Independent Review Board Research Articles

Chemotherapy effects on mitochondrial function in adipose tissue in oesophageal and gastroesophageal junction adenocarcinomas with or without associated cachexia: protocol for a prospective, comparative observational study (ChiFMeOE)

IntroductionCachexia is strongly associated with digestive cancers, particularly oesogastric cancer. Mitochondria in adipose tissue are involved in the regulation of metabolism and physiopathology of cancer cachexia in animal studies. Chemotherapeutic...

Ergonomic benefit using heads-up display compared to conventional surgical microscope in Japanese ophthalmologists.

Occupational musculoskeletal disorders are prevalent in ophthalmic surgeons and can impact surgeons' well-being and productivity. Heads-up displays may reduce ergonomic stress compared to conventional microscopes. This cross-sectional, non-interventional study compared ergonomic experience between heads-up display and conventional ocular microscopes. The study protocol was approved by the independent ethics committee and nonprofit organization MINS Institutional Review Board. An online questionnaire was distributed to a sample of ophthalmic surgeons in Japan with experience operating with heads-up display. The questionnaire captured surgeon-specific variables, the standardized Nordic Musculoskeletal Questionnaire, and custom questions to compare heads-up display and conventional microscope and understand long-term impacts of musculoskeletal disorders. Analysis was conducted on responses from 67 surgeons with a mean 25 years of practice and 2.7 years using heads-up display. Many surgeons agreed or strongly agreed that heads-up display reduced the severity (40%) and frequency (40%) of pain and discomfort, improved posture (61%), and improved overall comfort (61%). Of respondents who experienced asthenopia (n = 59) or pain/discomfort during operation (n = 61), 54% reported improvement in asthenopia and 72% reported feeling less pain/discomfort since using heads-up display. Overall, 69% reported preference for heads-up display. This study provides novel data on musculoskeletal disorders and the long-term impacts of ergonomic strain reported by ophthalmologists building on existing literature demonstrating ergonomic and other advantages of heads-up display. Future studies with objective ergonomic assessment are warranted to validate these findings.

Nationwide Etoricoxib Injection Clinical Experience (NICE): Real-World Evidence in Indian Patients.

Introduction Pain is a major health issue globally. Etoricoxib, a highly selective COX-2 inhibitor, given orally, has been found to be efficacious and safe in the management of acute and chronic pain. Oral etoricoxib has been extensively studied; however, there is a lack of research exploring the use of etoricoxib via alternative routes, specifically intramuscular (IM) injection. This study aimed to evaluate the effectiveness and safety of an innovative and novel formulation of IM etoricoxib injection 90 mg/mL in the management of patients with acute pain in India. Method This was a real-world, multicenter, retrospective, observational study to investigate the effectiveness and safety of IM etoricoxib injection in the management of patients with acute pain in India (outpatient setting). The clinical data of 383 patients from 42 centers across India were collected from November 2022 to April 2023. Following approval from the site investigator, comprehensive patient-level information encompassing demographic and clinical variables as well as comorbidities was collected and entered into a case report form. Approval from the Independent Ethics Committee (IEC) and Institutional Review Board (IRB) was sought. The safety and effectiveness at 30 minutes and 60 minutes of IM etoricoxib injection were then analyzed. Results Among the studied patients, etoricoxib was used for the management of knee arthritis, fracture, post-traumatic pain, postoperative cases, acute back pain, back injury, torn ligament, and muscle strain and sprain. Of 383 patients, 98.17% had moderate-to-severe pain at baseline on the visual analogue scale (VAS) (0 being no pain and 10 being severe unbearable pain). The percentage of patients with severe pain reduced to only 6.78% and 4.17% at 30 minutes and 60 minutes, respectively. The improvement in the VAS score was statistically significant from baseline to 30 minutes and 60 minutes, and at 60 minutes compared to 30 minutes (p < 0.0001). More than half the patients (56.91%) had no pain at the site of the injection. Most of the doctors (70.23%) opined that the IM etoricoxib injection was better than their currently used NSAID injections for pain relief. Only 12.79% of patients required rescue analgesia post-IM etoricoxib injection. IM etoricoxib injection was well tolerated as 98.69% of the patients did not experience or report any adverse events post-IM injection. Conclusion This real-world, multicenter, retrospective, observational study across India demonstrated that the innovative and novel formulation of etoricoxib (90 mg/mL IM injection) was effective and well-tolerated in the management of acute pain. Overall, this study provides valuable insights into the real-world effectiveness and safety of IM etoricoxib injections, suggesting it could be a promising therapy for the management of acute pain for optimal patient benefit.

TROPION-Breast03: a randomized phase III global trial of datopotamab deruxtecan ± durvalumab in patients with triple-negative breast cancer and residual invasive disease at surgical resection after neoadjuvant therapy.

Despite advances in the treatment of early triple-negative breast cancer (TNBC), patients with residual invasive disease after neoadjuvant therapy have a high risk of disease recurrence and worse survival outcomes than those who have pathological complete response (pCR). Improving outcomes in early TNBC remains an unmet need requiring new adjuvant treatment approaches. Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate comprising a humanized anti-trophoblast cell-surface antigen 2 immunoglobulin G1 (IgG1) monoclonal antibody attached via a plasma-stable, cleavable linker to a potent topoisomerase I inhibitor payload, with activity observed in advanced TNBC. TROPION-Breast03 is an ongoing phase III study evaluating the efficacy and safety of Dato-DXd alone or combined with durvalumab versus standard-of-care therapy as adjuvant treatment in patients with stage I-III TNBC with residual invasive disease at surgical resection following neoadjuvant treatment. Eligible patients, aged ⩾18 years, will be randomized in a 2:1:2 ratio to receive Dato-DXd [6 mg/kg intravenously (IV) every 3 weeks (Q3W); eight cycles] and durvalumab (1120 mg IV Q3W; nine cycles), Dato-DXd monotherapy (6 mg/kg IV Q3W), or investigator's choice of therapy (ICT; capecitabine, pembrolizumab, or capecitabine and pembrolizumab). The primary endpoint is invasive disease-free survival (iDFS) for Dato-DXd and durvalumab versus ICT. Key secondary endpoints include safety, distant disease-free survival, and overall survival for Dato-DXd and durvalumab versus ICT and iDFS for Dato-DXd monotherapy versus ICT. TROPION-Breast03 will be approved by the independent ethics committees or institutional review boards at each study site. All study participants will provide written informed consent. TROPION-Breast03 will help define the potential role of Dato-DXd in the treatment of patients with early-stage TNBC who do not have pCR after neoadjuvant therapy. ClinicalTrials.gov identifier: NCT05629585 (registration date: 29 November 2022).

