Oncology clinical trial disruption during the COVID-19 pandemic: a COVID-19 and cancer outcomes study.

BACKGROUND: COVID-19 disproportionately impacted patients with cancer as a result of direct infection, and delays in diagnosis and therapy. Oncological clinical trials are resource-intensive endeavors that could be particularly susceptible to disruption by the pandemic, but few studies have evaluated the impact of the pandemic on clinical trial conduct. PATIENTS AND METHODS: This prospective, multicenter study assesses the impact of the pandemic on therapeutic clinical trials at two large academic centers in the Northeastern United States between December 2019 and June 2021. The primary objective was to assess the enrollment on, accrual to, and activation of oncology therapeutic clinical trials during the pandemic using an institution-wide cohort of (i) new patient accruals to oncological trials, (ii) a manually curated cohort of patients with cancer, and (ii) a dataset of new trial activations. RESULTS: The institution-wide cohort included 4756 new patients enrolled to clinical trials from December 2019 to June 2021. A major decrease in the numbers of new patient accruals (-46%) was seen early in the pandemic, followed by a progressive recovery and return to higher-than-normal levels (+2.6%). A similar pattern (from -23.6% to +30.4%) was observed among 467 newly activated trials from June 2019 to June 2021. A more pronounced decline in new accruals was seen among academically sponsored trials (versus industry sponsored trials) (P < 0.05). In the manually curated cohort, which included 2361 patients with cancer, non-white patients tended to be more likely taken off trial in the early pandemic period (adjusted odds ratio: 2.60; 95% confidence interval 1.00-6.63), and substantial pandemic-related deviations were recorded. CONCLUSIONS: Substantial disruptions in clinical trial activities were observed early during the pandemic, with a gradual recovery during ensuing time periods, both from an enrollment and an activation standpoint. The observed decline was more prominent among academically sponsored trials, and racial disparities were seen among people taken off trial.

Physical Therapist Training Challenges for an Embedded Pragmatic Trial: Fibromyalgia TENS in Physical Therapy Study

Transcutaneous electrical nerve stimulation (TENS), a non-pharmacological treatment, is safe and effective for movement-evoked pain in individuals with Fibromyalgia (FM). The purpose of our NIH-funded pragmatic clinical trial, Fibromyalgia TENS in PT Study (FM-TIPS), assesses feasibility and effectiveness of adding TENS to usual physical therapy (PT) treatment in individuals with FM. We partnered with 33 sites in 6 healthcare systems, training 150+ Midwest clinicians. Outpatient PT clinic sites are cluster randomized to a TENS or a No-TENS intervention, stratified by system and clinic size. We will recruit ∼600 patients with a primary or secondary diagnosis of FM. We developed comprehensive communication and training procedures to ensure study fidelity and adapted over the course of the study to enhance learning. We will provide an overview and the impact of the pandemic on these procedures. Representatives for each healthcare system, each clinic and the study team were identified for communication and training. Training included initial study introduction, human subjects protection, and study procedures. We used a hybrid approach with written, video, onsite, and virtual instruction. All materials and procedures, for clinician and patient-facing materials, website, videos, equipment use (iPad for screening, TENS units), and clinician procedures for PT visits 1-3, were piloted and reviewed by clinicians from each healthcare system. Additional communication and feedback include weekly enrollment reports, monthly newsletters, relationship building with clinicians, enrollment incentives, and continuing education webinars. The pandemic required creative and evolving solutions to maintain study involvement and recruitment. Barriers for enrollment are screening PT Visit 1, comfort level of clinicians for PT Visits 2 and 3, delays/alterations in training and planning, clinician demands, clinicians/patient illness, and staff shortages in the clinics. Current enrollment, study training and implementation has been affected by COVID-19 and we developed creative methods for training and implementation for FM-TIPS. Grant support from Research supported in this USASP was supported by National Institutes of Health Heal Initiative Grant UG3/UH3 AR076387-01 and UL1TR002537.

