RESULTS OF A 12-WEEK OPEN-LABEL, NON-INTERVENTIONAL STUDY OF THE EFFICACY AND SAFETY OF OLOKIZUMAB THERAPY IN PATIENTS WITH RHEUMATOID ARTHRITIS AFTER SWITCHING FROM ANTI-B-CELL THERAPY DURING THE SARS-COV-2 PANDEMIC.

The COVID-19 pandemic has significantly changed the understanding of the safety profile of therapies for immunoinflammatory rheumatic diseases (IRDs). This is primarily due to the negative impact of a number of basic anti-inflammatory drugs (DMARDs) and biological DMARDs on the course and outcomes of a new coronavirus infection. A number of studies have shown that anti-B-cell therapy (rituximab) gave a statistically significant increase in the risk of severe COVID-19 and an increase in mortality. At the same time, the analysis of real clinical practice data dictated the need to establish a number of restrictions on the use of certain classes of biological DMARDs and to search for alternative therapy programs to maintain control over disease activity. Purpose of the study - to evaluate the efficacy and safety of the drug Artlegia (olokizumab), solution for subcutaneous injection, 160 mg/ml - 0.4 ml, manufactured by R-Pharm JSC, Russia) for the treatment of patients with rheumatoid arthritis in real clinical practice after switching with rituximab during the COVID-19 pandemic. Materials and methods. The study included 14 patients with a confirmed diagnosis of rheumatoid arthritis (RA), who were previously on rituximab therapy at a dose of 1000-500 mg twice with an interval of 2 weeks, who received at least one course of therapy with this drug. As RA worsened, patients were switched to olokizumab against the background of standard DMARDs. At 4, 8, 12 weeks after the switch, the severity of pain was assessed on the VAS scale, the number of painful and swollen joints (TJC28 and TSC28), the level of acute phase markers of inflammation, the DAS28 disease activity index calculated using ESR and CRP, and the CDAI (clinical activity index), functional state index HAQ, as well as assessment of the safety profile of therapy. Results. Data analysis was performed using median values (Me) were used for data analysis. A significant decrease of TJC28 was after the injection of olokizumab (Artlegia) in 8 and 12 weeks (Me baseline = 10;Me 8 weeks = 4;Me 12 weeks = 4;p<0.05) and a decrease of TSC28 in 4, 8 and 12 weeks (Me baseline = 9;Me 4 weeks = 3.5;Me 8 weeks = 2.5;Me 12 weeks = 2.0;p<0.05). Laboratory markers of inflammation showed a decrease in CRP and ESR levels after 4 weeks of treatment (CRP: Me baseline = 21, Me 4 weeks = 1 (p<0.05);ESR: Me baseline = 31, Me 4 weeks = 7 (p<0.05)). Positive dynamics persisted at 8 and 12 weeks (CRP: Me 8 weeks = 1, Me 12 weeks = 0;ESR: Me 8 weeks = 4, Me 12 weeks = 5). The level of CRP by the fourth week 4 became within the normal range, regardless of the initial values. All activity indices improved from the fourth week in each evaluation period compared to baseline: DAS28-ESR: Me baseline = 5.52, Me 4 weeks = 3.59, Me 8 weeks = 3.33, Me 12 weeks = 3.22 (p<0.05);DAS28-CRP: Me baseline = 5.39, Me 4 weeks = 3.71, Me 8 weeks = 3.35, Me 12 weeks = 3.45 (p<0.05);CDAI: Me baseline = 28.5, Me 4 weeks = 18.0, Me 8 weeks = 16.5, Me 12 weeks = 16.0 (p<0.05). All patients showed a reduction in pain (VAS scale) by week 8. The functional status of patients, according to the HAQ index, showed a significant decrease only by the 12th week of the study: Me baseline = 1.62, Me 12 weeks = 1.31 (p<0.05). Conclusion. The study found that switching from rituximab to olokizumab was effective and safe during the COVID-19 pandemic.Copyright © 2023 Ima-Press Publishing House. All rights reserved.

A clinician perspective on the treatment of chronic myeloid leukemia in the chronic phase.

