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Introduction/Objective: The COVID-19 pandemic stopped site visits for clinical outcome data collection in March 2020. We utilized several remote methods to collect data and assessed their relative effectiveness. Background(s): The ProtecT randomized trial (Prostate cancer testing and treatment trial) aimed to determine the effectiveness of active monitoring (surveillance), radiation and surgery for localized disease. The primary outcome is prostate cancer mortality with clinical secondary outcomes of disease progression and metastasis. There was no difference in the primary outcome at 10 years (published in 2016) between groups (differences in metastasis and functional problems) so followup was extended to 15 years (November 2020). Method(s): The 10-year analysis used annual paper case report forms (CRFs) completed by research nurses based at UK hospitals. In extended follow-up, it was intended that National Health Service routine data would identify participants with potential disease progression. Prior to the pandemic the research nurse reviewed electronic health records at eight English hospitals and completed an eCRF in REDCap software. It became unlikely that site visits were going to be possible in 2020. A shortened eCRF was created focussed on essential outcome data and site staff agreed to help collect clinical data in July 2020. Result(s): Ethical approval for extending the study end date and the sponsor updating GDPR terms of site agreements were delayed by COVID-19 research taking priority. This also prevented the research nurse updating their NHS Research Passport for Honorary Contracts to access sites. Approvals were gained in December 2020. At four sites, local staff completed REDCap eCRFs with support from the data manager and research nurse by email and virtual calls. The research nurse gained remote access to hospital electronic health records at three sites by April 2021, which required extensive research governance approvals, training on hospital IT systems and their software on multiple laptops. At one site, from December 2020, 2-h virtual calls were held with local staff who interrogated electronic medical records as trial staff completed REDCap eCRFs. On average, 15 note reviews were conducted each call which were planned around clinical commitments. Secondary clinical outcomes were collected remotely for 94% of participants in follow-up (1395/1474). There was no difference in the three methods: remote hospital record access 594/601 (98.8%);local staff completion 575/600 (95.8%);and online calls 215/221 (97.3%) although less data cleaning was required as data queries were resolved during calls. Benefits also included savings on time traveling to sites and accommodation and local clinical staff could access a wider range of health records and information outside their hospital. However, enabling remote data capture delayed data analysis by 6 months. Conclusion(s): In a prostate cancer treatment trial remote data capture of clinical outcomes was successful as site visits became impossible due to the pandemic. Online methods were tailored to sites requirements but required substantial preparation and governance approvals.
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Background: The advent of COVID-19 has meant that patients with chronic diseases needed to shield, however, investi-gations were needed to guide continual management of their disease. Remote monitoring options were evaluated to ensure the standard of care is not compromised. Purpose and Hypothesis: The aim was to validate remote (return-posted) capillary triazole blood testing and evaluate the potential role of remote TDM in chronic antifungal therapy. Material(s) and Method(s): A single-center prospective cross-sectional study of remote finger prick capillary blood testing compared with gold standard venesection was performed. Remote finger prick capillary blood testing was validated compared to local standard venesection using comparative statistical analysis Comparative statistical analysis: Paired t-test, correlation and Bland-Altman were used to determine if there was agreement or association between the sampling methods. Result(s): A total of 66 patients receiving triazole therapy were recruited and 57 pooled pairs of remote capillary and venous triazole concentrations and metabolites wereprospectively analyzed, with the rest of the blood samplesnot being analyzed due to insufficient sample, hemolysis, or undetectable triazole level of < 0.2 mg/l. There was a significant difference in the comparison of the two methods of sampling with paired t-test at P <.0001. Bland-Altman analysis yielded wide bias (-49.07%) and wide limits of agreement (-85.5% to -12.64%). On average capillary triazole, concentrations were 37% lower than venous concentrations (Fig. 1). There was however a very strong correlation between capillary and venous tests (Pearson's correlation coefficient r = 0.9219, P <.0001, Fig. 2). Conclusion(s): Remote capillary triazolesampling does not appear interchangeable with venoussampling, but being strongly correlated and on average 2/3rd of the venous value, could be a predictor of venous triazole level, or be useful for intra-patient longitudinal monitoring. When incorporated into an outpatient clinical pathway it can improve shared decision-making and patient experience.Further research is required to determine appropriate target reference ranges if the new lower capillary levels can be used routinely, especially in the climate of COVID-19 where social distancing measures limit patient access to hospitals and clinics for routine investigations.