Response characteristics of tislelizumab combined with chemotherapy in first-line treatment of locally advanced or metastatic non-squamous non-small cell lung cancer

Objective: To investigate the response characteristics of patients with locally advanced/metastatic non-squamous non-small cell lung cancer (nsq-NSCLC) treated with tislelizumab in combination with chemotherapy in the first line. Methods: Patients with nsq-NSCLC who achieved complete or partial remission after treatment with tislelizumab in combination with chemotherapy or chemotherapy alone in the RATIONALE 304 study, as assessed by an independent review board, were selected to analyze the response characteristics and safety profile of the responders. Time to response (TTR) was defined as the time from randomization to the achievement of first objective response. Depth of response (DpR) was defined as the maximum percentage of tumor shrinkage compared with the sum of the baseline target lesion length diameters. Results: As of January 23, 2020, 128 patients treated with tislelizumab in combination with chemotherapy achieved objective tumor response (responders), representing 57.4%(128/223) of the intention-to-treat population, with a TTR of 5.1 to 33.3 weeks and a median TTR of 7.9 weeks. Of the responders (128), 50.8%(65) achieved first remission at the first efficacy assessment (week 6), 31.3%(40) at the second efficacy assessment (week 12), and 18.0%(23) at the third and subsequent tumor assessments. The percentages of responders who achieved a depth of tumor response of 30% to <50%, 50% to <70% and 70% to 100% were 45.3%(58/128), 28.1%(36/128) and 26.6%(34/128), respectively, with median progression-free survival (PFS) of 9.0 months (95% CI: 7.7 to 9.9 months), 11.5 months (95% CI: 7.7 months to not reached) and not reached (95% CI: 11.8 months to not estimable), respectively. Tislelizumab plus chemotherapy were generally well tolerated in responders with similar safety profile to the overall safety population. Conclusion: Among responders to tislelizumab in combination with chemotherapy for nsq-NSCLC, 82.0%(105/128) achieves response within the first two tumor assessments (12 weeks) and 18.0%(23/128) achieves response at later (18 to 33 weeks) assessments, and there is a trend toward prolonged PFS in responders with deeper tumor response.

Abstract 9859: Randomized Comparison of Bare Metal Stents Plus Colchicine vs Drug Eluting Stents: Preliminary Analysis of the Orca Trial (Oral Colchicine in Argentina)

Background: The use of colchicine has been associated with reduction of adverse cardiac events in patients with coronary artery disease (CAD). The role of this drug after percutaneous coronary intervention (PCI) with bare metal stents (BMS) has not been evaluated against isolated PCI with drug eluting stents (DES). Aim: The study was designed to test an improved cost-effectiveness with BMS plus colchicine (group BMS+C) compared to DES alone (group DES), provided its noninferiority in terms of major adverse cardiac events (MACE) at 1 year. Methods: This is a prospective, multicenter, randomized controlled trial performed in 4 centers. The trial has been registered at clinicaltrials.gov (NCT04382443). Study protocol and informed consent have been approved by an Independent Ethical and Review Board Committee and were presented to Argentina National regulatory authorities for Health, Technology and Medications. Patients in the BMS+C group received 0.5mg oral doses twice a day of colchicine for 3 months. Outpatient visits were scheduled at 1, 3, 6 and 12 months as well as at 3 and 5 years. Primary endpoints were to compare cost-effectiveness and MACE defined as composite of death, myocardial infarction (MI), cerebrovascular accident and ischemia-driven target vessel revascularization. Results: During February 2020 to April 2022, 412 patients with clinically indicated PCI were randomized in the study. Because 2 patients with COVID 19 at the time of randomization were excluded, the final study population was composed of 410 patients (205 patients in each group). Baseline demographic and angiographic characteristics were well balanced diabetes 19.5% vs 21.4%, Acute Coronary Syndromes 78% vs 75%, ST elevation MI 23% vs 21% multiple vessel CAD 44% vs 46%, culprit left anterior descending artery 58% vs 57.8%, peripheral vascular disease 3.4% in BMS+C and DES groups respectively.2.9% of patients in BMS+C didn’t complete the treatment for side effects (diarrhea). Presently, patients were follow at mean of 381 days ( range 45 to 839),1 -year follow-up was completed in 61%. Conclusion: A 3-month treatment with colchicine after PCI with BMS was feasible and safe. Final 1-year clinical outcomes and cost-effectiveness results will be available at the time of presentation.

Test reliability and comparability of paper and Chinese electronic version of the western Ontario and McMaster University osteoarthritis index: protocol for a randomised controlled clinical trial

IntroductionThe Western Ontario and McMaster University osteoarthritis index (WOMAC) is the most commonly used indicator of disease-specific outcome in knee osteoarthritis for its convenience and reliability. It has two formats...

O-10: SICKLE CELL HEALTH AWARENESS, PERSPECTIVES AND EXPERIENCES (SHAPE) SURVEY: FINDINGS ON THE BURDEN OF SICKLE CELL DISEASE AND UNMET NEEDS AS REPORTED BY PATIENTS AND CAREGIVERS

Purpose: Sickle cell disease (SCD) has a substantial emotional and physical burden on patients and their caregivers. Research on the impact of SCD on patient and caregiver quality of life (QOL) is limited, including on the health inequalities faced by different groups around the world. The limitations in research underscore the need for greater understanding of the challenges of living with SCD in different communities. The SHAPE survey aims to broaden the understanding of the global impact of SCD on patients living with the condition, on caregivers caring for those living with the condition, and on healthcare professionals (HCPs) who treat SCD. Materials and methods: The SHAPE survey comprised online, quantitative surveys of patients, caregivers, and HCPs conducted in 10 countries: France, Germany, UK, US, Canada, Brazil, Saudi Arabia, United Arab Emirates, Bahrain, and Oman (patients only). The surveys required participants to answer a range of closed-ended questions about their circumstances and experiences in order to build a robust and reliable dataset on which descriptive statistics were performed. This analysis focuses on findings from the patient and caregiver survey portion of the study. Patients were included if they were diagnosed with SCD by an HCP and were aged ≥12 years. Caregivers were included if they were caring for someone diagnosed with SCD and were aged ≥18 years. Informed consent was obtained from all participants, and all identifiable information was kept private and secure. The study protocol was reviewed and approved by an independent institutional review board. Results: A total of 919 patients and 207 caregivers completed the survey. The mean patient age was 32.3 years, and most patients and caregivers were female. Nearly all patients stated that reducing the risk of long-term complications, such as organ damage (93%) and hemolytic anemia (84%), was important to them (Figure). Caregivers felt that most areas of their lives—particularly their ability to attend and succeed at school or work (56%) and their own overall wellbeing (53%) and mental health (52%)—were impacted by caring for someone with SCD. The symptom experienced by patients with SCD that most impacted caregivers’ lives was fatigue/tiredness (49%), and 54% of caregivers reported a notable impact on their earning potential. Those caring for patients aged <18 years were more likely to have their ability to attend and succeed at school or work impacted than those caring for patients aged ≥18 years (61% vs 38%, respectively). A total of 46% of patients and 33% of caregivers reported that emergency room (ER) HCPs did not believe patients about their symptoms, and 48% of patients felt they were treated as a drug seeker by ER HCPs. Similarly, 54% of patients and 40% of caregivers reported ER HCPs provided poor care due to their lack of knowledge about SCD. Conclusion: The experience of a global group of patients with SCD shows that what most impacted caregivers’ lives was fatigue/tiredness and loss of earnings and this provides insight on the broad impacts of SCD and highlights areas that need greater support or improvement.Figure. Percentage of Patients or Caregivers Who Agreed With or Endorsed the Following Statements I. ODAME declares a conflict of interest: Consultancy, Expert: Novartis, Novo Nordisk, Global Blood Therapeutics F. COSTA declares a conflict of interest: Consultancy, Expert: Novartis;GBT B. INUSA declares a conflict of interest: Consultancy, Expert: Novartis Ltd Global therapeutics Vertex Agios Invitation to national or international congresses: European Hematology Association Sickle cell disease association of America Mumbai international haematology National blood transfusion Society Nigeria Patent or product inventor: none Research support/Scientific studies: Horizon 2020 ARISE (African Reserach and Innovative Initiative for Sickle cell education) Paget foundation Trainings, Teaching: academy for sickle cell and thalassaemia (ASCAT) W. JASTANIAH declares a conflict of interest: Consultancy, Expert: Novartis, Amgen, Servier Research support/Scientific studies: Novartis, Amgen