Tyrosine kinase inhibitors (TKIs) have vastly improved long-term outcomes for patients with chronic myeloid leukemia (CML). After imatinib (a first-generation TKI), second- and third-generation TKIs were developed. With five TKIs (imatinib, dasatinib, bosutinib, nilotinib, and ponatinib) targeting BCR::ABL approved in most countries, and with the recent approval of asciminib in the USA, treatment decisions are complex and require assessment of patient-specific factors. Optimal treatment strategies for CML continue to evolve, with an increased focus on achieving deep molecular responses. Using clinically relevant case studies developed by the authors of this review, we discuss three major scenarios from the perspective of international experts. Firstly, this review explores patient-specific characteristics that affect decision-making between first- and second-generation TKIs upon initial diagnosis of CML, including patient comorbidities. Secondly, a thorough assessment of therapeutic options in the event of first-line treatment failure (as defined by National Comprehensive Cancer Network and European LeukemiaNet guidelines) is discussed along with real-world considerations for monitoring optimal responses to TKI therapy. Thirdly, this review illustrates the considerations and importance of achieving treatment-free remission as a treatment goal. Due to the timing of the writing, this review addresses global challenges commonly faced by hematologists treating patients with CML during the COVID-19 pandemic. Lastly, as new treatment approaches continue to be explored in CML, this review also discusses the advent of newer therapies such as asciminib. This article may be a useful reference for physicians treating patients with CML with second-generation TKIs and, as it is focused on the physicians' international and personal experiences, may give insight into alternative approaches not previously considered.

A review of the impact of the COVID-19 pandemic on the delivery of hospital oncology pharmacy services

Background: All aspects of healthcare have been challenged during the COVID-19 pandemic. Cancer services adapted to reduce disease transmission while maintaining essential services. International and national guidelines emerged rapidly to support optimal delivery of cancer care during the pandemic. This review aimed to identify the impact of COVID-19 on the delivery of hospital oncology pharmacy services. Method: We searched multiple databases: PubMed, Medline, EMBASE and CINAHL to March 2021. These were supplemented with manual searching. The key search terms used were 'oncology' OR 'cancer' AND 'COVID-19' AND 'pharmacy'. Full text guidelines or recommendations for service adaptations and papers focusing on the impact of the pandemic on hospital oncology pharmacy services published in English were included. s were excluded. We identified the strategies for service adaptations and grouped them into themes. Results: Weidentified four guidelines, two from France and one each from England and Saudi Arabia, that made recommendations for service adaptations due to COVID-19. A further two global surveys assessed the impact of the pandemic on oncology pharmacy practice.1-6 All included papers were published within the first 6 months of the World Health Organisation declaring a global pandemic. The common modifications to services focused on four themes: reducing frequency of patient visits, reducing healthcare practitioner exposure to COVID-19, increasing use of digital technology and maintaining the supply of essential medicines. Several approaches were used to reduce the frequency of patient visits to healthcare settings, and included delaying treatment, switching intravenous treatment to subcutaneous or oral routes, using extended dosing schedules, home administration and discontinuation of some treatment e.g., clinical trials. Pharmacy practitioners applied distancing and safety rules in the workplace in line with government recommendations. Some services introduced remote and/or flexible working patterns. Hospital pharmacy teams used digital technologies to maintain communication within the pharmacy team, e.g., through holding virtual meetings, and with patients through the use of telephone and video consultations. Medicine shortages due to disruption of supply chains were described. Shortages were reported for several medicines e.g., drugs used to treat COVID-19, e.g., remdesivir, systemic anti-cancer therapies and supportive care medicines. To ensure continuity of supplies, additional staff were deployed to facilitate sourcing and procurement of essential medicines. Discussion: We collated the impact of COVID-19 on hospital oncology pharmacy practice across different countries. Despite disparate healthcare services, the approaches for safeguarding patients and practitioners against COVID-19 transmission were common. However, the impact of treatment changes on patient outcomes and service re-configurations is yet to be evaluated. Unsurprisingly, this review identified a small number of studies, likely due to prioritization of service delivery. Despite the challenges to healthcare, the pandemic has created opportunities for hospital oncology pharmacy teams to embrace technology and innovative ways of working.