Disruption to care of patients with thoracic malignancies: A COVID-19 and cancer outcomes study

Introduction: Patients with thoracic malignancies are susceptible to severe outcomes from coronavirus disease 2019 (COVID-19). The aim of this study was to evaluate the disruption to care of patients with thoracic malignancies during the COVID-19 pandemic. Methods: The COVID-19 and Cancer Outcomes Study (CCOS) is a multicenter prospective cohort study comprised of adult patients with a current or past history of hematological malignancy or invasive solid tumor who had an outpatient medical oncology visit on the index week between March 2 and March 6, 2020 at the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai in New York, NY (MSSM) or the Dana-Farber Cancer Institute in Boston, MA (DFCI). An electronic data capture platform was used to collect patient-, cancer-, and treatment-related variables during the three months prior to the index week (the baseline period) and the following three months (the pandemic period). Two-by-three contingency tables with Fisher's exact tests were computed. All tests were two-tailed and considered statistically significant for p<0.05. All analyses were done in the R statistical environment (v3.6.1). Results: The overall cohort included 2365 patients, of which 313 had thoracic malignancies, 1578 had other solid tumors, and 474 had hematological malignancies. At a median follow-up of 84 days (95% confidence interval, 82-84), 13 patients with thoracic malignancies (4.1%) had developed COVID-19 (vs. other solid: 63 [4.0%] and hematological: 52 [11.0%];p<0.001). When comparing data from the pandemic period to the baseline period, patients with thoracic malignancies had a decrease in the number of in-person outpatient visits (thoracic: 209 [66.8%] vs. other solid: 749 [47.5%] vs. hematological: 260 [54.9%];p<0.001) and an increase in the number of telehealth visits (thoracic: 126 [40.3%] vs. other solid: 465 [29.5%] vs. hematological: 168 [35.4%];p<0.001). During the pandemic period, 33 (10.5%) patients with thoracic malignancies experienced treatment delays due to the pandemic (vs. other solid: 127 [8.0%] and hematological: 79 [16.7%];p<0.001), and 26 (8.3%) patients with thoracic malignancies experienced delays in cancer imaging or diagnostic procedures (vs. other solid: 63 [4.0%] and hematological: 26 [5.5%];p=0.003). Discussion: In this prospective cohort study, patients with thoracic malignancies were not at increased risk of developing COVID-19 compared to patients with other cancers, but experienced significant cancer care disruption during the COVID-19 pandemic with a higher likelihood of decreased in-person visits and increased telehealth visits compared to patients with other malignancies. Focused efforts to ensure continuity of care for this vulnerable patient population are warranted.

Prolonged N-95 Mask Use Did Not Result in Carbon Dioxide Retention or Clinically Significant pH Changes in One Cohort of Health Care Workers

Study Objective: Concerns over emerging infectious diseases spread via airborne or respiratory droplet transmission have highlighted the importance of respiratory protection for health care workers. During the current COVID-19 pandemic, widespread use of N95 masks by health care workers helped to prevent transmission and contraction of SARS-CoV2. It is not clear if prolonged continuous use of an N-95 during clinical duties results in any detrimental physiological effects and clinical features from increased carbon dioxide. The primary objective of the study was to evaluate for carbon dioxide retention and/or clinically significant changes in pH with prolonged use of N-95 masks. Secondary objective assessed for changes in vital signs and any unexpected subjective symptoms experienced by the study participants. Methods: 10 healthy emergency medicine residents between the ages of 27 and 31 years old provided written consent. All subjects denied history of structural lung disease (asthma, COPD, interstitial lung disease) and had been previously fit-tested for the correct size of N-95 mask. Each participant was provided a new N-95 mask and instructed to don as if they were about to enter a clinical scenario that would require this degree of respiratory protection. All subjects remained in a seated position and asked to refrain from speaking in order maximize fit of the mask. Venous blood gas samples were obtained prior to donning their mask followed by three additional intervals at, 20, 40, and 60 minutes. In addition, vital signs (heart rate, pulse oximetry, blood pressure and respiratory rate) were recorded at each of those four intervals and subjects were ask to self-record any symptoms they experienced prior to each blood draw. Each sample collected consisted of acquiring 2 ml of venous blood, which were analyzed within 30 minutes at the University of Nebraska Medical Center’s core lab. PCO2 and pH was assessed at each of the time intervals and fit with a linear mixed effect model to determine if statistically significant change over time for these measurements. Mean and standard deviations were used to describe the values at each time point. Pairwise comparisons between time points were adjusted using Tukey’s method. All analysis was done using SAS, Version 9.4 and a p-value < 0.05 was considered statistically significant. Results: The mean carbon dioxide levels at time 0 and 60 minutes were 48.9 (CI, 49.0-56.0) and 48.5 (CI 39.0- 57.0) and there was no statistically significant change across any of the time intervals (p=0.20). There was a small significant increase in the mean pH between the 20-minute assessment and baseline [(7.367, CI 7.350- 7.400) vs (7.381, CI 7.350-7.410) p=0.019], which was not clinically significant. In addition, there were no significant changes in vital signs or report of unexpected clinical symptoms by any the subjects. Conclusion: In this small cohort of subjects, there was no evidence of carbon dioxide retention or clinically significant changes in pH with prolonged use of N-95 masks. [Formula presented]

