mean squared error (MSE), and 95% confidence interval coverage probability. Results: For setting-1, IPW-PP outperforms IV-methods in terms of bias, SE, MSE, and coverage for <80% non-adherence but produces high bias beyond that point. IPW-PP also has high biases, but 2SLS and 2SRI work well for setting-2. For setting-3, 2SLS and 2SRI perform the worst in all scenarios; IPW-PP produces unbiased estimates when necessary confounders are measured and adjusted. For setting-4, IPW-PP has less bias, but 2SLS and 2SRI have higher SE and MSE. NPCB has wider bounds in all scenarios. We also analyze a two-arm trial to estimate the effect of vitamin A supplementation on childhood mortality after addressing non-adherence. Conclusion: We need to be cautious using the IPW-PP when non-adherence is very high or strong unmeasured confounding and should avoid using the IV methods when the exclusion restriction assumption is violated or high differential non-adherence. Since assumptions are different and often untestable for IPW-PP and IV methods, we suggest analyzing data using both methods for a robust conclusion.