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Supplementary data | The following is the Supplementary data to this article: | PMC10447494 | ||
Multimedia component1 | Supplementary data to this article can be found online at | PMC10447494 | ||
Introduction | deaths, Annual Trivalent | VIRUS, ADVERSE EVENTS, INFLUENZA B, INFLUENZA, INFLUENZA A, INFLUENZA, VIRAL ILLNESS | Influenza is an acute viral illness of the respiratory tract and poses a substantial public health burden in terms of morbidity, mortality, and costs. The World Health Organization (WHO) reported that 3–5 million cases of severe influenza occur each year worldwide, resulting in about 290,000 to 650,000 related deaths per year. One of the goals of the Global Influenza Strategy for 2019–2030 is to reduce the burden of seasonal influenza by promoting research and innovation for improved influenza vaccines [Internationally available vaccines for controlling seasonal influenza are safe and effective and have the potential to prevent significant annual morbidity and mortality. The WHO annually recommends composing vaccines based on global virological surveillance. Annual Trivalent influenza HA vaccines (TIVs) contain two influenza A strains (H1N1 and H3N2) and only one influenza B virus [In February 2009, the Food and Drug Administration (FDA), considered in adding an additional influenza B strain in the antigenic composition of seasonal influenza vaccines [At first, Bio Farma formulated TIVs and have conducted several studies on seasonal TIVs between 2008 and 2014. The results of these studies were consistent. TIVs were well-tolerated and induced high antibody titer against influenza antigens and no serious adverse events (AEs) during the study [ | PMC10449119 |
Materials and methods | PMC10449119 | |||
Study design | BLIND, INFLUENZA | This was an experimental, randomized, double blind, four arm parallel group bridging study to assess immune response and safety after one dose of quadrivalent and trivalent influenza HA vaccine in subjects 9–40 years old in clinically health children and adults aged 9–40 years. The study was a collaboration between the Department of Child Health, Faculty of Medicine, Universitas Padjadjaran, and PT Bio Farma (Persero), Indonesia. This study was approved by the Research Ethics Committee of the Faculty of Medicine, Universitas Padjadjaran, and conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. Written informed consent was obtained from the participants or their parents before performing any study-specific procedure. | PMC10449119 | |
Study subjects | illness, fever, blood disorders, coagulopathy, chronic disease | BLOOD DISORDERS, INFLUENZA, ALLERGY TO EGGS, COAGULOPATHY, CHRONIC DISEASE, INFLUENZA | A total of 540 subjects were enrolled in this study. Subjects were enrolled from 3 primary care centers in Bandung City, Ibrahim Adjie Primary Health Center, Puter Primary Health Center, and Garuda Primary Health Center, from October 2017 to June 2018. The primary inclusion criteria included healthy children and adults aged 9–40 years who have signed the informed consent form and committed to complying with study instructions and trial schedules. Subjects were not eligible if the subject have enrolled or scheduled to be enrolled in another trial, presented with mild, moderate, or severe illness with a fever (axillary temperature ≥37.5⁰C), history of allergy to egg, chicken protein, or other vaccine, uncontrolled coagulopathy or blood disorders contraindicating intramuscular injection, received in the previous 4 weeks a treatment likely to alter the immune response [intravenous immunoglobulins, blood-derived products, or long-term corticosteroid therapy (>2 weeks)], pregnancy and lactation (adult), have any abnormality or chronic disease which according to the investigator might interfere with the assessment of the trial objectives, have already immunized with influenza vaccine within 1 year or any vaccination within 1 month before and after immunization of Quadrivalent Influenza Vaccine. | PMC10449119 |
Randomization and blinding | For each subject recruited, the inclusion number was allocated in the chronological order of the subject, which was included in the trial from I-001 to I-180 (for the 9–12-year age group), II-001 to II-180 (for the 13–17-year age group), and III-001 to III-180 (for the 18–40-year age group). The subjects were randomized into treatment groups. The doctor strictly followed the list of randomization provided by Bio Farma. Treatment was allocated in accordance with a randomization list so that each randomization number corresponded to only one strictly randomly assigned treatment group (QIV batch A, QIV batch B, QIV batch C, and TIV). | PMC10449119 | ||
Vaccines and vaccination schedule | The QIV vaccine was formulated by PT Bio Farma (Persero), Indonesia, using bulks imported from Japan. The investigational QIV contained 15 μg HA from each of 4 strains, A/California/7/2009 (X-179A) (H1N1) pdm09n, A/Hong Kong/4801/2014 (X-263) (H3N2), B/Texas/2/2013, and B/Phuket/3073/2013, in a 0.5 ml dose, with batch numbers A: 3070117, B: 3070217, and C: 3070317. TIV contained 15 μg HA of each of 3 strains, A/California/7/2009 (X-179A) (H1N1) pdm09n, A/Hong Kong/4801/2014 (X-263) (H3N2), and B/Texas/2/2013, in 0.5 ml dose. Each subject received one dose (0.5 ml) of TIV or QIV with different batch numbers: 3070117, 3070217, and 3070317 for batches A, B, and C, respectively, according to the randomization. | PMC10449119 | ||
Sample size | The sample size was determined based on a 95% confidence interval (CI) and a test power of 80%. The required sample size was 112 in each batches, with the assumption that not all the subjects could complete the study, the total number of subjects was added at least 20% from the minimum requirement (N x 1.2) = 134. Approximately 135 subjects per group will be involved in this study. | PMC10449119 | ||
Study analysis | injection-site, redness, myalgia, fatigue, fever, swelling, pain, Redness, Fever, Fatigue | ADVERSE EVENTS, INFLUENZA, INDURATION, SECONDARY, REDNESS, HAND SWELLING, EVENTS, INFLUENZA | Demographic data were expressed as mean, standard deviation, and range values. Analysis of Geometric Mean Titer (GMT), seroprotection, and seroconversion rates between the vaccine groups was performed using Kruskal-Wallis and Chi-square or Kolmogorov-Smirnov tests. Values of The safety analyses were based on the intention-to-treat population analyses. The safety data were collected up to 28 days after the vaccination. The subjects were provided with a diary card to record the appearance, duration, and intensity (mild, moderate, or severe) of any solicited AE (local pain, redness, swelling, induration, fever, fatigue, and myalgia) and unsolicited AE. Local pain was graded as mild (mild pain at the injection-site when touched), moderate (pain with movements), and severe (significant pain at rest). Redness, induration, and swelling intensity were measured using a plastic bangle and categorized as mild (<5 cm), moderate (5–10 cm), and severe (>10 cm). Fever was graded as mild (38.0°C–38.4°C), moderate (38.5°C–38.9°C), and severe (≥39.0°C). Fatigue, myalgia, and unsolicited events were graded as mild (no interference with activity), moderate (some interference with activity), and severe (prevents daily activity, requires medical intervention).The primary outcome was to evaluate the percentage of subjects with anti-HI titer ≥ 1:40, 28 days after Influeza HA vaccination. The secondary outcome was to evaluate geometric mean titres, percentage of subjects with increasing antibody titer ≥ 4 times and/or percentage of subjects with transition of seronegative to seropositive between one dose of quadrivalent and trivalent influenza HA vaccine in subjects 9–40 years old and between each batch number of Quadrivalent Influenza HA vaccine and the incidence rate and intensity of adverse events or any serious adverse events within 30 minutes, 72 hour and 28 days after immunization. | PMC10449119 |
Results | The demographic characteristics of study participants showed a fair distribution in gender and age ( | PMC10449119 | ||
Demographic characteristics of study participants. | In this study, 405 and 135 subjects were enrolled in the QIV (Batch A, B and C) and TIV groups, respectively. Of the 405 subjects in the QIV group, three were excluded from immunogenicity analysis because of protocol non-compliance ( | PMC10449119 | ||