Translating Clinical Research to Clinical Care in Nephrology: A Qualitative Study of Nephrology Clinicians

Rationale & ObjectiveThe translation of clinical research to practice has been the subject of intense scrutiny in the efforts to identify ways to improve the uptake of findings that can enhance patient care.Study DesignThis study evaluated the experience of nephrology health care providers who manage patients with autosomal dominant polycystic kidney disease (ADPKD) to identify promoters and barriers to the translation of research results into clinical practice. We used inductive thematic analysis to evaluate the experience, attitudes, and beliefs of physicians in the evaluation and translation of research findings into clinical practice for the care of patients with ADPKD.Setting & ParticipantsParticipants in a continuing education activity on ADPKD volunteered for semistructured interviews exploring their experience translating new knowledge into care for patients with ADPKD. An independent institutional review board (Solutions IRB) found the study to be exempt as an educational survey.Analytical ApproachTranscripts were coded and excerpted, and emergent themes and relationships were identified through an analysis performed using Dedoose software. Particular attention was paid to characterizing the facilitators and barriers to research translation at different levels of the health care environment.ResultsTextual interpretation of data from 13 interviews showed that while well-established barriers to research translation are prevalent among health care providers managing patients with ADPKD, these clinicians also face unique challenges. Principal among these is the burden of interpreting the clinical research literature given the lack of official guidelines.LimitationsThis study did not explore the translation of all levels of research, such as basic science and animal studies, and it was limited to the translation of knowledge from clinical studies. The number of participants was limited but was found to be sufficient for saturation.ConclusionsWe identified factors that may either enhance or impede research translation for nephrology health care providers. These observations may help in the design of continuing education interventions to promote innovation.

Prophetic EU: Prospective Identification of Pneumonia in Hospitalized Patients in the Intensive Care Unit–A Comparison of European and United States Cohorts

Background: Prospective identification of patients at high risk of nosocomial pneumonia may improve clinical trial feasibility and foster antibacterial development. Clinical criteria prospectively identified patients at highest risk of hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP) in the United States (US). Whether these findings are applicable in a European population is unknown. Methods: Adults considered high risk for pneumonia (treatment with ventilation or high levels of supplemental oxygen) in the intensive care units of seven European hospitals were prospectively enrolled. We estimated the proportion of high-risk patients developing HABP/VABP, defined according to US Food and Drug Administration (FDA) guidance, and the subset potentially eligible for antibacterial trial enrollment. We compared patient characteristics, exposures, and HABP/VABP incidence in European and US cohorts. Findings: Of 888 high-risk patients enrolled between June 12 and December 27, 2017, 211/888 (24%) were treated for possible pneumonia and 150/888 (17%) met the FDA definition for HABP/VABP. A higher proportion of European high-risk patients treated for possible pneumonia met the HABP/VABP definition (150/211 [71%] versus 537/1464 [37%] in US, p<0·001). Among patients developing HABP/VABP, a higher proportion in the European cohort met antibacterial trial eligibility criteria (124/150 [83%] versus 371/537 [69%], p<0·001). Interpretation: Readily available clinical criteria prospectively identified patients with high rates of HABP/VABP in this European cohort of high-risk patients. Despite higher rates of established risk factors and incident HABP/VABP, European high-risk patients were significantly less likely to receive antibiotics for possible pneumonia than US patients. Different treatment practices may contribute to lower rates of antibacterial trial enrollment observed in the US. Funding: U.S. Food and Drug Administration Declaration of Interest: SP Bergin: Dr. Bergin reports consulting for Aridis Pharmaceuticals and C3J Therapeutics. SB Calvert: Dr. Calvert reports salary support from the U.S. FDA grant R18FD005292 and CTTI membership fees. J Farley: Dr. Farley reports no conflicts related to this work. J-L Sun: Ms. Sun reports no conflicts related to this work. K Chiswell: Dr. Chiswell reports no conflicts related to this work. W Dieperink: Dr. Dieperink reports no conflicts related to this work. J Kluytmans: Dr. Kluytmans reports no conflicts related to this work. JC Lopez-Delgado: Dr. Lopez-Delgado reports no conflicts related to this work. R Leon-Lopez: Dr. Leon-Lopez reports no conflicts related to this work. MJ Zervos: Dr. Zervos reports serving as a consultant for ContraFect and receiving research grants from Merck, Moderna, Janssen, Pfizer, and Serono. MH Kollef: Dr. Kollef reports support by the Barnes-Jewish Hospital Foundation. M Sims: Dr. Sims reports grants from Aridis Pharmaceuticals Inc, Cidara Therapeutics, ContraFect, Cubist Pharmaceuticals Inc (now Merck), Curetis Ag, Curetis GmBM, CutisPharma, DiaSorin Molecular LLC, Epigenomics Inc, EUROIMMUN US, Finch Therapeutics, Genentech USA Inc, Gilead Sciences, IBIS Biosystems, Iterum Therapeutics, Janssen Research and Development, LLC, Kinevant Sciences GmBH, Leonard-Meron Biosciences, Merck, Nabriva Therapeutics, NeuMoDx Molecular, Paratek Pharmaceuticals, Pfizer, Prenosis, Regeneron Pharmaceuticals, Sanofi Pasteur Inc, Seres Therapeutics Inc, Shire, Summit Therapeutics BA Kabchi: Dr. Kabchi reports no conflicts related to this work. D Rubin: Dr. Rubin reports no conflicts related to this work. J Santiago: Dr. Santiago reports no conflicts related to this work. M Natarajan: Dr. Natarajan reports no conflicts related to this work. P Tenaerts: Dr. Tenaerts reports salary support from the U.S. FDA grant R18FD005292 and CTTI membership fees. VG Fowler Jr.: Dr. Fowler reports serving as chair of the V710 Scientific Advisory Committee (Merck); has received grant support from Cerexa/Actavis/Allergan, Pfizer, Advanced Liquid Logics, NIH, MedImmune, Basilea Pharmaceutica, Karius, ContraFect, Regeneron Pharmaceuticals, and Genentech; has NIH Small Business Technology Transfer/Small Business Innovation Research grants pending with Affinergy, Locus, and Medical Surface; has been a consultant for Achaogen, Astellas Pharma, Arsanis, Affinergy, Basilea Pharmaceutica, Bayer, Cerexa Inc., ContraFect, Cubist, Debiopharm, Durata Therapeutics, Grifols, Genentech, MedImmune, Merck, the Medicines Company, Pfizer, Novartis, NovaDigm Therapeutics Inc., Theravance Biopharma, and XBiotech; has received honoraria from Theravance Biopharma and Green Cross; and has a patent pending in sepsis diagnostics. TL Holland: Dr. Holland reports consulting for Basilea Pharmaceutica (ceftobiprole), Genentech (immunotherapeutic), Motif Bio (iclaprim), Aridis (monoclonal antibody) and Lysovant (lysin). MJ Bonten: Mr. Bonten reports no conflicts related to this work. SJ Hullegie: Mr. Hullegie reports grants from ZonMW, outside the submitted work. Ethical Approval: The study protocol was approved, and a waiver of informed consent was granted by an independent review board (Copernicus Group, CTTI_001, DCR2-15-710), or when required, the institutional review board of participating US institutions, and by ethics committees of each country in Europe.