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Background: TGF-beta signaling plays an essential role in tissue fibrosis and mediates profibrotic programs after SARS-CoV-2 infection in the kidney and lung. SARS-CoV-2 also induces humoral immune responses controlled by cytokines, including TGF-beta. Studies have found that the incidence of SARS-CoV-2 infection and the severity of Covid-19 in cystic fibrosis (CF) patients is lower than the general population. We studied how SARS-CoV-2 regulates TGF-beta-mediated gene expression in the CF airway. Method(s): Small RNAseq was performed in human bronchial epithelial cells CFBE41o-from a patient homozygous for the F508del mutation in the CFTR gene on Illumina NextSeq 500's. Pathway analysis was done by Ingenuity Pathway Analysis (IPA) software (QIAGEN) and miRNet browser. IPA was used for analyzing coronavirus associated pathways affected by differentially regulated miRNAs. miRNAs predicted to target the coronavirus associated genes were collected from TargetScan Human release 7.2, miRmap, Diana-TarBase v.8, and miRBase bioinformatics tools. Anti-miRNA oligonucleotide miRCURY LNATM Power Inhibitors or control (Exiqon) were used. Cells expressing F508del or wild type CFTR were used to compare the results in CF and non-CF models. Findings were validated in primary human bronchial epithelial (HBE) cells. Result(s): Compared to vehicle control, TGF-beta1 dysregulated 48 miRNAs;38 and 19 pathways were uniquely affected by the upregulated and downregulated miRNAs, respectively. We found 43 miRNAs targeting 119 different mRNA of the proteins associated with coronavirus pathogenesis pathway and 21 miRNAs targeting 21 different mRNA of the proteins associated with coronavirus replication pathway. Two miRNAs upregulated by TGF-beta1 target the host receptor for SARS-CoV-2 invasion, angiotensin converting enzyme 2 (ACE2). We confirmed the results by qRT-PCR that TGF-beta1 increased expression of specific miRNAs targeting ACE2 mRNA. Upregulation of the miRNAs was followed by inhibition of ACE2 mRNA and protein levels and the effect was blocked by specific anti-miRNA oligonucleotides. The above results differed between the CF and non-CF cells. Conclusion(s): miRNAs may be important effectors of TGF-beta modulating SARSCoV-2 pathogenicity and replication in the CF airway. Ongoing studies focus on elucidating the mechanisms of SARS-CoV-2 invasion of kidney cells.
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Background and aims: In trials conducted in India, recombinant granulocyte colony stimulating factor (GCSF) improved survival in alcohol-associated hepatitis (AH). The aim of this trial was to determine the safety and efficacy of pegfilgrastim, a long-acting recombinant GCSF, in patients with AH in the United States. Method: This prospective, open label trial randomized patients with a clinical diagnosis of AH and a Maddrey discriminant function score ≥32 to standard of care (SOC) or SOC+pegfilgrastim (0.6 mg subcutaneously) on Day 1 and Day 8. SOC was 28 days of either pentoxifylline or prednisolone, as determined by the patient’s primary physician. The second injection of pegfilgrastim was not administered if the white blood cell count exceeded 30, 000/mm3 on Day 8. Primary outcomewas survival at Day 90. Secondary outcomes included the incidence of acute kidney injury (AKI), hepatorenal syndrome (HRS), hepatic encephalopathy, or infections. Results: The study was terminated early due to COVID19 pandemic. Eighteen patients were randomized to SOC and 16 to SOC+pegfilgrastim. All patients received prednisolone as SOC. Nine patients failed to receive a second dose of pegfilgrastin due to WBC>30, 000/ mm3 on Day 8. Survival at 90 days was similar in both groups (SOC: 0.83 [95% confidence interval {CI}: 0.57–0.94] vs. pegfilgrastim: 0.73 [95% CI: 0.44–0.89];p > 0.05). The incidences of AKI, HRS, hepatic encephalopathy, and infections were similar in both treatment arms and therewere no serious adverse events attributed to pegfilgrastim. Conclusion: This phase II trial found no survival benefit at 90 days among subjects with AH who received pegfilgrastim+prednisolone compared with subjects receiving prednisolone alone.