Flow Chart for the participants enrollment. | Comparison of the percentage of subjects with anti-HI titer ≥1:40 28 days after QIV and TIV was shown on | PMC10449119 | ||
Influenza seroprotection rate before and 28 days after immunization. | *Chi-square test.Comparison of GMT between subjects who received QIV and TIV was shown on | PMC10449119 | ||
Hemagglutination inhibition (HI) Geometric Mean Titers (GMT) before and 28 days after QIV and TIV immunization. | PMC10449119 | |||
QIV batch-to-batch comparison. | Age 9–12 years: Age 13–17 years: Age 18–40 years: Solicited and unsolicited post-vaccination AEs were categorized as immediate (within 30 min), intermediate (30 min to 72 h), and delayed (72 h to 28 days) reactions (Figs | PMC10449119 | ||
Intensity of reported local and systemic adverse events (AEs). | PMC10449119 | |||
Intensity of reported local and systemic AEs on each QIV batch. | myalgia, pain | ADVERSE REACTION | Most local and systemic AEs reported in the QIV and TIV groups had mild intensity. Mild pain was the most local adverse reaction, which occurred in 15.3% and 17.8% of the subjects in the QIV and TIV groups, respectively. Mild myalgia was the most systemic adverse reaction, which occurred in 13.6% and 9.6% of the subjects in the QIV and TIV groups, respectively. | PMC10449119 |
Discussion | injection-site, myalgia, Injection-site pain, fatigue, A/H1N1 | ADVERSE EVENTS, EVENT, INFLUENZA B, EMA, ADVERSE EFFECTS, EVENTS | This study was conducted on subjects aged 9–40 years, while a previous study by Dhamayanti et al. was conducted on infants to children aged 8 years [The inclusion of a fourth strain in QIV did not interfere with the EMA criteria for immune responses in adult vaccine recipients. In adults, post-vaccination seroprotection rates were ≥99%, seroconversion rates were >59%, and post-vaccination/pre-vaccination GMT ratios were ≥7.3 for all four vaccine strains. These data demonstrate that the presence of a second influenza B strain in QIV does not negatively affect the immune response to the other strains. Moreover, the immune responses to all strains contained in the two vaccines were robust, with the highest responses to the A/California/7/2009 (H1N1) strain.The seroconversion rates regarding the percentage of subjects with increasing antibody titer ≥4 times and transition of seronegative to seropositive and of QIV were not significantly different from those of TIV. The superior QIV immunogenicity is expected to correspond with superior protection against influenza B relative to TIV in a season when there is lineage mismatch or cocirculation of two influenza B lineages. These findings are similar to those of the meta-analysis study by Moa in 2015, which confirmed that the inactivated QIV had similar efficacy against the three strains shared in common with the TIV (A/H1N1, A/H3N2, and the B lineage included in the TIV) [This study also showed that the immunogenicity of the three batches of QIV was equivalent for the four strains. Batch-to-batch equivalence of all three batches of QIV was demonstrated for all four strains. The seroprotection rates of three batches for A/California/7/2009 (X-179A) (H1N1) pdm09, A/Hong Kong/4801/2014 (X-263) (H3N2), B/Texas/2/2013, and B/Phuket/3073/2013 were (99.3; 100; 99.3), (99.3; 99.2; 100), (88.8; 95.5; 94.8), and (98.5; 100; 98.5), respectively. The increase in the overall post-vaccination GMTs for each pair of batches for each strain was not different.During this study, no serious AEs related to the vaccine were observed. This study found comparable reactogenicity and safety profiles between the QIV candidate and the TIV in both adult and adolescent groups. Both vaccines were well-tolerated by both age groups. Local and systemic reactogenicity profiles were also similar between the vaccine groups. Most reactions were mild or moderate in severity and lasted for 1–3 days. Most solicited injection-site and systemic reactions with either vaccine were mild to moderate and resolved within a few days.Injection-site pain was the most frequently reported solicited local event, and fatigue and myalgia were the commonly reported solicited systemic events among the studies. A meta-analysis study by Moa in 2015 showed the same result, injection-pain was more common in QIV compared to TIV [The QIV and TIV groups showed similar rates of systemic AEs. In both vaccine groups, mild myalgia was the most frequent systemic AE. These findings are similar to those reported by Wang et al. [Frequencies of unsolicited AEs in the 28 days following vaccination with QIV were similar between the adult and adolescent groups. These data are consistent with the results of a meta-analysis of five randomized clinical trials, demonstrating no significant difference between QIV and TIV in terms of the frequency of aggregated local and systemic AEs within 7 days after vaccination [QIV and TIV have similar reactogenicity and AE profiles, with no apparent adverse effects on the tolerability of the higher antigen content in QIV (60 μg HA for 4 strains compared with 22.5 μg for 3 strains in the TIV). Furthermore, the safety profiles of the two vaccine groups were comparable. The results of this study demonstrated that the additional B strain in QIV did not compromise safety compared with TIV. These findings are similar to those of the meta-analysis, which were no statistically significant differences between the adverse events in QIV and TIV groups [In this study, immunogenicity was only assessed 28 days after the last vaccination. Hence, we do not know the duration of antibody responses to the 4 strains. Further study is needed to evaluate the antibody persistence of the QIV. | PMC10449119 |
Conclusion | INFLUENZA, COMPLICATIONS, EMA | In conclusion, this study demonstrated that QIV can be reproducibly manufactured to yield a well-tolerated, safe, and immunogenic vaccine in people aged 9–40 years and that it met all EMA immunogenicity criteria in adults. In adults, inactivated QIV induced comparable immune responses to TIV for A strains and the B lineage common to both QIV and TIV.These data support the use of Bio Farma QIV for seasonal vaccination in children and adult subjects, which may enhance the protection against influenza and decrease the burden associated with influenza complications. The immunogenicity of the three batches of QIV was equivalent for all four strains. | PMC10449119 | |
Supporting information | PMC10449119 | |||
CONSORT 2010 checklist of information to include when reporting a randomised trial*. | SITI | (DOC)Click here for additional data file.(PDF)Click here for additional data file.We would like to thank Dr. Iskandar, the Director of Bio Farma, for supporting this study. Thanks to Dr. Novilia S. Bachtiar, dr., M.Kes who has passed away for her contribution during various stages of the paper preparation. We would also like to thank the participants, Rita Verita Sri Hasniarty, the Head of Bandung District Health Office, Nitta Kurniati, the Head of Garuda Primary Health Center, and her staff, Siti Nurhasijatiningsih, the Head of Ibrahim Adjie Primary Health Center, and her staff, and Sylvie Virgianti, the Head of Puter Primary Health Center, and her staff for their work in this study. We also thank Mr. Hadyana Sukandar for his statistical work in this study and acknowledge the Indonesian National AEFI Committee as the auditor of serious AEs in this study. We would also like to express our appreciation to the staff at the Clinical Research Unit of Growth Development-Social Pediatric Division for the invaluable administrative assistance. | PMC10449119 | |
Background | presenteeism | Loss of productivity is a result of absence from work (absenteeism) or of working with limitations due to illness (presenteeism). Recently, occupational mental health interventions have increasingly been delivered in digital format, as this is thought to be more convenient, flexible, easily accessible, and anonymous. However, the effectiveness of electronic mental health (e-mental health) interventions in the workplace to improve presenteeism and absenteeism remains unknown, and could be potentially mediated by psychological variables such as stress levels. | PMC10365609 | |
Objective | presenteeism | The aim of this study was to determine the effectiveness of an e-mental health intervention to reduce absenteeism and presenteeism in employees, as well as to investigate the mediating role of stress in this effect. | PMC10365609 | |