Impact of COVID-19 on a Pragmatic, Cluster Randomized Clinical Trial for Fibromyalgia

Our objective was to present our experience on adapting to the challenges of COVID-19 pandemic on a pragmatic clinical trial. Transcutaneous Electrical Nerve Stimulation (TENS) in Physical Therapy (PT) Study (FM-TIPS) is a pragmatic, cluster-randomized clinical trial examining if the addition of TENS to routine PT improves movement-evoked pain in fibromyalgia (FM). FM patients (n=600) were enrolled from 24 PT clinics (12 PT only, 12 PT with TENS) across five healthcare systems. COVID-19 has significantly impacted PT practice and in-person interactions. In response, all PT clinics saw reduced volumes of patients, some clinics furloughed PTs, and some clinics were permanently closed. This led us to put contracts, reliance agreements, and training of clinics on hold and to seek additional clinics that could fill the gap for those who could no longer participate. It also led to a delay in onboarding healthcare systems and inpatient enrollment. In order to protect the integrity of the study and minimize missing data due to potential restrictions of in-person visits we developed alternative strategies. This includes procedures for home instruction of TENS via telehealth, a plan for bringing on backup clinics, and a plan for training virtually and in-person using personal protective equipment and social distancing. Assessment of primary outcome and questionnaire data were transitioned for the patient to perform at home through a patient-portal with embedded patient-specific videos. We have also set up a phone line for patients to call with additional questions or concerns. The impact of COVID-19 on statistical design and analysis was discussed including a plan for uneven enrollment across clinics and a sub-analysis of data for patients enrolled during or after the pandemic. In conclusion, COVID-19 altered the original study design of this large-pragmatic trial to account for greater flexibility for providers and patients to facilitate continued enrollment. NIH.

Disparities in cancer during the COVID-19 pandemic: COVID-19 and cancer outcomes study (CCOS)