Enhancing the Content of the EORTC QLQ-C30 to Maximize the Detection of Treatment Benefit in Higher-Risk Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, and Low-Blast Acute Myeloid Leukemia Using the EORTC Item Bank

INTRODUCTIONMyelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), and acute myelogenous leukemia (AML) are rare hematological stem cell disorders resulting in cytopenias, disease-related complications, and substantial impact on health-related quality of life (HRQOL). A literature review, clinician interviews, and qualitative interviews with high risk (HR) MDS, CMML, and low blast (LB) AML patients confirmed the relevance of concepts assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) for measuring HRQL, but also suggested that concepts important to evaluate the complete experience of patients with these conditions were missing, or only addressed in a limited fashion.The present study involved testing supplemental items from the EORTC item bank with patients to confirm item relevance and aimed to enhance the content of the EORTC QLQ-C30 to detect treatment benefit in patients with HR MDS, CMML and LB AML.METHODSSupplemental items were selected from the EORTC item bank to address the conceptual gaps of the core EORTC QLQ-C30 instrument in this patient population. Items were selected based on concepts drawn from the literature review and prior qualitative work with patients. After ethical approval from an independent review board, HR MDS, CMML, and LB AML patients were identified through clinical sites and the MDS Foundation and screened for eligibility. Using a semi-structured interview guide, 45-minute cognitive debriefing interviews (CDIs) were conducted with each patient to evaluate item understanding, response option clarity, and item relevance. Audio-recorded interviews were transcribed, coded, and analyzed. Patient responses to the EORTC QLQ-C30 and supplemental items were collected for quantitative analysis (i.e., item level endorsement frequencies). An interview with a hematologist provided additional clinical perspective on the results.RESULTSCDIs were performed with 18 patients (mean age 68 (±10.1); 56% female; n=14 HR MDS, n=3 CMML, and n=1 LB AML). Most patients were treated with azacitidine (n=12; 67%), had an ECOG status of 1 (n=6, 33%) or a patient-rated ECOG of 2 (n=6, 33%), and were diagnosed within the last 12 months (n=10, 56%).To address conceptual gaps identified in our initial qualitative work, 9 supplemental symptom items (bone pain, weakness, feeling slowed down, easily tired, lacking energy, bruising/petechiae, dizziness, and shortness of breath [2 items]) and 4 supplemental impact items (limitations with climbing stairs or getting up out of a chair, travel limitations, doing housework, and shopping or running errands) were selected from the EORTC item bank. These items were presented to patients for additional testing. Supplemental items were generally well understood and considered relevant, with two exceptions. Bone pain was often attributed to injury or arthritis rather than MDS, CMML, or AML or its treatments; travel limitations lacked clarity as patients were unsure what type of travel to consider (i.e., car travel vs. air travel). Item level endorsement frequencies showed good distribution across most response options without skewness, indicating that most supplemental items assessed concepts relevant to this sample (Table 1). Clinician feedback confirmed the relevance of most supplemental items and reinforced that the bone pain and travel limitation items were problematic. Based on the qualitative and quantitative analysis of the CDIs, the bone pain and travel limitation supplemental items were removed (Table 2). A total of 11 supplemental items were retained to enhance the content of EORTC QLQ-C30 instrument to better capture treatment benefit from the patient perspective.CONCLUSIONSOur study suggests that engagement with patients to address conceptual gaps in EORTC QLQ-C30 coverage provided valuable information regarding supplemental items from the EORTC item bank that could potentially provide more clinically relevant and better targeted measurement of HRQOL in HR MDS, CMML, and LB AML patients, thus improving the detection of treatment benefit. To confirm this, the EORTC QLQ-C30 and the proposed supplemental items should be tested in a larger clinically-defined sample to evaluate their combined measurement properties in these patient populations. [Display omitted] DisclosuresBell:Takeda Pharmaceuticals: Employment, Equity Ownership. Galaznik:Takeda Pharmaceuticals: Employment, Equity Ownership. Pompilus:Takeda Pharmaceuticals: Research Funding; Modus Outcomes: Employment. Strzok:Takeda Pharmaceuticals: Research Funding; Modus Outcomes: Employment. Bejar:AbbVie/Genetech: Honoraria, Other: Ad-hoc advisory board; Genoptix: Consultancy, Honoraria, Patents & Royalties; Modus Outcomes: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: DSMB, Steering Committee, Research Funding; Otsuka/Astex: Honoraria, Other: Ad-hoc advisory board; Foundation Medicine: Honoraria, Other: Ad-hoc advisory board. Fram:Takeda Pharmaceuticals: Consultancy; BeyondSpring Pharmaceuticals, Inc.: Consultancy. Faller:Takeda Pharmaceuticals: Employment, Equity Ownership. Marquis:Takeda Pharmaceuticals: Research Funding; Modus Outcomes: Employment.