Methods | REGRESSION | Employees of six companies in two countries participated in a randomized controlled trial (n=210 in the intervention group and n=322 in the waitlist control group). Participants in the intervention group could use the Kelaa Mental Resilience app for 4 weeks. All participants were asked to complete assessments at baseline, during the intervention, postintervention, and at a 2-week follow-up. Absenteeism and presenteeism were assessed by means of the Work Productivity and Activity Impairment Questionnaire: General Health, while general and cognitive stress were assessed through the Copenhagen Psychosocial Questionnaire-Revised Version. Regression and mediation analyses were performed to evaluate the effect of the Kelaa Mental Resilience app on presenteeism and absenteeism. | PMC10365609 | |
Results | The intervention did not have a direct effect on presenteeism or absenteeism, neither at postintervention nor at follow-up. Nevertheless, general stress significantly mediated the intervention effect on presenteeism ( | PMC10365609 | ||
Conclusions | stress reduction | While no direct effect of the e-mental health intervention on productivity was found in this study, our findings suggest that stress reduction could mediate the effect of the intervention on presenteeism and absenteeism. As such, e-mental health interventions that address stress in employees might also indirectly reduce presenteeism and absenteeism in these employees. However, due to study limitations such as an overrepresentation of female participants in the sample and a high proportion of attrition, these results should be interpreted with caution. Future research is needed to better understand the mechanisms of interventions on productivity in the workplace. | PMC10365609 | |
Trial Registration | ClinicalTrials.gov NCT05924542; https://clinicaltrials.gov/study/NCT05924542 | PMC10365609 | ||
Introduction | PMC10365609 | |||
Background | depression, Lazarus and Folkman [, presenteeism | DISORDERS | Mental disorders and mental health–related conditions such as stress contribute to productivity loss, with an estimated cost of €400 billion (~US $440 billion) every year in Europe [In recent years, occupational mental health interventions [Studies about the effectiveness of e-mental health interventions to reduce absenteeism and presenteeism in the workplace are scarce, and the evidence mainly comes from cost-effective analyses. One example is a study of Happy@Work, a web-based guided self-help intervention to reduce depression at work [One of these factors could be the stress level of workers. Lazarus and Folkman [ | PMC10365609 |
Study Objectives and Hypotheses | The Kelaa Mental Resilience app, a science-based health and well-being mobile phone app provided by Soma Analytics (London, United Kingdom), was found to significantly decrease stress (β=–.15, SE=.04; First, we hypothesized that after using the app for 4 weeks, participants in the intervention group would report lower levels of presenteeism and absenteeism than participants in the waitlist control group (direct effect). Second, presenteeism and absenteeism scores were expected to be associated with higher levels of stress in all participants, irrespective of group. Finally, we expected a decrease in stress levels to also have an indirect impact on presenteeism and absenteeism levels (indirect effect). | PMC10365609 | ||
Methods | PMC10365609 | |||
Study Design and Procedures | BLIND | This study followed a longitudinal RCT experimental design with a 2-week follow-up. The trial started in January 2018 and ended in September 2018. Human resources managers were blind to the participants’ group allocation and participants were blind to the goals and hypotheses of the study; however, they were not blind to their group allocation. While blinding is of course desirable in practice, a naturalistic study is often not possible to achieve in a digital health intervention.Participants were randomly assigned to one of the two experimental conditions (intervention group or waitlist control group) after signing up and giving their informed consent. Randomization was implemented through a software program invoking an unbiased random number generator; subjects were assigned to a group without human intervention immediately after giving their consent. Measurements of all participants were collected online via Qualtrics at baseline (T0, week 0), midintervention (T1, week 2), postintervention (T2, week 4), and at the 2-week follow-up (T3, week 6). Participants belonging to the app (intervention) group were asked to first complete the questionnaires before downloading and starting to use the app. Reminders and invitations to the follow-up questionnaires were sent via email. Participants had 7 days to complete the questionnaires. As soon as they had completed the follow-up measurement, all participants were thanked and fully debriefed.The intervention lasted 4 weeks. During these 4 weeks, participants in the intervention group could complete a maximum of 28 sessions (1 per day) and track a maximum of 28 nights. However, it was completely up to the user to decide to what extent they wanted to engage with the app. They could also decide whether to use the app on their personal phone or their work phone. Reminders were sent through push notifications, although users had the option to turn them off. After the 4 weeks of the intervention, the interventional module within the app was withdrawn for the intervention group. A 2-week follow-up measurement was then taken to assess which gains from the 4-week intervention persisted. Participants belonging to the waitlist control group had no access to the intervention for the duration of the trial (ie, 6 weeks). They received access to the intervention and the tracking modules once the study was completed. | PMC10365609 | |
Participants | RECRUITMENT | The recruitment of employees from the private and public sector took place in six different European businesses in Germany, England, and Northern Ireland. Potential participants were informed about trial participation through intraorganization communication channels such as emails, newsletters, intranet posts, or word of mouth, which varied by trial site. In total, 678 participants were recruited, of whom 621 completed the questionnaires at baseline, 483 completed the midintervention questionnaires, 396 completed the postintervention questionnaires, and 363 completed the 2-week follow-up questionnaires. Of the participants randomized into the app group (intervention group), 137 did not use the app at all and were therefore excluded from the analyses. Nine participants in the waitlist group downloaded the app before the end of the trial and were also excluded. Thus, the final sample consisted of 532 participants, with 210 in the intervention group and 322 in the waitlist control group (Participation flow diagram. | PMC10365609 | |
Kelaa Mental Resilience App | Details of the app-based intervention tool have been previously reported [In the tracking module, through the use of scientifically validated questionnaires, the users of the app could track their stress levels, well-being, and resilience. Additionally, using inbuilt sensors (eg, accelerometer), they were also able to monitor their sleep quantity and quality. They were then given personalized feedback according to their questionnaire scores and sleep data. Within the intervention module, “Kelaa” provided content in different categories (“Kelaa Goals”), including stress recovery, happiness, or sleep. Within these weekly topics, users were provided with evidence-based interventions based on current research such as CBT, positive psychology, and mindfulness. All users had the opportunity to choose any topic that suited them best based on their outcomes resulting from the tracking module and personal interest. After choosing a goal, the user received six to seven “daily sessions” that were gradually unlocked, guiding them through their self-selected goals. Screenshots of the Kelaa Mental Resilience app. Copyright Soma Analytics United Kingdom. | PMC10365609 | ||
Measures | PMC10365609 | |||
Productivity Measures | The impact of health problems on the ability to undertake regular activities and to work over the previous week was assessed by means of the Work Productivity and Activity Impairment Questionnaire: General Health V2.0 (WPAI:GH) [ | PMC10365609 | ||