Background: The COVID-19 pandemic has rapidly altered cancer care. However, the ways in which it has done so and the associated impact at the individual and societal levels remains poorly defined. Methods: CCOS is a multicenter prospective cohort study designed to define the impact of the pandemic on cancer care delivery and outcomes. The CCOS cohort comprised consecutive outpatients with cancer seen at two US cancer centers from March 2 to March 6, 2020 (index visit). Data was collected at baseline, retrospectively from the preceding 3 months, and prospectively at 3-month follow up. Per patient changes in numbers of visits were compared using Wilcoxon signed rank tests. Correlates of increases in telehealth visits and decreases in in-person visits were evaluated using multivariable logistic regression models. Adjusted Odds ratios [aOR] and 95% confidence intervals (CI) were reported. Results: Of 2365 included patients, 1219 (51.6%) had a decrease in in-person visit frequency during the pandemic period relative to the preceding 3 months. Conversely, 760 (32.2%) had an increased frequency of telehealth visits (decrease in in-person and increase in telehealth visits;both p<0.01). 128 (5.4%) patients developed COVID-19. Compared to White patients, Black and Hispanic patients were less likely to have telehealth visits, had no significant change in frequency of in-person visits, and were more likely to develop COVID-19 (Table). [Formula presented] Conclusions: Significant disruptions to routine cancer care were observed during the pandemic period relative to the prior 3 months. Racial and ethnic barriers to the adoption of telehealth, and related socioeconomic factors, place these vulnerable populations simultaneously at disproportionate risk for decreased cancer-related visits and COVID infection, thereby exacerbating existing racial and ethnic health disparities. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: D. Doroshow: Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Ipsen;Honoraria (self), Advisory/Consultancy: Boehringer Ingelheim;Honoraria (self), Advisory/Consultancy: Athenaeum Partners;Honoraria (self), Advisory/Consultancy: Boston Healthcare Associates. A.L. Schmidt: Travel/Accommodation/Expenses: Pfizer;Travel/Accommodation/Expenses: Astellas. Z. Bakouny: Non-remunerated activity/ies: Bristol Myers Squibb;Research grant/Funding (self): Genentech/ImCore. M.M. Awad: Advisory/Consultancy, Research grant/Funding (self): Bristol Myers Squibb;Advisory/Consultancy, Research grant/Funding (self): Lilly;Advisory/Consultancy, Research grant/Funding (self): AstraZeneca;Advisory/Consultancy, Research grant/Funding (self): Genentech;Advisory/Consultancy: Merck;Advisory/Consultancy: Achilles;Advisory/Consultancy: AbbVie. R. Haddad: Advisory/Consultancy, Research grant/Funding (self): Bristol Myers Squibb;Advisory/Consultancy, Research grant/Funding (self): Merck;Advisory/Consultancy, Research grant/Funding (self): Pfizer;Advisory/Consultancy, Research grant/Funding (self): Genentech;Advisory/Consultancy, Research grant/Funding (self): AstraZeneca;Advisory/Consultancy, Research grant/Funding (self): GlaxoSmithKline. M.D. Galsky: Shareholder/Stockholder/Stock options: Rappta Therapeutics;Honoraria (self): BioMotiv;Honoraria (self): Janssen;Honoraria (self): Dendreon;Honoraria (self): Merck;Honoraria (self): GlaxoSmithKline;Honoraria (self): Lilly;Honoraria (self): Astellas Pharma;Honoraria (self): Genentech;Honoraria (self): Bristol-Myers Squibb;Honoraria (self): Novartis;Honoraria (self): Pfizer;Honoraria (self): EMD Serono;Honoraria (self): AstraZeneca;Honoraria (self): Seattle Genetics;Honoraria (self): Incyte;Honoraria (self): Alleron Therapeutics;Honoraria (self): Dracen;Honoraria (self): Inovio Pharmaceuticals;Honoraria (self): NuMab;Honoraria (self): Dragonfly Therapeutics;Honoraria (institution): Janssen Oncology;Honoraria (institution): Dendreon;Honoraria (institution): Novartis;Honoraria (institu ion): Bristol-Myers Squibb;Honoraria (institution): Merck;Honoraria (institution): AstraZeneca;Honoraria (institution): Genentech/Roche. T.K. Choueiri: Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): AstraZeneca;Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Alexion;Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Bayer;Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): BristolMyersSquibb;Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Cerulean;Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Eisai;Honoraria (self), Research grant/Funding (self): Foundation Medicine;Honoraria (self), Research grant/Funding (self): Exelixis;Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Ipsen;Research grant/Funding (self): 16 Tracon;Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Genentech;Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Roche;Honoraria (self), Research grant/Funding (self): Roche Products Limited;Honoraria (self), Research grant/Funding (self): Hoffman-LaRoche;Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): GlaxoSmithKline;Advisory/Consultancy, Research grant/Funding (self): Lilly;Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Merck;Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Novartis;Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Peloton;Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Pfizer;Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Prometheus labs;Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Corvus;Research grant/Funding (self): Calithera;Research grant/Funding (self): Analysis Group;Honoraria (self), Research grant/Funding (self): Sanofi/Aventis;Research grant/Funding (self): Takeda;Honoraria (self), Advisory/Consultancy: EMD Serono;Honoraria (self), Advisory/Consultancy: UpToDate;Honoraria (self): NCCN;Honoraria (self), Advisory/Consultancy, Dr. Choueiri reports research support from AstraZeneca, Alexion, Bayer, Bristol Myers Squibb/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Ipsen, 16 Tracon, Genentech, Roche, Roche Products Limited, F. Hoffmann-La Roche, GlaxoSmithKline, Lilly, Merck, Novartis, Peloton, Pfizer, Prometheus Labs, Corvus, Calithera, Analysis Group, Sanofi/Aventis, Takeda;Honoraria: AstraZeneca, Alexion, Sanofi/Aventis, Bayer, Bristol Myers-Squibb/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Genentech, Roche, Roche Products Limited, F. Hoffmann-La Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Ipsen, Up-to-Date, NCCN, Analysis Group, NCCN, Michael J. Hennessy (MJH) Associates, Inc (Healthcare Communications Company with several brands such as OnClive, PeerView and PER), Research to Practice, L-path, Kidney Cancer Journal, Clinical Care Options, Platform Q, Navinata Healthcare, Harborside Press, American Society of Me: Analysis Group. All other authors have declared no conflicts of interest.