Patient Perspectives on Symptom Experience and Impact on Health-Related Quality of Life in Higher-Risk Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia and Low-Blast Acute Myeloid Leukemia

INTRODUCTIONMyelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), and acute myeloid leukemia (AML) are rare hematological stem cell disorders resulting in cytopenias, disease-related complications, and death. Given the lack of curative treatment options available to patients with these conditions, patient quality of life is a significant factor when making treatment decisions. The Food and Drug Administration defines health-related quality of life (HRQL) as a multidimensional concept encompassing a patient's overall disease- and treatment-related impact experience associated with physical, psychological (including emotional and cognitive), and social functioning domains. Importantly, regulatory agencies are emphasizing patient-centeredness in clinical trial design to capture benefits of new treatments, and qualitative research is essential to ensure that important aspects of the patients' experiences are captured in pivotal trials. Unfortunately, research on patients' perspectives on their symptoms, treatment and impact on HRQL is limited.This study aimed to better understand the overall symptom experience and impact on HRQL from the perspective of patients living with higher risk (HR) MDS, CMML, and low blast (LB) AML. Findings informed the development of a conceptual framework (CF) for disease- and treatment-related symptoms and impacts on HRQL.METHODSA literature review was conducted in Medline (January 2000-July 2016) for studies reporting on patient symptoms and impacts related to HR MDS, CMML, and LB AML, and supplemented with further medical and advocacy website reviews. Relevant information regarding patients' symptom experience and impact on HRQL was compiled. Semi-structured qualitative interviews with clinicians (n=3) and patients (n=14) elicited further information about core symptoms and related impacts of disease and treatment. Following approval from an independent review board, HR MDS, CMML, and LB AML patients were recruited through the MDS Foundation or physician referral. Patients were screened and compensated. Symptom and impact concepts from all sources were organized into a CF describing the patients' disease and treatment experience and impact on HRQL.RESULTSForty-four disease- and treatment-related symptoms and 49 impacts on HRQL were identified through the literature and website reviews. Clinical experts provided additional background on symptoms of the conditions and common treatment regimens, associated side effects, and potential impact on HRQL. The mean age of patients interviewed was 69 years (±8.5); 64% female; n=11 HR MDS, n=2 CMML, n=1 LB AML. Most patients were treated with azacitidine (n=9; 64%) and date of diagnosis ranged from 4-55 months, with 76% of patients diagnosed within the last 2 years. Eastern Cooperative Oncology Group (ECOG) status was reported by clinicians (n=8; 87% ECOG: 1) or patients (n=6; 83% ECOG: 2). Symptom and impact concepts elicited from patients reflected those identified in the literature review and expert interviews; however, patients provided additional detail that was not reported in other sources. All patients reported fatigue (n=14, 100%); most reported shortness of breath (n=12, 86%), weakness (n=11, 79%), pain (n=10, 64%), nausea (n=9, 64%), bruising (n=9, 64%), constipation (n=9, 64%) and dizziness (n=9, 64%). Symptoms of the disease and treatment had substantial impact on HRQL. Most patients reported difficulty walking (n=11, 79%); performing daily activities such as working (n=9, 64%), household chores (n=8, 57%), shopping (n=7, 50%); and participating in activities that could expose them to infection such as caring for grandchildren (n=7, 50%), traveling (n=6, 43%), and eating out (n=4, 29%). Concepts derived from the literature reviews and clinician and patient interviews were consolidated into two draft CFs (see figures) for disease- and treatment-related symptoms (n=49 concepts) and impacts on HRQL (n=54 concepts).CONCLUSIONSIncorporation of the patient voice allowed for direct patient engagement, which provided valuable in-depth insight about the patient experience with HR MDS, CMML and LB AML. The CF for disease- and treatment-related symptoms and impacts on HRQL can guide the evaluation of treatment benefit from the patient perspective in these diseases, which will fill an important gap and help to inform treatment decision making. [Display omitted] DisclosuresBell:Takeda Pharmaceuticals: Employment, Equity Ownership. Galaznik:Takeda Pharmaceuticals: Employment, Equity Ownership. Pompilus:Modus Outcomes: Employment; Takeda Pharmaceuticals: Research Funding. Strzok:Takeda Pharmaceuticals: Research Funding; Modus Outcomes: Employment. Fram:BeyondSpring Pharmaceuticals, Inc.: Consultancy; Takeda Pharmaceuticals: Consultancy. Faller:Takeda Pharmaceuticals: Employment, Equity Ownership. Marquis:Takeda Pharmaceuticals: Research Funding; Modus Outcomes: Employment.

60 A retroperitoneal approach to endometriosis excision: Surgical outcomes & 7-year follow-up

The objective of this mixed method retrospective study was to investigate the outcomes for women up to 7 years after undergoing laparoscopic surgery using a retroperitoneal approach to isolate and lateralize the ureters and excise endometriosis. The 2-part design included a case series of 350 patients who underwent laparoscopic surgical excision at a GYN-only ambulatory surgery center between October 2013 and September 2020; and a voluntary survey of the same patient population administered via email in September 2020 to evaluate symptom relief and triangulate reoperation rate. Surgeries were identified by procedural code and confirmed via operative notes during the medical chart review process. Patient characteristics and operative outcomes were analyzed using descriptive statistics. IntegReview IRB, an independent institutional review board, deemed both the retrospective review and patient survey exempt from informed consent (IRB #CIGC-001; IRB #CIGC-3206). A total of 350 patients with Stage III and IV were included in the case series. The mean age of participants was 33 ± 7.8 years. Intraoperative complication rate was 2.6%; postoperative 2.3%. More than one-third (34.6%) of patients had at least 1 previous surgical procedure for endometriosis, ranging from 1 to 10 procedures. The majority (77.8%) of intraoperative complications occurred in this group. The cumulative reoperation rate for pelvic pain associated with recurring endometriosis was 3.1%. Preliminary results of the patient survey administered to the same population up to 7 years after surgery support a low reoperation rate. Future studies should aim to collect detailed quality of life measures using prospective standardized survey instruments in order to collect baseline data. Endometriotic implants should be thoroughly excised for optimal surgical outcomes.1,2 However, pelvic pathology of endometriosis and adhesions from previous surgeries may distort normal anatomy and limit the ability to visualize pelvic landmarks, impeding the use of blunt dissection.3 Dissection of the retroperitoneum enables skilled surgeons to identify critical structures, preventing unintentional injury to ureters and retroperitoneal pelvic vessels. Entering the retroperitoneum also facilitates complete excision of endometriosis resulting in a low reoperation rate.