Absenteeism | For absenteeism, the scores were calculated according to the following formula:[Number of hours missed from work because of health problems/(Number of hours missed from work because of health problems+Number of hours worked)]×100This resulted in a percentage of work time missed due to health ranging from 0 to 100, where 0 represents no impairment and 100 represents that the person was completely absent from work during the previous 7 days. | PMC10365609 | ||
Presenteeism | Based on the answer to the question “During the past 7 days, how much did health problems affect your productivity while you were working?,” the proportion of impairment while working due to health was calculated. This measure multiplied by 100 was used as a measure of presenteeism. This yielded a score of 0 to 100, where 0 represents no presenteeism and 100 indicates the maximum amount of presenteeism. | PMC10365609 | ||
Stress | The Copenhagen Psychosocial Questionnaire-Revised Version (COPSOQ II) [ | PMC10365609 | ||
Ethical Considerations | Ethics approval was granted by an Independent Ethics Advisory Board (EAB) according to the European Commission Horizon 2020 Ethics Appraisal Procedure [ | PMC10365609 | ||
Statistical Analysis | cognitive stress, presenteeism | Descriptive statistics of the variables of interest were calculated for all the participants and for the two groups (intervention group vs control group) separately. Wilcoxon rank-sum tests and To test the intervention effect on presenteeism and absenteeism, we used multilevel modeling for repeated measures with measurements (level 1) nested within subjects (level 2). Since the number of cases for each level would have been less than 30 [We constructed mediational models to determine the mediating role of general and cognitive stress in the association between groups (intervention vs control) and presenteeism and absenteeism [Data were analyzed using the statistical programming language R [ | PMC10365609 | |
Results | PMC10365609 | |||
Discussion | PMC10365609 | |||
Principal Findings | The Kelaa Mental Resilience app, a mobile-based intervention, has previously been shown to be effective in reducing stress in workers [In contrast to our findings, some previous studies reported significant effects of digital workplace interventions on presenteeism and absenteeism [ | PMC10365609 | ||
Strengths, Limitations, and Practical Implications | This research has several strengths. The fact that the study was conducted in different work environments, disciplines, and countries allowed the results to represent different working conditions. Furthermore, the Kelaa Mental Resilience app is grounded both in theory (ie, the JDR model [Some limitations also need to be considered when interpreting our results. First, the sample is not representative of the general working population as there was an overrepresentation of female participants and the educational level of the participants was high. Thus, the results might not be generalized to other workplace settings. Second, the scales used to assess our outcomes may not have been sensitive enough to capture smaller changes that occurred. Additionally, as a technical constraint, the range of answers sometimes exceeded the size of the mobile phone screen and would have required scrolling to see the full scale, which may have resulted in an overrepresentation of the scores displayed on the screen. Third, the intervention was personalized according to the workers’ profiles, making it difficult to identify which elements contributed to the effects found. For such analyses, more data points and a larger data set would be needed. Fourth, participants were not blinded to the intervention allocation, which may have increased the bias. Fifth, attrition during the study was high; 47.2% of the participants had dropped out at the postintervention time pint (T2), while 50.1% had dropped out at follow-up (T3). Such high attrition adds bias to the results of the study, as it might have resulted in a self-selection mechanism and therefore limit the conclusions drawn from the study, consequently affecting the internal validity of the results. Related to this, the Kelaa Mental Resilience app might not have been suitable for everyone, again resulting in a self-selection mechanism and high attrition rates.A broader scope of the app content could result in a more applicable intervention for a larger variety of users. High attrition rates can also suggest that better communication strategies are needed in the trial sites to increase users’ engagement. Generally, understanding the needs of the target population may lead to better outcomes by providing them with an intervention fitting their needs [ | PMC10365609 | ||
Conclusion | Soma Analytics/DNAFit | Overall, our findings suggest that the effects of a mobile mental health intervention on stress levels might have a positive effect on presenteeism and absenteeism in workers. However, such effects do not seem to be persistent 2 weeks after finishing using the intervention, except in the case of the impact of the interventions via cognitive stress on presenteeism. While further studies are needed to replicate our findings and examine further pathways through which mobile mental health interventions might influence workers’ productivity, our results add to the sparse research on the mechanisms of preventative e-mental health interventions in the workplace regarding productivity outcomes. This study adds evidence of the impact of the intervention on productivity measures. Future interventional studies focusing on mental health in the workplace context should consider both theory and evidence when further developing interventions. Future studies should include a more representative sample and a longer follow-up to further disentangle the effects of e-mental health in occupational settings.This project received funding from the European Union’s Horizon 2020 Research and Innovation Program under grant agreement number 725832. CdM received funding in the form of a predoctoral grant from the Generalitat de Catalunya (PIF-Salut grant, code SLT017/20/000138). BO is supported by a Miguel Servet (CP20/00040) contract, funded by the Instituto de Salud Carlos III and cofunded by the European Union (ERDF/ESF, “Investing in your future”).Authors' Contributions: SW conceptualized and designed the randomized controlled trial. CL implemented the study and organized the database. CdM wrote the manuscript, performed the statistical analyses, interpreted the results, and created the tables and figures with the assistance of BO, MVM, and JMH. All authors contributed to the manuscript revision and approved the submitted version.Conflicts of Interest: SW was an independent research consultant with Soma Analytics/DNAFit, the developers and providers of the app. As a freelancer, she was compensated for her work on this research by Soma Analytics/DNAFit as part of the European Union’s Horizon 2020 project. CL is a cofounder and was an employee of Soma Analytics/DNAFit, the developers and providers of the app. The other authors declare no conflict of interest.
This randomized study was retrospectively registered. The authors prospectively registered their project on a public repository, however, the repository was not a clinical trial registry. The editor granted an exception from ICMJE rules mandating prospective registration of randomized trials because the risk of bias appears low. However, readers are advised to carefully assess the validity of any potential explicit or implicit claims related to primary outcomes or effectiveness, as retrospective registration does not prevent authors from changing their outcome measures retrospectively.CONSORT EHEALTH Checklist (V 1.6.1). | PMC10365609 | |
Abbreviations | healthJob | cognitive behavioral therapyCopenhagen Psychosocial Questionnaire-Revised VersionEthics Advisory Boardelectronic mental healthJob Demands-Resources modelrandomized controlled trialWork Productivity and Activity Impairment Questionnaire: General Health V2.0 | PMC10365609 | |
Data Availability | The data sets generated during and/or analyzed during the current study are available from author SW on reasonable request. | PMC10365609 | ||
Purpose: | cancer | CANCER | Mistletoe extract (ME) is widely used for patients with cancer to support therapy and to improve quality of life (QoL). However, its use is controversial due to suboptimal trials and a lack of data supporting its intravenous administration. | PMC9973409 |