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Background: Patient-trial matching is a critical step in clinical research recruitment that requires extensive review of clinical data and trial requirements. Prescreening, defined as identifying potentially eligible patients using select eligibility criteria, may streamline the process and increase study enrollment. We describe the real-world experience of implementing a standardized, universal clinical research prescreening protocol within a VA cancer center and its impact on research enrollment. Methods: An IRB approved prescreening protocol was implemented at the VACT Cancer Center in March 2017. All patients with a suspected or confirmed diagnosis of cancer are identified through tumor boards, oncology consults, and clinic lists. Research coordinators perform chart review and manually enter patient demographics, cancer type and stage, and treatment history into a REDCap (Research Electronic Data Capture) database. All clinical trials and their eligibility criteria are also entered into REDCap and updated regularly. REDCap generates real time lists of potential research studies for each patient based on his/her recorded data. The primary oncologist is alerted to a patient's potential eligibility prior to upcoming clinic visits and thus can plan to discuss clinical research enrollment as appropriate. Results: From March 2017 to December 2020, a total of 2548 unique patients were prescreened into REDCAP. The mean age was 71.5 years, 97.5% were male, and 15.5% were African American. 32.57 % patients had genitourinary cancer, 17.15% had lung cancer, and 46.15% were undergoing malignancy workup. 1412 patients were potentially eligible after prescreening and 556 patients were ultimately enrolled in studies. The number of patients enrolled on therapeutic clinical trials increased after the implementation of the prescreening protocol (35 in 2017, 64 in 2018, 78 in 2019, and 55 in 2020 despite the COVID19 pandemic). Biorepository study enrollment increased from 8 in 2019 to 15 in 2020. The prescreening protocol also enabled 200 patients to be enrolled onto a lung nodule liquid biopsy study from 2017 to 2019. Our prescreening process captured 98.57% of lung cancer patients entered into the cancer registry during the same time period. Conclusions: Universal prescreening streamlined research recruitment operations and was associated with yearly increases in clinical research enrollment at a VA cancer center. Our protocol identified most new lung cancer patients, suggesting that, at least for this malignancy, potential study patients were not missed. The protocol was integral in our program becoming the top accruing VA site for NCI's National Clinical Trial Network (NCTN) studies since 2019.
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Background: The emergence of SARS-CoV-2 viral variants threatens current anti-viral and preventative strategies, including monoclonal antibodies and vaccines. Critically, the limited supply of vaccines and the complex logistics surrounding the delivery of infusion-based therapies herald the need for an easily produced, distributed, and specific direct-acting antiviral for COVID-19 that limits progression of illness and ideally prevents transmission. Methods: The efficacy of molnupiravir was evaluated in a double-blind, randomized, placebo-controlled, Phase 2 dose-range finding study using realtime polymerase chain reaction (RT-PCR) and virus isolation was conducted at 11 study sites in the U.S. Participants were randomized if they had signs or symptoms of COVID-19 within 7 days, and a positive SARS-CoV-2 RT-PCR within 4 days of enrollment. Initially, participants were randomized in a 1:1 ratio to receive 200 mg molnupiravir or placebo twice daily for 5 days. Subsequently, in the dose-range finding portion of the study, participants were randomized in a 3:1 ratio to receive 200, 400, or 800 mg molnupiravir or placebo twice daily for 5 days. Nasopharyngeal swabs were analyzed from 175 subjects at enrollment, Day 3, and Day 5 for SARS-CoV-2 infectivity. Samples were stored at 4°C for up to 72 hours, shipped refrigerated, aliquoted, and stored at -80°C until testing. Vero E6 cell monolayers were infected with the sample for 1 hour. Culture medium was analyzed for viral load at 2 and 5 days post-infection by RT-PCR. Results: Seventy-eight (45%) participants, median 4.62 days (min. 1.40, max. 7.54) from symptom onset, had a positive SARS-CoV-2 culture at enrollment (52 on active and 26 on placebo). The percentage of participants with a positive viral culture at enrollment who were positive on Day 3 was 20.4% on active and 28% on placebo (p = 0.56). At day 5, 24% of placebo participants were culturethe positive compared to none treated with molnupiravir (p = 0.001). Between treatment, comparisons were performed using Fisher's exact test. Conclusion: This is the first demonstration of reduced infectiousness by antiviral therapy in people with SARS-2 infection. This simple, short-course oral therapy may benefit individuals and public health and is unlikely to be impacted by spike-protein variants.