Towards an Integrative “Lightness” of Being

Towards an Integrative “Lightness” of Being

P11.03 Importance of Capturing the Patient Experience of Overall Symptoms and HRQoL Impact in Patients With ALK+ NSCLC

Non–small cell lung cancer (NSCLC) with the anaplastic lymphoma kinase-positive (ALK+) mutation is a rare subtype of NSCLC. Available treatments include several ALK inhibitor therapies (eg, crizotinib, alectinib, ceritinib, and brigatinib) with some showing health-related quality of life (HRQoL) benefits. HRQoL, including disease- and treatment-related symptoms and impacts, is a significant factor when making treatment decisions. However, qualitative research on HRQoL among ALK+ patients is limited. The aim of this study was to better understand the overall symptom experience and HRQoL impact from the perspective of ALK+ NSCLC patients. Interviews with expert oncologists were conducted to provide the clinical perspective and guide patient interviews. Following approval by an independent review board, semi-structured qualitative interviews were conducted with NSCLC patients with epidermal growth factor receptor or ALK mutations who had been symptomatic in the past month. During interviews, patients described their symptoms and the related HRQoL impact. Six oncologists were interviewed, identifying NSCLC symptoms, particularly: shortness of breath (100%), fatigue (100%), cough (83%), pain (67%), and hemoptysis (67%). The most common impacts were anxiety (50%), depression (50%), and confusion/bewilderment surrounding the diagnosis (50%), as most patients were never smokers and younger. A total of 36 NSCLC patients were interviewed, including 8 ALK+ patients (median age 48.5 years [28–53]; 50% female, median disease duration 2.8 years [0–7]). All ALK+ patients had received radiation, 87.5% had received chemotherapy, and 62.5% had received targeted therapy. The most commonly reported symptoms from ALK+ patients were shortness of breath (100%), phlegm/congestion (100%), pain (87.5%), feeling tired/fatigue (87.5%), weight loss (75%), cough, coughing blood, appetite loss, constipation, and diarrhea (all 62.5%). Patients described experiencing negative impacts on daily activities (87.5%), including household chores and the ability to do hobbies. Additionally, impacts on social, emotional (both 62.5%), and physical functioning (50%) were also commonly reported. The patient experience with the core symptoms of lung cancer (dyspnea, cough, and pain) among ALK+ NSCLC patients was similar across our sample, irrespective of mutation. This qualitative research also confirmed the selection of patient-reported outcome instruments to assess core concepts that best capture the patient experience of ALK+ patients in a clinical trial setting, including a recent clinical trial of brigatinib versus crizotinib in ALK+ NSCLC. In this clinical trial, patients on brigatinib showed significant HRQoL benefits compared with crizotinib in the most common symptoms or impacts reported in the current qualitative study, including fatigue, nausea and vomiting, appetite loss, constipation, as well as emotional, social functioning, and global health status/QoL. Incorporation of the patient voice through direct patient engagement provided valuable in-depth insight about patient experience in ALK+ NSCLC. This qualitative research provided insights into the unmet needs and patient goals for treatment, which may then be measured in a clinical trial to demonstrate treatment benefit from the patient perspective. It is important to measure what matters most to patients to improve treatment decision-making.

High-Flow Nasal Cannula Therapy for the Management of Hypoxaemic Respiratory Failure in Patients with SARS-CoV-2 Pneumonia: An Observational Cohort Study

Background: The utility of high-flow nasal cannula (HFNC) to reduce the need for invasive mechanical ventilation (IMV) in patients with hypoxaemic respiratory failure due to COVID-19 is poorly understood.Methods: We designed a prospective observational study of a large cohort of patients at the Temporary COVID-19 Hospital (TCH) in Mexico City who had COVID-19-related hypoxaemic respiratory failure. The primary outcome was the success rate of HFNC to prevent the progression to IMV. We also evaluated the risk factors associated with HFNC success or failure.Findings: This study included 378 patients who met the criteria for hypoxaemic respiratory failure and for HFNC use. This study showed that HFNC effectively prevented IMV in 71.4% of patients (n=270; 95% CI: 66·6–75·8). Factors that were significantly different between patients who were only treated with HFNC and those who progressed to IMV included age, the presence of hypertension, and the Charlson comorbidity index. Predictors of HFNC failure included the CALL score at admission (adjusted hazard ratio [HR]: 1·27; 95% CI, 1·09–1·47; pInterpretation: The present study showed that treating patients with HFNC at admission was effective and prevented the worsening of symptoms in some patients with COVID-19.Funding: Carlos Slim FoundationDeclaration of Interests: APC, ESL, MGN, RRVV, HHB, LMJ, MAA, LERG, LMC, RVB, RVAW, BSO, and MLRC are fulltime employees of the Temporary COVID-19 Hospital. HGR, JLG, LAMJ, and RTC are full-time employees of the Carlos Slim Foundation in Mexico. The authors declare no other conflicts of interest or outside funding from any other organizations.Ethics Approval Statement: The study protocol was approved by an independent Investigation Commission and Ethical Review Board. This study was submitted to the ethics committee of the National Autonomous University of Mexico (FM/DI/099/2020).

Abstract OT-13-06: Solti-1503 PROMETEO: Talimogene laherparepvec (T-VEC) + atezolizumab combination in early breast cancer

Abstract Background Residual disease (RD) after standard neoadjuvant chemotherapy (NAC) is composed of drug resistant cells and associates with increased risk of relapse, especially in triple negative, HER2-positive, and highly proliferative Luminal tumors. Immunotherapy combinations can induce of specific anti-tumor immune responses, such as those mediated by T-cells, and which might represent an additional strategy for the control or elimination of residual tumor cells. Preliminary results in melanoma showed that the combination of T-VEC with an anti PD-L1 or anti CTLA4 has greater efficacy than either therapy alone, without additional safety concerns beyond those expected for each agent. The presence of RD after neoadjuvant chemotherapy (NAC) in early BC patients remains an unmet medical need. We hypothesize that combining T-VEC with Atezolizumab may offer clinical benefit in the preoperative setting for early breast cancer (BC) patients with intermediate to high risk of recurrence who present RD after standard NAC. Methods SOLTI-1503 PROMETEO is an open-label, multicenter trial of T-VEC + Atezolizumab in patients with RD after completing standard NAC. Thirty patients with triple negative BC (TNBC) or Luminal B-like/HER2- will be included. RD must be confirmed by core-biopsy and have a diameter ≥ 15 mm measured by magnetic resonance imaging. Adequate organ function and ECOG PS 0-1 are required. T-VEC is administered intratumorally in week 1 (106 plaque-forming units/mL [pfu/mL]), then in week 4 and every 2 weeks thereafter (108 pfu/mL) for 4 injections. Atezolizumab (840 mg) is administered intravenously every 2 weeks for 4 infusions, beginning in week 4. BC surgery will be carried out 1 to 3 weeks after completion of treatment. A protocol amendment was approved, the steering committee of the study decided to change the primary objective of the trial to a more clinical endpoint that is to evaluate the efficacy by the rate of RCB class 0/1 at surgery. Secondary endpoints include rate of pCR, ORR, safety and the increase of mean expression of a gene signature tracking activated CD8 T-cells. The first safety analysis was performed in October 2019. Independent safety date review board considered the trial safe and supported its continuation. To date, 8 patients have been included at 4 sites in Spain. Second safety and efficacy data analysis is planned after 10 patients have completed treatment. If a rate of PD higher than 50% is observed in the first 10 patients, then the trial will be permanently stopped. We expect to achieve 10 patients in July 2020. We thank AMGEN for their provision of Talimogene Laherparepvec and their financial contribution to this clinical study. We thank ROCHE for their provision of Atezolizumab and their financial contribution to this clinical study. Clinical trial identification: NCT03802604 Citation Format: Tomás Pascual, Juan M Cejalvo, Mafalda Oliveira, Maria Vidal, Estela Vega, Sergi Ganau, Ana Julve, Esther Zamora, Ignacio Miranda, Ana Delgado, Begoña Bermejo, Luis de la Cruz-Merino, Manel Juan, Juan M Ferrero-Cafiero, Jordi Canes, Xavier González-Farré, Patricia Villagrasa, Aleix Prat. Solti-1503 PROMETEO: Talimogene laherparepvec (T-VEC) + atezolizumab combination in early breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-13-06.