Materials and Methods: | tumor | TUMOR, SOLID TUMOR | This phase I trial of intravenous mistletoe (Helixor M) aimed to determine the recommended phase II dosing and to evaluate safety. Patients with solid tumor progressing on at least one line of chemotherapy received escalating doses of Helixor M three times a week. Assessments were also made of tumor marker kinetics and QoL. | PMC9973409 |
Results: | nausea, fatigue, cancer, chills, Cancer | ADVERSE EVENTS, CANCER, DISEASE, CANCER | Twenty-one patients were recruited. The median follow-up duration was 15.3 weeks. The MTD was 600 mg. Treatment-related adverse events (AE) occurred in 13 patients (61.9%), with the most common being fatigue (28.6%), nausea (9.5%), and chills (9.5%). Grade 3+ treatment-related AEs were noted in 3 patients (14.8%). Stable disease was observed in 5 patients who had one to six prior therapies. Reductions in baseline target lesions were observed in 3 patients who had two to six prior therapies. Objective responses were not observed. The disease control rate (percentage of complete/partial response and stable disease) was 23.8%. The median stable disease was 15 weeks. Serum cancer antigen-125 or carcinoembryonic antigen showed a slower rate of increase at higher dose levels. The median QoL by Functional Assessment of Cancer Therapy-General increased from 79.7 at week 1 to 93 at week 4. | PMC9973409 |
Conclusions: | toxicities | DISEASE, SOLID TUMOR | Intravenous mistletoe demonstrated manageable toxicities with disease control and improved QoL in a heavily pretreated solid tumor population. Future phase II trials are warranted. | PMC9973409 |
Significance: | cancers, nausea, fatigue, toxicities, chills | DISEASE, CANCERS | Although ME is widely used for cancers, its efficacy and safety are uncertain. This first phase I trial of intravenous mistletoe (Helixor M) aimed to determine phase II dosing and to evaluate safety. We recruited 21 patients with relapsed/refractory metastatic solid tumor. Intravenous mistletoe (600 mg, 3/week) demonstrated manageable toxicities (fatigue, nausea, and chills) with disease control and improved QoL. Future research can examine ME's effect on survival and chemotherapy tolerability. | PMC9973409 |
Introduction | cancer, tumor, Tumor, pain | TUMOR, TUMOR, CANCER, DISEASE, SOLID TUMOR, HAND SWELLING, CYTOTOXICITY | Patients with cancer experience physical impairment and a decline in quality of life (QoL) related to disease and therapy. The use of complementary medicine to support treatment and improve QoL has been increasingly popular, rising from 25% of patients in the 1970s to 50% by 2000 (Preparations from ME are the most frequently prescribed complementary medicine in cancer treatment in German-speaking countries, either as a sole treatment or during chemotherapy or radiotherapy (Traditional ME therapy is administered subcutaneously, but local subcutaneous injection is limited because of pain and swelling at the injection site (There are three types of ME, Helixor-P (pine trees), Helixor-M (apple trees), and Helixor-A (fir trees; ref. In light of the preclinical cytotoxicity of Helixor-M, its widespread use, yet controversial efficacy, and especially the lack of safety data for its intravenous administration, this phase I trial (ClinicalTrials.gov identifier: NCT03051477) tested intravenous Helixor-M in patients with solid tumor to determine its safety and MTD. Tumor responses, serum cytokines, tumor markers, and QoL were also measured. | PMC9973409 |
Materials and Methods | cancer, autoimmune disease, Cancer | DISEASE PROGRESSION, CHRONIC INFECTION, BRAIN METASTASES, CANCER, SOLID TUMORS, METASTATIC DISEASE, ONCOLOGY, AUTOIMMUNE DISEASE, CANCER | Patients were recruited at the Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center (SKCCC). Eligible adult patients (≥18 years) had advanced solid tumors and had received at least one standard systemic therapy with chemotherapy, immunotherapy, hormonal therapy, or other therapies for metastatic disease and had disease progression according to the RECIST guideline, version 1.1. Patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 and had a life expectancy longer than 3 months. Major exclusion criteria included (i) history or evidence of brain metastases, (ii) chemotherapy, radiation, hormonal therapy, or biological cancer therapy within 28 days before study treatment initiation, (iii) prior mistletoe treatment, (iv) anticipated other forms of concurrent systemic or localized antineoplastic therapy, and (v) a history of chronic autoimmune disease or chronic infection. | PMC9973409 |
Study Treatment and Dose Escalation | DLTs | Helixor-M was administered intravenously on Monday, Wednesday, and Friday on a weekly basis. Four dose levels of mistletoe were evaluated: 150, 300, 600, and 900 mg. The dose frequency and starting and maximum dose levels were informed by the phase I trial of intravenous Helixor P (A traditional 3 + 3 method was employed, where dose escalation continued when at least 3 patients completed a safety evaluation at a given dose level with DLTs in fewer than a third of patients. The MTD was defined as the dose level immediately below the dose level at which 2 or more patients in a cohort (dose level) experienced a treatment-related DLT. | PMC9973409 | |
Safety and Efficacy | Patients were followed for 28 days after the last dose. Thereafter, patients were contacted every 6 months to monitor overall survival (OS). Safety evaluations (clinical and laboratory examinations) were conducted every 28 days, beginning from the first dose. AEs were graded according to revised Common Terminology Criteria for AEs, version 4.03. Efficacy evaluations with imaging were conducted at baseline, week 8, and every 8 weeks thereafter, except for patients who came off trial before 8 weeks or those for whom imaging assessment was deemed necessary due to symptoms of clinical progression. Response and progression were assessed using the revised RECIST guideline, version 1.1 (for details, see the trial protocol in | PMC9973409 | ||
Pharmacodynamic Analysis | Serum was collected from patients at baseline, every 4 weeks, and after treatment to identify potential therapeutic targets, biomarkers, and response predictors. Carcinoembryonic antigen (CEA) was evaluated when clinically expressed. Serum analysis for cytokine production by peripheral blood mononuclear cells was performed using a Human Cytokine/Chemokine/Growth Factor panel consisting of 38 analytes (see the trial protocol in | PMC9973409 | ||
Quality | The Investigational New Drug (IND) application for this study was approved by the FDA. The study was approved by the Johns Hopkins University Institutional Review Board. All patients (or their legal representatives) gave written informed consent before enrollment. The study was conducted in accordance with the Declaration of Helsinki and the International Council for Harmonization Good Clinical Practice guidelines and monitored externally by the SKCCC Clinical Research Office and Safety Monitoring Committee.The SKCCC was the IND sponsor of this study and was responsible for study design, data collection, analysis, and result interpretation. All the authors attest to the fidelity of trial conduct to its protocol, vouch for the accuracy and completeness of the data, and decided to submit the article for publication. The manufacturer of Helixor-M provided study drugs and information for the IND but played no role in the study design, execution, or result interpretation. | PMC9973409 | ||
Statistical Analysis | DLTs | Patient baseline characteristics and AEs were summarized, and the number of patients treated at each dose level and their DLTs were tabulated. AEs were tabulated by type and grade. The best objective response and time to progression were plotted for individual patients. Kaplan–Meier curves were plotted for progression-free survival and OS. A pairwise Wilcoxon signed-rank test was used for FACT-G QoL. | PMC9973409 | |
Data Availability | The trial data are available upon request through communication with the corresponding author. | PMC9973409 | ||
Results | PMC9973409 | |||