How the estimand addendum tothe ICH E9 guideline helps structure clinical objectives, analyses, and conclusions-a series of oncology case studies

Background: The estimand framework aims to increase the dialogue between functional areas working on proper alignment of trial objectives formulation, design, conduct, statistical analyses, and conclusions. The draft addendum on Estimands and Sensitivity Analysis in Clinical Trials to the ICH E9 guideline on Statistical Principles for Clinical Trials was released in August 2017. In December 2019, the final version of the ICH E9 estimand addendum was published. The new framework requires clarity and precision in description of the treatment effect, in particular, explicitly accounting for events which occur after randomization/treatment start and either preclude observation of the variable of interest or affect its interpretation (''intercurrent events''). It highlights the need for a discussion among key stakeholders during the design phase, resulting in more precise clinical trials objective. The estimand framework is anticipated to have a major impact on drug development. The estimand that reflects the trial objectives will determine the trial design, data collection, trial conduct, analysis, and interpretation. This work is a result of a cross-industry working group of statisticians and clinicians working on connecting the ICH E9 addendum concepts to applications in oncology. The working group was formed in February 2018 and currently has 34 members (14 EU + 20 US) from 21 companies to ensure common understanding and consistent definitions for time-to-event estimands in oncology. Methods: Followed by a general introduction to the estimand framework, we illustrate the impact of the addendum by applying it to a series of oncology case studies: Censoring mechanisms: evaluate the use of censoring to handle intercurrent events, related assumptions, and interpretation, discussing the often performed sensitivity analyses and possible alternatives in view of the estimand framework. Treatment switching: describe how the estimand framework allows to explicitly account for different types of treatment switching and offers a systematic and transparent approach for assessment. Solid and hematologic tumors: focus on relevant estimands, intercurrent events, and sensitivity analyses and demonstrate how the estimand framework seeks to increase transparency on the treatment effect of interest and facilitates communications between stakeholder. COVID-19: assess the impact of COVID-19 on the clinical trial objective, propose strategies to handle COVID-19-related intercurrent events, and show how the estimand framework provides a common language to discuss the impact of COVID-19 in a structured and transparent manner. Results: Key findings from this exercise are that the estimand framework: (1) makes implicit assumptions transparent, (2) facilitates the discussions about patients' journeys, (3) seeks to increase transparency on the clinical question of interest and facilitates a precise definition of the treatment effect, (4) prospectively plans the handling of certain intercurrent events, potentially leading to a different data collection strategy, and (5) is useful for structuring discussions about the impact of pandemics and mitigating measures one can take. Conclusion: Recommendations for design, data collection, analysis, and reporting for clinical trials planned post-addendum will be given. Key clinical implications of this work are that the treatment effect reflecting the clinical question posed by a given clinical trial objective will need to be more precisely defined in study protocols, guidelines, and publications. If the estimate is likely to be biased in light of an unforeseen impact like COVID-19, the estimand framework provides various stakeholders a common language to discuss the impact in a structured and transparent manner.

A SMARTTT approach to Treating Tobacco use disorder in persons with HIV (SMARTTT): Rationale and design for a hybrid type 1 effectiveness-implementation study.

BACKGROUND: Tobacco use disorder is a leading threat to the health of persons with HIV (PWH) on antiretroviral treatment and identifying optimal treatment approaches to promote abstinence is critical. We describe the rationale, aims, and design for a new study, "A SMART Approach to Treating Tobacco Use Disorder in Persons with HIV (SMARTTT)," a sequential multiple assignment randomized trial. METHODS: In HIV clinics within three health systems in the northeastern United States, PWH with tobacco use disorder are randomized to nicotine replacement therapy (NRT) with or without contingency management (NRT vs. NRT + CM). Participants with response (defined as exhaled carbon monoxide (eCO)-confirmed smoking abstinence at week 12), continue the same treatment for another 12 weeks. Participants with non-response, are re-randomized to either switch medications from NRT to varenicline or intensify treatment to a higher CM reward schedule. Interventions are delivered by clinical pharmacists embedded in HIV clinics. The primary outcome is eCO-confirmed smoking abstinence; secondary outcomes include CD4 cell count, HIV viral load suppression, and the Veterans Aging Cohort Study (VACS) Index 2.0 score (a validated measure of morbidity and mortality based on laboratory data). Consistent with a hybrid type 1 effectiveness-implementation design and grounded in implementation science frameworks, we will conduct an implementation-focused process evaluation in parallel. Study protocol adaptations related to the COVID-19 pandemic have been made. CONCLUSIONS: SMARTTT is expected to generate novel findings regarding the impact, cost, and implementation of an adaptive clinical pharmacist-delivered intervention involving medications and CM to promote smoking abstinence among PWH. ClinicalTrials.govidentifier:NCT04490057.