Cambridge Hybrid Closed-Loop Algorithm in Children and Adolescents with Type 1 Diabetes: A Multicentre 6-Month Randomised Trial

Background: Closed-loop insulin delivery systems have the potential to address the issue of suboptimal glucose control in children and adolescents with type 1 diabetes. We compared safety and efficacy of Cambridge hybrid closed-loop algorithm with usual care over six months in this population. Methods: In a multicentre, multinational, one-period, parallel randomised controlled trial, participants aged 6-18 years using insulin pump therapy were recruited at seven UK and five US paediatric diabetes centres. We randomly assigned participants to closed-loop insulin delivery or to usual care (control) for six months. The Cambridge closed-loop algorithm running on a smartphone was used with either (i) modified Medtronic 640G pump, Medtronic Guardian 3 sensor, and Medtronic prototype phone enclosure (FlorenceM configuration) or (ii) Sooil Dana RS pump and Dexcom G6 sensor (CamAPS FX configuration). Primary endpoint was change in HbA1c at six months combing data from both configurations. Analysis was by intention-to-treat. Trial registration ClinicalTrials.gov, NCT02925299. Findings: We randomised 133 participants (mean±SD baseline HbA1c 8·2±0·7% vs 8·3±0·7%), 65 to closed-loop and 68 to control. At six months, HbA1c was 0·32% lower with closed-loop compared to control (95%CI 0·04 to 0·59; p=0·02). Closed-loop usage was low with FlorenceM due to failing phone enclosures (40% [26, 53]; median [IQR]), but consistently high with CamAPS FX (93% [88, 96]). In post-hoc analysis, HbA1c in the CamAPS FX closed-loop cohort (n=21) was 1·05% lower (95%CI 0·67 to 1·43; p<0·0001) and time in target range 3·9‑10·0mmol/L 15·0 percentage points higher (95%CI 8·0 to 22·1; p=0·0001) compared to control (n=25), without increasing hypoglycaemia (p=0·15). Severe hypoglycaemia and DKA events were similar between closed-loop and control. Interpretation:The Cambridge hybrid closed-loop algorithm is safe and improves glycaemic control in children and adolescents with type 1 diabetes. Efficacy requires high usage of closed-loop as demonstrated with CamAPS FX. Clinical Trial: Trial registration ClinicalTrials.gov, NCT02925299. Funding: NIDDK. Declaration of Interest: MT reports receiving speaker honoraria from Novo Nordisk. RPW reports receiving grant support from MannKind, and Novo Nordisk, grant support and lecture fees from Dexcom, grant support, and advisory board fees from Eli Lilly, and grant support, travel support, and lecture fees from Tandem Diabetes Care. BAB reports receiving grant support, donated supplies, and advisory board fees from ConvaTec, grant support from Dexcom, grant support and honoraria from Insulet, grant support and advisory board fees from Medtronic MiniMed, and grant support from Tandem Diabetes Care. LADM reports grants from Medtronic. NM reports receiving grant support for devices from Medtronic. REJB reports receiving speaking honoraria from Eli Lilly and Springer Healthcare. SAW reports receiving consulting fees from Eli Lilly, Sanofi US Services, and Zealand, speaker honoraria from Dexcom, Insulet, Medtronic, and Tandem Diabetes Care, and grant support to his institution from Abbott and Medtronic. LK reports receiving grant support from Tandem Diabetes Care. CK reports receiving grant support from Tandem Diabetes Care. RWB reports receiving grant support and donated supplies from Abbott Diabetes Care, Ascensia Diabetes Care US, Beta Bionics, and Roche Diabetes Care, grant support, donated supplies, and consulting fees from Dexcom, Novo Nordisk, and Tandem Diabetes Care, grant support and consulting fees from Bigfoot Biomedical, and consulting fees from Eli Lilly and Insulet. RH reports receiving speaker honoraria from Eli Lilly, Dexcom and Novo Nordisk, receiving license fees from B. Braun and Medtronic; patents related to closed-loop, and being director at CamDiab. MEW reports patents related to closedloop and being a consultant at CamDiab. JW, CKB, JMA, AT, JS, LD, FC, ND, KKH, AG and DSF declare no competing financial interests exist. Ethical Approval: Approval was received from an independent research ethics committee in the UK (East of England–Cambridge East Research Ethics Committee), an independent review board in the USA (Jaeb Center for Health Research Institutional Review Board), regulatory authorities in the UK (Medicines and Healthcare products Regulatory Agency), and in the USA (Food and Drug Administration). Safety aspects were overseen by an independent data safety monitoring board.