Baseline Patient Characteristics | uterine leiomyosarcoma cancer, melanoma | SOLID TUMORS, MELANOMA, SYNOVIAL SARCOMA | Between March 2017 and January 2021, 21 patients with advanced solid tumors, including 7 colorectal, 3 ovarian, 2 pancreatic, and 1 each with appendix, basal cell, breast, lung, melanoma, neuroendocrine, salivary, synovial sarcoma, and uterine leiomyosarcoma cancer, were treated with ME. The median follow-up duration was 15.3 weeks (range, 2–101.1 weeks). All patients were included in the efficacy and safety analyses.The median age was 57 years (range, 34–81 years), and 14 patients (66.7%) were female. ECOG performance status was 0 for 5 patients, 1 for 12 patients, and 2 for 4 patients (Baseline characteristics by dose levelAbbreviation: SD: standard deviation. | PMC9973409 |
Safety | toxicity | The MTD was determined to be 600 mg three times a week. Dose-level summary with DLTsNote: Four patients, 2 each at dose levels 150 and 600 mg, missed more than 25% of the first 4 weeks of treatments. Therefore, 2 additional patients were recruited for each dose level.Abbreviations: DLT: dose-limiting toxicity.AEs of any grade were reported in 20 of 21 patients (95.2%; Summary of all AEs ( | PMC9973409 | |
Reasons for Discontinuation | DISEASE PROGRESSION | Fifteen of the 21 patients (71.4%) discontinued because of disease progression ( | PMC9973409 | |
Clinical Activity | NSCLC, PD, tumor, death | TUMOR, DISEASE, BEST, SMALL CELL LUNG CANCER, NSCLC | Seventeen patients (80.9%) had follow-up scans after baseline to evaluate tumor response. Their best tumor response is shown in Best objective response. NSCLC: non–small cell lung cancer; PD: progressive disease; SD: stable disease. Note: Waterfall plot of patients treated with Helixor-M and had follow-up scans after baseline to evaluate tumor response (
Time to stable disease, progressive disease, and death. NSCLC: non–small cell lung cancer; PD: progressive disease; SD: stable disease. Note: Time to stable disease, progression, and death of all patients treated with Helixor-M ( | PMC9973409 |
Tumor Marker Kinetics | DISEASE | Serum CEA was positive in 7 patients (JHU-002, 009, 005, 007, 014, 015, 016) and increased over time in 3 patients at doses of 150 and 300 mg, and was stable over time in 2 patients with doses of 600 and 900 mg; the remaining 2 patients had baseline CEA level only (Serum cytokines, chemokines and growth factors were analyzed. The percent change for all the analytes was calculated by normalizing them to respective baseline levels. Chemokines, cytokines, and growth factors in patients showing stable disease. Note: Serum cytokine/chemokine/growth factor profiling. | PMC9973409 | |
Longitudinal Outcomes and QoL | DISEASE | The median progression-free survival was 46 days [95% confidence interval (CI), 44–48 days]. The median OS was 10.1 months (95% CI, 3.5 months to not reached). No significant difference was observed across dose levels. The median total score of FACT-G first increased from 79.7 [interquartile range (IQR), 65.5–93] at week 1 to 93 (IQR, 88–100) at week 4 and then decreased slightly to 89 (IQR, 78.2–98) at the end of treatment. Similar trends were observed in physical, social/family, emotional, and functional wellbeing. Though statistically nonsignificant, patients’ QoL measured by FACT-G improved by the end of treatment from week 1 in the total score and in physical, social/family, and functional well-being, with the improvement greater in patients who experienced stable disease than in patients whose disease progressed without stabilizing ( | PMC9973409 | |
Discussion | nausea, tumor, fatigue, toxicity, toxicities, ill, chills | RECRUITMENT, DISEASE, SOLID TUMORS, TUMOR | To our knowledge, this was the first phase I trial to assess the safety and antitumor activity of intravenous Helixor-M in patients with heavily pretreated advanced solid tumors. We found that the MTD was 600 mg three times a week. The product was found to have an overall manageable safety profile. One patient discontinued treatment within 600 mg, the MTD level, due to treatment-related fatigue. The most common treatment-related AEs were fatigue, nausea, and chills. Grade 3 or 4 treatment-related AEs occurred in 14.8% of patients. Although 5 patients had stable disease and 3 patients experienced tumor reduction receiving a dose within the MTD, there were no objective responses. Serum CEA levels that were positive at baseline stabilized for patients at higher doses, suggesting a dose–response effect. Though statistically nonsignificant, patients’ QoL improved by the end of treatment in total score and in physical, social/family, and functional wellbeing.The safety profile of Helixor-M observed in this study is similar to that of Helixor-P reported in Huber and colleagues (Serum cytokine profiles varied markedly among the subjects due to tumor type differences. Patients with stable disease showed elevated CXCL9 and CXCL10. CXCL9, CXCL10, and CXCL11 share a common receptor, CXCR3, and can mediate the recruitment of cytotoxic T and natural killer cells to solid tumors (Systematic reviews summarized research findings regarding the effects of ME on QoL, chemotherapy toxicity, survival, cancer-related fatigue, and safety. A systematic review suggests that positive effects of ME on QoL and chemotherapy toxicity were found in most RCTs. However, these RCTs had methodologic deficits (e.g., a lack of blinding, high attrition; ref. In conclusion, ME has common toxicities with manageable safety profiles. The MTD is likely dependent upon dose frequency and disease severity. Although no objective responses were recorded in this study, stable disease and tumor shrinkage were observed in some heavily pretreated patients (one to six lines of prior therapy). Moreover, a trend toward stabilization of tumor markers at higher doses was observed, suggesting that higher doses may have led to better responses had less severely ill patients been treated. Finally, ME may improve the QoL of patients with heavily pretreated advanced solid tumors. Improved QoL may enable patients to tolerate therapy longer. Future phase II trials can explore the optimal timing and dose frequency of intravenous mistletoe extracts. Furthermore, interested investigators can combine ME infusions with chemotherapy or targeted therapy and assess the impact of the infusions on treatment time and patient QoL along with functional immune correlates with rigorously designed and conducted RCTs. | PMC9973409 |
Supplementary Material | cancer, tumor | ADVERSE EVENTS, CANCER, TUMOR | Supplementary Materials and Methods show the trial protocolClick here for additional data file.Table S1 shows summary of all adverse eventsClick here for additional data file.Table S2 shows treatment-related adverse events by dose levelClick here for additional data file.Table S3 shows reasons for discontinuation with patient charateristicsClick here for additional data file.Figure S1 shows tumor marker over timeClick here for additional data file.Figure S2 shows summary of normalized serum levels of cytokins/chemokines/growth factors at week 4Click here for additional data file.Figure S3 shows functional assessment of cancer therapy - general over timeClick here for additional data file.Figure S4 shows functional assessment of cancer therapy - general over time by responseClick here for additional data file.Figure S5 shows physical wellbeing over timeClick here for additional data file.Figure S6 shows physical well-being over time by responseClick here for additional data file.Figure S7 shows social/family well-being over timeClick here for additional data file.Figure S8 shows social/family well-being over time by responseClick here for additional data file.Figure S9 shows emotional well-being over timeClick here for additional data file.Figure S10 shows emotional well-being over time by responseClick here for additional data file.Figure S11 shows functional well-being over time by responseClick here for additional data file.Figure S12 shows functional well-being over time by responseClick here for additional data file. | PMC9973409 |
Acknowledgments | Wilfried Tröger | We thank Dr. Peter Hinderberger, Dr. Nasha Winters, Dr. Roman Huber, Dr. Wilfried Tröger, and Dr. Gunver Kienle for your willingness to share your insights, knowledge, and expertise in mistletoe treatment.To the patients and their families who participated, we extend our heartfelt thanks for your trust. Your contribution and collaborative engagement with the entire study team will have a lasting impact on the medical community and the future patients who will benefit from the results.