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Background: Approximately 50,000 women in the U.S. are diagnosed with ductal carcinoma in situ (DCIS)annually. Without treatment, it is estimated that 20-30% of DCIS will lead to invasive breast cancer. Currently, morethan 97% of women undergo surgery, with many also undergoing radiation. An alternative to surgery for low-riskDCIS is active monitoring (AM), an approach in which regularly scheduled mammography and physical exams areused to monitor breast changes and determine if, or when, surgery is needed. Trial design: COMET, a multicenterphase III prospective randomized trial, opened in the U.S. in June 2017 (clinicaltrials.gov reference: NCT02926911).The hypothesis is that management of low-risk DCIS using an AM approach does not yield inferior invasive breastcancer and/or quality of life outcomes compared to surgery. Eligibility criteria: Patients with a new diagnosis of unilateral, bilateral, unifocal, multifocal, or multicentric DCIS, or atypia verging on DCIS are eligible. Patients mustbe ≥40 years of age, have no contraindication for surgery, and pathologic confirmation of grade I/II DCIS. DCIS mustbe ER and/or PR≥ 10% and HER2-negative without invasion, diagnosed within 120 days of registration. Breasttissue, blood and imaging are collected at trial entry and if invasive cancer subsequently occurs, and are stored incentral repositories. Specific aims: The primary aim is to assess whether the 2-yr ipsilateral invasive breast cancerrate for AM is non-inferior to surgery. Secondary aims include comparison of 2-, 5-, and 10-yr mastectomy rate, contralateral invasive breast cancer rate, overall survival and invasive breast cancer-specific survival, as well as 5-and 10-yr ipsilateral invasive breast cancer rate between groups. Patient reported outcomes (PRO) using validatedtools are critical secondary endpoints, and will enable comparison of health-related quality of life and psychosocialoutcomes between surgery and AM groups at prespecified time points over a period of 5 years. Statisticalmethods: An accrual goal of 1200 was estimated using a 2-group test of noninferiority of proportions, with the 2-yrinvasive breast cancer rate in the surgery group assumed to be 0.10, including accounting for upstaging. Theprojected drop-out rate is 25%, for a total of 900 patients treated per allocation arm. The non-inferiority boundarywas set at 0.05. Based on a 1-sided un-pooled z-test, with alpha=0.05, a sample size of n=446 per group will have80% power to detect the specified noninferiority margin. Intention-to-treat analysis of the 2-yr invasive breast cancerrate will be conducted using all patients as randomized, and will be completed using Kaplan-Meier estimates,stratified by group, combined with Greenwood's confidence interval. Several sensitivity analyses (per protocol, as-treated, and instrumental variable) are also planned to account for loss of follow-up, rejection of randomizationallocation and withdrawals. Present and target accrual: Trial accrual as of 7/1/20 is 540 randomized patients from84 activated Alliance for Clinical Trials in Oncology sites. Despite logistical challenges posed by the COVID-19crisis, patients continue to be recruited to the COMET trial. Over 80% of patients have sample sets/images stored inthe tissue and image repositories. This trial will provide definitive clinical, quality of life and biomarker evidenceregarding the trade-offs of surgery vs AM in patients with low-risk DCIS.