Imatinib Therapy for Patients with Recent-Onset Type 1 Diabetes: A Randomised Blinded Phase 2 Trial

Background: Type 1 diabetes results from autoimmune-mediated destruction of beta cells. The tyrosine kinase inhibitor imatinib may impact relevant immunologic and metabolic pathways, and preclinical studies show that it reverses and prevents diabetes. Our goal was to evaluate the safety and efficacy of imatinib in preserving beta cell function in subjects with recent-onset type 1 diabetes. Methods: We conducted a phase 2, randomised, placebo-controlled, blinded clinical trial. Patients with recent-onset type 1 diabetes, aged 18-45 years, and with peak C-peptide ≥ 0.2 nmoles/L on mixed meal tolerance test (MMTT) were enrolled from 9 sites in the USA and Australia. Participants were randomly assigned 2:1 to receive either 400 mg imatinib or matching placebo for 26 weeks, respectively, using a computer-generated blocked randomisation scheme stratified by study site. The primary endpoint was the change in 2-hour area under the curve (AUC) C-peptide response to MMTT from baseline to 12 months, with further observation out to 24 months. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01781975. Findings: Patients were screened and enrolled into the trial between February 12, 2014 and May 19, 2016. 45 patients were assigned to imatinib, 22 to placebo. The study met its primary endpoint: the 12-mo C-peptide AUC mean was 0·583 (95% CI: 0·519, 0·650) nmoles/L in the imatinib group versus 0·489 (95% CI: 0·403, 0·579) nmoles/L for the placebo group, adjusted for baseline C-peptide, age, and gender (p = 0·048, 1-tail test). In secondary analyses, compared to the placebo group, imatinib-treated subjects required less exogenous insulin and trended towards lower HbA 1c , with higher beta cell glucose sensitivity, lower proinsulin/C-peptide ratios, improved insulin sensitivity, and higher serum adiponectin levels. No significant changes were noted in autoantibody titers and immune cell phenotyping. Interpretation: A 26-wk course of imatinib preserves beta cell function at 12 months in adults with recent onset type 1 diabetes. Although no overt effects on immune responses were detected, imatinib may have novel metabolic effects on both beta cell function and insulin sensitivity. Trial Registration: This study is registered with ClinicalTrials.gov, number NCT01781975. Funding: Juvenile Research Diabetes Foundation Declaration of Interests: SG has served on advisory boards for Avotres, Provention Bio, and Tolerion, and participated in clinical trials with Intrexon, Janssen, Provention Bio, and Tolerion. JB has consulted for Vertex Pharmaceuticals, Inc, and participated in clinical trials for Avotres, Caladrius, Janssen, and Tolerion. PG has served on advisory boards for Caladrius, Bristol Myers Squibb, and Lilly, received grant support from Caladrius, Novo Nordisk and Pfizer, and is co-founder and chief medica officer for ImmunoMolecular Therapeutics, Inc. RM has a patent application for DNA methylation in inflammatory disease. SW reports serving on advisory boards for Boehringer Ingelheim Pharmaceuticals, Inc. and Medtronic, and a DSMB for the National Institutes of Health. All other authors report no potential conflicts of interest. Ethics Approval Statement: This phase 2, randomised, placebo-controlled, double-blinded clinical trial was conducted according to the Declaration of Helsinki and in accordance with good clinical practice guidelines, performed under an investigational new drug application (IND 117644) and was approved by independent institutional review boards at each participating center.

Efficacy and Safety of the CVnCoV SARS-CoV-2 mRNA Vaccine Candidate: Results from Herald, a Phase 2b/3, Randomised, Observer-Blinded, Placebo-Controlled Clinical Trial in Ten Countries in Europe and Latin America

Background: Additional safe and effective vaccines are needed to control the COVID-19 pandemic.Methods: HERALD is an ongoing phase 2b/3 randomised, observer-blinded, placebo-controlled clinical trial in ten countries in Europe and Latin America. SARS-CoV-2 naïve adults were randomised 1:1 to receive two doses of CVnCoV mRNA vaccine candidate or placebo 28 days apart. Primary efficacy analysis included symptomatic COVID-19 more than 14 days after second dose. Solicited adverse events (AEs) were assessed in phase 2b participants and unsolicited AEs in all participants. The study is registered at ClinicalTrials.gov (NCT04652102).Findings: Between 11 December 2020 and 12 April 2021, 39 680 participants were randomised and 39 529 received CVnCoV (19 783) or placebo (19 746). Overall VE was 48·2% (95% CI: 31·0–61·4; 83/12 851 vs. 145/12 221 in CVnCoV and placebo recipients, respectively). Overall VE against moderate-to-severe COVID-19 was 70·7% (95% CI: 42·5–86·1; 12/12 851 vs. 37/12 211, respectively). In participants aged 18–60 years VE was 52·5% (95% CI: 36·2–64·8; 71/11 532 vs. 136/11 031, respectively). Too few cases occurred in participants aged ≥61 years (CVnCoV: 12, placebo: 9) precluding VE evaluation. Wild type SARS-CoV-2 was detected in 7/204 (3%) sequenced cases, with 14 variants being responsible for the other cases. Solicited adverse events, mostly systemic, were more common in CVnCoV recipients; 542/2002 CVnCoV recipients and 61/1980 placebo recipients reported grade 3 events. Unsolicited serious AEs were reported for 82/19 746 CVnCoV recipients and 66/19 746 placebo recipients; 8 and 2 SAEs, respectively were considered related to vaccination. Fatal SAEs were reported for 8 and 6 CVnCoV and placebo recipients.Interpretation: CVnCoV is efficacious in the prevention of COVID-19 of any severity and has an acceptable safety profile.Trial Registration: Study number: ClinicalTrials.gov Identifier: NCT04652102. Funding: This trial was funded by the German Federal Ministry of Education and Research (grant01KI20703), and CureVac AG.Declaration of Interest: MB declares institutional funding from CureVac during the conduct of this study, from Janssen Vaccines, molecular partners, and Merck outside of the submitted work, and consulting fees from Janssen Vaccines. EJLDB, and MFMR, TO and XSL declare institutional funding from CureVac during the conduct of this study. LE, and LG declare institutional funding from CureVac during the conduct of this study and outside of the submitted work. CFL declares institutional funding from CureVac during the conduct of this study, and outside of the submitted work, and is a member of WHO Covid-19 Vaccine Effectiveness Working Group and WHO Product Development for Vaccines Advisory Committee (PDVAC). CL declares institutional funding from CureVac during the conduct of this study, and is a member of the of German Society of Infection board. ILR declares institutional funding from CureVac during the conduct of this study and from J &J, and OSE Immunotherapeutics outside of the submitted work. PGK declares institutional funding from CureVac during the conduct of this study, and is a member of the scientific advisory board for the HERALD clinical trial. VVRH declares institutional funding from CureVac during the conduct of this study, and speakers fees from Gilead outside of the submitted work. HJ declares consultant fees from CureVac, is the Medical Responsible Person for the HERALD clinical trial, and is co-chair of DSMB for the HERALD clinical trial. AK and PM are employed by CureVac, and hold stock options. OSK declares consultant fees from CureVac during the conduct of this study, and is a member of the DSMB for a CVnCoV phase 1 trial. TV declares consultant fees from CureVac during the conduct of this study, and consultant fees from CureVac, AstraZeneca, Pfizer, Johnson&Johnson, and Moderna outside of the submitted work. LO is employed by CureVac, and holds stock options, and is the holder of a pending patent. The other authors declare no competing interests.Ethical Approval: The trial protocol and amendments have been approved by the appropriate independent ethics committee or institutional review board at each study centre