| PMC9973409 | |
Authors’ Disclosures | tumor | DIAZ, TUMOR | C.J. Paller reports grants from Believe Big and NCI, grants and other from Helixor during the conduct of the study. C.F. Meyer reports personal fees from Deciphera, AAdi, BioAlta, and Adaptimmune outside the submitted work. S. Gaillard reports personal fees from Arcus, Elevar Therapeutics, Immunogen, Lumanity, Novartis, Sermonix, Verastem; grants and personal fees from AstraZeneca, GSK; grants from Rigel, Iovance, PharmaMar, Tempest, and Genentech outside the submitted work; in addition, S. Gaillard has a patent to United States Patent Nos 10,258,604 and 10,905,659 issued and licensed. J.R. Brahmer reports personal fees and non-financial support from Merck; grants, personal fees, and non-financial support from Bristol Myers Squibb; grants and personal fees from AstraZeneca; personal fees from Regeneron, Sanofi, Johnson and Johnson, Amgen, Janssen, Genentech/Roche, and Eli Lilly outside the submitted work. Mrs. Page reports other from Helixor during the conduct of the study. L.A. Diaz reports personal fees from See below during the conduct of the study; personal fees from See Below outside the submitted work; in addition, L.A. Diaz has a patent to See below pending, issued, and licensed; and L.A. Diaz is a member of the board of directors of Jounce Therapeutics and Epitope. L.A. Diaz is a compensated consultant to PetDx, Innovatus CP, Se'er, Delfi, Blackstone, Kinnate, and Neophore. L.A. Diaz is an inventor of multiple licensed patents related to technology for circulating tumor DNA analyses and mismatch repair deficiency for diagnosis and therapy. Some of these licenses and relationships are associated with equity or royalty payments to the inventors. L.A. Diaz holds equity in Epitope, Jounce Therapeutics, PetDx, Se'er, Delfi, Kinnate and Neophore. L.A. Diaz divested his equity in Personal Genome Diagnostics to LabCorp in February 2022 and divested his equity in Thrive Earlier Detection to Exact Biosciences in January 2021. L.A. Diaz's spouse holds equity in Amgen. The terms of all these arrangements are being managed by Memorial Sloan Kettering in accordance with their conflict-of-interest policy. No disclosures were reported by the other authors. | PMC9973409 |
Authors’ Contributions | PMC9973409 | |||
References | PMC9973409 | |||
Purpose | cancers | CANCERS | To determine the safety and efficacy of PARP plus PD-L1 inhibition (olaparib + durvalumab, O + D) in patients with advanced solid, predominantly rare cancers harbouring homologous recombination repair (HRR) defects. | PMC10403555 |
Patients and methods | In total, 48 patients were treated with O + D, 16 with | PMC10403555 | ||
Results | PEComa, cancers, tumour | CANCERS, ENDOMETRIAL CANCER, ADVERSE EVENTS, TUMOUR, PECOMA, CHOLANGIOCARCINOMA | The PFS6 rate was 35% and 38% with durable objective tumour responses (OTR) in 3(19%) and 3(9%) in groups 1 and 2, respectively. Rare cancers achieving an OTR included cholangiocarcinoma, perivascular epithelioid cell (PEComa), neuroendocrine, gallbladder and endometrial cancer. O + D was safe, with five serious adverse events related to the study drug(s) in 3 (6%) patients. A higher proportion of CD38 high B cells in the blood and higher CD40 expression in tumour was prognostic of survival. | PMC10403555 |
Conclusions | toxicity, cancers, HRR defects | CANCERS | O + D demonstrated no new toxicity concerns and yielded a clinically meaningful PFS6 rate and durable OTRs across several cancers with HRR defects, including rare cancers. | PMC10403555 |
Subject terms | PMC10403555 | |||
Background | DNA DAMAGE | Homologous recombination repair (HRR) is comprised of interwoven pathways that function in the repair of DNA double-stranded breaks and interstrand crosslinks [The use of poly-ADP ribose polymerase (PARP) inhibitors has synthetically lethal activity in the presence of non-functional HRR. Olaparib monotherapy has yielded a prolonged progression-free survival in patients with relapsed platinum-sensitive high-grade serous ovarian cancer, particularly in the presence of germline or somatic There is significant interest in the immunological consequences of DNA damage. Preclinical data suggest that DNA damage detected by the cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) pathway triggers a proinflammatory cascade of cytokines [ | PMC10403555 | |
Patients and methods | PMC10403555 | |||
Study design and participants | Cancer | ONCOLOGY, DISEASE, CANCER | This was a Phase II, open-label trial conducted at a single Australian centre (ACTRN12617001000392) within the framework of the Cancer Molecular Screening and Therapeutics (MoST) program [Patients were required to have an Eastern Cooperative Oncology Group performance status (ECOG PS) 0–2; evaluable disease by Response Evaluation Criteria in Solid Tumours (RECIST v1.1) [ | PMC10403555 |
Ethics approval and consent | The study was performed in accordance with the Declaration of Helsinki, with central or institutional ethics and local research governance approval. The MoST program has been approved by the St Vincent’s Hospital Sydney Human Research Ethics Committee (reference, HREC/16/SVH/23), as has this clinical trial. All participants provided written informed consent to partake in this study. An independent data and safety monitoring committee provided independent assessments of patient safety and trial progress. | PMC10403555 | ||
Endpoints | tumour, TTP | TTP, TUMOUR | The primary endpoint was the clinical activity of O + D, as measured by progression-free survival at 6 months (PFS6). PFS6 is the Kaplan–Meier estimate of the proportion of patients who remain alive and progression-free at 6 months from the date of registration. Secondary endpoints included objective tumour response, overall survival (OS), ratio of time to progression (TTP) on trial (TTP2), to TTP on the last line of therapy (TTP1) prior to trial entry, health-related quality of life measured by the EORTC QLQ-C30 [ | PMC10403555 |
Exploratory biological analyses | cancers, Tumour, T-cell inflammation, tumour | CANCERS, TUMOUR, MICROSATELLITE INSTABILITY, TUMOUR, INFILTRATING, APPENDIX | Where available, prior germline testing results were retrieved for all patients. When HRR alterations identified at screening met bioinformatic thresholds for potentially germline, germline testing was performed. Determination of a post hoc HRR defect score was planned but could not be undertaken due to tissue and sequencing assay limitations. Similarly, microsatellite instability status was also not evaluable.Tumour mutational burden (TMB) has variable predictive capacity for immunotherapy benefit across a range of tumour types [Tumour cell (PD-L1) expression was evaluated by immunohistochemistry using the Ventana PD-L1 (SP263) assay with cut-offs for positivity set at ≥1%. Archival tumour tissue was used to assess tumour infiltrating lymphocytes (TILs) and gene expression signatures corresponding to T-cell inflammation [The neutrophil:lymphocyte ratio (NLR) was determined using a baseline full blood count, defined as the ratio of absolute neutrophil count to absolute lymphocyte count, with a cut-off of four selected based on published thresholds for clinical benefit from immune checkpoint inhibition across various cancers [Peripheral blood mononuclear cells (PBMC) collected at baseline, week 4 and week 8 were stained for immune markers of interest using multiparametric flow cytometry and screened for putative variables associated with treatment benefit. Data were acquired using LSR II Fortessa and FACS Diva software. Immunophenotyping data were analysed using FlowJo 199 (BD v10.6.2). For detailed information on optimised panels, refer to Appendix | PMC10403555 |
Statistical considerations | This trial comprised of three modules of 16 patients each as defined by the MoST framework protocol [ | PMC10403555 | ||
Results | PMC10403555 | |||
Patient disposition and baseline characteristics | PANCREATIC ADENOCARCINOMA, APPENDIX | Of 162 molecularly eligible patients, 96 patients received a MoST MTB recommendation indicating trial eligibility. Forty-eight patients were subsequently enrolled on trial over a 15-month period (November 2017 and February 2019) and allocated to the two study cohorts (groups 1 and 2). Reasons for non-enrolment on trial are outlined in Appendix Pancreatic adenocarcinomas ( | PMC10403555 | |
Primary clinical endpoint | After a median follow-up period of 34 months, the PFS6 rate was 35% (95% confidence interval (CI), 13– 58%) in group 1 and 38% (95% CI 21–54%) in group 2. The median PFS was 3.7 (95% CI 1.8–7.8) and 3.6 months (95% CI 1.7–7.1) in group 1 and group 2, respectively. The Kaplan–Meier analyses are shown in Fig. | PMC10403555 | ||
Swimmer plot characterising secondary trial endpoints by the individual patients within each group. | Group 1: | PMC10403555 | ||
Safety and tolerability | anaemia, nausea, vomiting | ADVERSE EVENTS, DISEASE, ANAEMIA | In terms of treatment exposure, four patients came off the study whilst receiving olaparib alone and did not commence durvalumab: two due to progressive disease and two due to adverse events. The median relative dose intensity (the ratio of administered doses to planned doses) was 100% (range 70–100%). The dose of olaparib was reduced in 8 patients (17%), with six of these patients also requiring treatment delays. These dose reductions were mainly due to anaemia, nausea and vomiting, or elevated creatinine. An additional 14 patients (29%) required delays in olaparib without dose reductions and four patients required a delay of durvalumab. At the time of study analysis, there were two patients in each group still receiving olaparib.The most common AEs across grades were nausea (Compared to visit 1, no change was observed in mean on-study global health status based on the QLQ-C30, +1.3 (95% CI: −5.3 to +7.9) across all study participants. Importantly, no change was observed in mean global health status amongst 16 patients progressing before 6 months, +0.7 (95% CI: −9.7 to +11.1), while the 17 patients who remained progression-free at 6 months experienced a modest increase in mean global health status of +1.9 (95% CI: −7.4 to +11.2). Overall, none of these changes in global health status met thresholds for clinically meaningful differences [ | PMC10403555 |
Predictors of response to PARP inhibition | Eight (17%) patients had ClinVar pathogenic/ likely pathogenic germline variants in | PMC10403555 | ||
Predictors of response to immunotherapy | death, tumour | TUMOUR | Fifteen (94%) in group 1 and 31 (97%) in group 2 had an evaluable TMB; 7 and 3 patients in group 1 and 2, respectively, had a high TMB of ≥10 mutations/megabase. In group 1 median PFS was 4.3 months for high, compared with 2.9 months for low TMB (HR 0.35, 95% CI 0.10–1.23; log-rank PD-L1 expression was available for 13 patients (81%) in group 1 and 29 patients (91%) in group 2. Median tumour PD-L1 expression was 1 and 0% for groups 1 and 2, respectively, with 44 and 41% meeting the PD-L1 expression cut-off of ≥1%. PD-L1 expression by group, or across study participants did not correlate with PFS (HR 1.11, 95% CI 0.58–2.14, Exploratory analysis using an NLR threshold of 4 demonstrated that patients across both groups with an NLR ≥ 4 demonstrated a shorter OS (median 10.1 months) compared with NLR < 4 (median 15.3 months), HR for death 1.64 (95% CI 0.85–3.18; | PMC10403555 |
Detailed overview of the qualifying and co-occurring mutational profile for individual patients. | cancer histotype, tumour, TTP | TTP, TUMOUR | Includes select clinical outcomes—best response, progression-free survival ≥ 6 months, time to progression 2 to time to progression 1 ratio, TTP2/TTP1 ≥ 1.3) by treatment group; clinical parameters—cancer histotype, no. of prior lines of treatment, prior platinum; and biomarkers of interest—genomic alteration type, tumour mutational burden, and PD-L1 status. HR homologous recombination repair, NLR neutrophil-lymphocyte ratio, PFS progression-free survival, TTP time to progression, TMB tumour mutational burden.We next used flow cytometry to assess a broad range of circulating immune biomarkers in peripheral blood at baseline, weeks 4 and 8, binned into good responders (OTR or PFS >6 months and OS ≥2 years), and poor responders. Figure | PMC10403555 |
Discussion | histotype-based, cancers, toxicity, tumours, cancer, TTP, high-grade glioma, cancer deaths, tumour, gallbladder cancers, cancer histotypes, cholangiocarcinoma | CANCERS, PERIVASCULAR EPITHELIOID CELL TUMOUR, ADVERSE EVENTS, GALLBLADDER ADENOCARCINOMA, DISEASE, TUMOURS, METASTATIC CHOLANGIOCARCINOMA, CANCER, RELAPSED OVARIAN CANCER, TUMOUR, NEUROENDOCRINE CARCINOMA, GALLBLADDER CANCERS, TTP, CHOLANGIOCARCINOMA | In this signal-seeking trial, 14 of 48 patients (29%) achieved either an OTR or a favourable TTP ratio. This encouraging result fulfils the original co-primary endpoint of objective response and TTP2/1 >1.3.O + D demonstrates a signal of clinical activity with a PFS6 rate of 35% (group 1) and 38% (group 2) across a range of tumour histotypes harbouring a HRR gene alteration. This is further supported by the durability of the objective tumour responses and an improvement in disease trajectory for individual patients, captured by the TTP2/1 ratios. Three patients (19%) achieved an OTR in group 1, along with three additional TTP2/1 evaluable patients (23%) who experienced a TTP2/1 ratio >1.3. In group 2, three patients (9%) achieved an OTR, and five additional patients (18%) demonstrated an improved TTP2/1 ratio. A median OS of 11.3 (group 1) and 15.1 (group 2) months is also favourable in a cohort comprised of rare cancers with poor prognoses. Combination treatment revealed no new toxicity concerns, with adverse events consistent with earlier trials [To our knowledge, this study is the first to demonstrate durable objective tumour responses to PARP plus PD-L1 inhibition in a gallbladder adenocarcinoma, cholangiocarcinoma, neuroendocrine carcinoma, a uterine perivascular epithelioid cell tumour (PeCOMA) and high-grade glioma, all selected on the basis of somatic or germline HRR gene alterations. Most of the cancers where we observed an OTR have limited therapeutic options beyond the first-line setting. Median OS for patients with locally advanced or metastatic cholangiocarcinoma and gallbladder cancers treated with cisplatin-gemcitabine, or gemcitabine alone is only 11.7 and 8.1 months, respectively [Without randomisation, it is not possible to separate out the role of PARP inhibition and/ or PD-L1 inhibition in these durable objective responses and/or disease stabilisation. Earlier trials examining the safety and efficacy of PARP plus PD-L1 have mostly been histotype-specific and/or limited in their molecular eligibility. In the MEDIOLA basket studies, all cohorts were histotype-limited, with the advanced breast and relapsed ovarian cancer cohorts permitting only germline The first randomised trial of O + D versus durvalumab alone was published recently [All objective responses in this trial were in tumours harbouring Exploratory biological studies compared baseline to week 4 samples after olaparib exposure alone, and then following exposure to O + D. The correlation of high baseline CD38+ B-cell populations with improved clinical outcomes is novel, although we did not observe an effect of olaparib priming on this cell population and cannot delineate histotype-based associations with high baseline levels. B cells can promote anti-tumour immunity through the release of cytokines such as IL-12, IFNγ, granzyme B and TRAIL57 [The strengths of this signal-seeking study are inclusion of less common cancer histotypes and a rich range of correlative biomarkers that add depth to understanding individual responses. As rare and less common cancers account for half of all cancer deaths, their inclusion in clinical trials is vital to improving survival outcomes for patients with cancer as a whole. This however does introduce heterogeneity into the study population based on inherent differences in prognosis between cancer types. Also, the use of archival tissue for dynamic biomarker evaluation can challenge their interpretation. | PMC10403555 |
Conclusion | cancer | CANCER | In sum, this study demonstrates a modest signal of activity for olaparib and durvalumab in understudied cancer populations. Clinical benefit was greatest amongst patients with | PMC10403555 |
Supplementary information | The online version contains supplementary material available at 10.1038/s41416-023-02311-0. | PMC10403555 | ||
Acknowledgements | The authors thank all study participants and their families. We kindly acknowledge Astra Zeneca for funding and provision of olaparib and durvalumab for the trial. | PMC10403555 | ||
Author contributions | AJ, DT, MB and LS contributed to the conceptualisation and development of the trial. MK, TC, CB, US, ST, FL and DT contributed to the correlative science within this manuscript. ST, MK, FL, DE, CL, JS, AJ and DT contributed to the implementation, investigation and clinical trial analysis. JG, FL, ST, MK, MB, PM, AJ and DT played a key role in the bioinformatics and genomics analysis of patients screened and enrolled on the trial. All authors were involved in writing, reviewing and editing the manuscript. | PMC10403555 |
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